Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
Sponsor
Children's Oncology Group (Other)
Overall Status
Completed
CT.gov ID
NCT00103285
Collaborator
National Cancer Institute (NCI) (NIH)
5,377
236
8
191.6
22.8
0.1
Study Details
Study Description
Brief Summary
This randomized phase III trial is studying different combination chemotherapy regimens and comparing how well they work in treating patients with newly diagnosed acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
PRIMARY OBJECTIVES:
-
To determine whether the substitution of three intensified phases of post-Induction treatment for standard phases will improve the event free survival (EFS) of children with SR-average acute lymphoblastic leukemia (ALL).
-
Determine whether the substitution of intensified Consolidation for standard Consolidation will improve the EFS of children with SR-average ALL.
-
To determine whether the addition of four doses of percutaneous endoscopic gastrostomy (PEG) asparaginase, given once every three weeks during Consolidation and Interim Maintenance phases, will improve the EFS for children with SR-low ALL.
SECONDARY OBJECTIVES:
-
Identify potentially modifiable factors associated with impaired health related quality of life (HRQOL) at different periods of therapy in the patients who are SR-average enrolled on the standard risk ALL study.
-
Determine the critical time periods when future intervention studies to mitigate adverse HRQOL outcomes should occur.
-
Correlate day 29 minimal residual disease (MRD) with EFS and overall survival (OS) of patients treated with these regimens.
-
Correlate early marrow response with day 29 MRD status. V. To improve outcome by identifying additional high risk patients by Day 29 MRD for treatment with fully augmented Berlin-Frankfurt-Munster (BFM).
-
To examine the relative contributions of genetic factors and early treatment response to outcome by comparing the outcome of patients with and without TEL-AML1 fusion or triple trisomy and low levels of MRD at end Induction who are treated with identical therapy on the standard arms of the SR-low and SR-average trials.
OUTLINE: This is a 2-part, partially randomized, multicenter study. Patients are stratified according to early response to study induction therapy (rapid early response [standard risk (SR)-low or SR-average acute lymphoblastic leukemia (ALL)] vs slow early response [SR-high ALL]). After completion of induction therapy but before proceeding to part II therapy, patients are assigned to 1 of 3 groups based on stratification.
PART I:
INDUCTION THERAPY: All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.
EXTENDED INDUCTION THERAPY: Patients receive dexamethasone IV or PO BID on days 1-14; vincristine IV on days 1 and 8; pegaspargase IM on day 4, 5, or 6; and daunorubicin hydrochloride IV over 15 minutes to 2 hours on day 1. Patients with M1 bone marrow and MRD < 1% after extended induction therapy proceed to therapy in part II. Patients with M2 or M3 bone marrow after extended induction therapy are removed from the study.
PART II:
GROUP 1 (SR-low ALL): Patients are randomized to 1 of 2 treatment arms.
ARM I:
STANDARD CONSOLIDATION THERAPY: Patients receive vincristine IV on day 1; mercaptopurine PO on days 1-28; and methotrexate IT on days 1, 8, and 15. Patients with Down syndrome (DS) receive leucovorin calcium (PO) at 48 and 60 hours after each dose of methotrexate IT.
STANDARD INTERIM MAINTENANCE THERAPY: Patients receive vincristine IV on days 1 and 29; dexamethasone IV or PO BID on days 1-5 and 29-33; mercaptopurine PO on days 1-50; methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, and 50; and methotrexate IT on day 29. Patients with DS receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT.
STANDARD DELAYED INTENSIFICATION (DI) THERAPY: Patients receive vincristine IV on days 1, 8, and 15; dexamethasone IV or PO BID on days 1-21; doxorubicin hydrochloride IV over 15 minutes to 2 hours on days 1, 8, and 15; pegaspargase IM on day 4, 5, or 6; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39; thioguanine PO on days 29-42; and methotrexate IT on days 1 and 29. Patients with DS receive dexamethasone IV or PO BID on days 1-7 and 15-21 and leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT.
ARM II:
EXPERIMENTAL CONSOLIDATION THERAPY: Patients receive vincristine, mercaptopurine, methotrexate, and leucovorin calcium as in arm I and pegaspargase IM on days 1 and 22.
EXPERIMENTAL INTERIM MAINTENANCE THERAPY: Patients receive vincristine, dexamethasone, mercaptopurine, methotrexate PO, and methotrexate IT as in arm I and pegaspargase IM on days 15 and 36.Standard DI therapy: Patients receive standard DI therapy as in arm I.
GROUP 2 (SR-average ALL): Patients are randomized to 1 of 4 treatment arms.
ARM I: Patients receive standard consolidation therapy, standard interim maintenance therapy, and standard DI therapy as in group 1, arm I.
ARM II:
STANDARD CONSOLIDATION THERAPY: Patients receive standard consolidation therapy as in group 1, arm I. Augmented interim maintenance therapy: Patients receive vincristine IV and methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase IM on days 2 and 22; and methotrexate IT on days 1 and 31. Patients with DS receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Augmented DI therapy: Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on days 1-21; doxorubicin hydrochloride IV over 15 minutes to 2 hours on days 1, 8, and 15; pegaspargase IM on day 4, 5, or 6 AND day 43; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or SC on days 29-32 and 36-39; thioguanine PO on days 29-42; and methotrexate IT on days 1, 29, and 36. Patients with DS receive dexamethasone on days 1-7 and 15-21 and leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT.
ARM III:
INTENSIFIED CONSOLIDATION THERAPY: Patients receive cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; pegaspargase IM on days 15 and 43; and methotrexate IT on days 1, 8, 15*, and 22*. Patients with DS receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT*.
NOTE: *Patients with CNS3 disease at diagnosis do not receive methotrexate on days 15 and 22 or leucovorin calcium.
STANDARD INTERIM MAINTENANCE THERAPY: Patients receive standard interim maintenance therapy as in group 1, arm I.
STANDARD DI THERAPY: Patients receive standard DI therapy as in group 1, arm I.
ARM IV:
INTENSIFIED CONSOLIDATION THERAPY: Patients receive intensified consolidation therapy as in group 2, arm III.
AUGMENTED INTERIM MAINTENANCE THERAPY: Patients receive augmented interim maintenance therapy as in group 2, arm II.
AUGMENTED DI THERAPY: Patients receive augmented DI therapy as in group 2, arm II.
GROUP 3 (SR-high ALL): Patients receive the following therapy: Intensified consolidation therapy: Patients receive intensified consolidation therapy as in group 2, arm III.
AUGMENTED INTERIM MAINTENANCE* THERAPY: Patients receive augmented interim maintenance therapy as in group 2, arm II. Treatment repeats every 56 days for 2 courses.
NOTE: *As of Amendment #7, all SR-High patients currently receiving AIM 1 therapy should complete this phase of therapy and proceed to ADI 1 therapy as originally planned including Capizzi methotrexate during AIM 1. Upon completion of ADI 1, patients should receive a second Interim Maintenance phase with high-dose methotrexate (IM HD) rather than Capizzi methotrexate. Patients should then proceed to ADI 2 and then Maintenance.
AUGMENTED DI* THERAPY: Patients receive augmented DI therapy as in group 2, arm II. Treatment repeats every 56 days for 2 courses**.
NOTE: *As of Amendment #7, all SR-High patients currently receiving ADI 1 therapy should complete this phase of therapy as originally planned. Upon completion of ADI 1, patients should receive a second Interim Maintenance phase with IM HD. Patients should then proceed to ADI 2 and then Maintenance.
NOTE: **Patients with CNS3 disease at diagnosis also undergo cranial radiotherapy on days 29-33 and 36-40 during course 2 only; these patients do not receive methotrexate on day 36, thioguanine, or leucovorin calcium.
MAINTENANCE THERAPY: All patients receive vincristine IV on days 1, 29, and 57; oral dexamethasone twice daily on days 1-5, 29-33, and 57-61; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine on days 1-84; and methotrexate IT* on day 1. Courses repeat every 84 days for a total of 2 years from the start of interim maintenance therapy for female patients and 3 years from the start of interim maintenance therapy for male patients.
NOTE: *SR-High or CNS3 patients should receive up to a maximum of 23 intrathecal treatments for females and 26 intrathecal treatments for males.
After the completion of study treatment, patients are followed every 1-2 months for 2 years, every 3 months for 1 year, and then every 6-12 months for 2 years.
Study Design
Study Type:
Interventional
Actual Enrollment
:
5377 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Standard Risk B-precursor Acute Lymphoblastic Leukemia (ALL)
Actual Study Start Date
:
Apr 11, 2005
Actual Primary Completion Date
:
Dec 30, 2013
Actual Study Completion Date
:
Mar 31, 2021
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group 0 Induction Therapy All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. |
Drug: Cytarabine
Given IV or SC
Other Names:
Drug: Dexamethasone
Given IV or PO
Other Names:
Drug: Leucovorin Calcium
Given PO
Other Names:
Drug: Methotrexate
Given IM or IT
Other Names:
Drug: Pegaspargase
Given IM
Other Names:
Drug: Vincristine Sulfate
Given IV
Other Names:
|
| Active Comparator: Group 1-SR-low ALL, Arm I (combination chemotherapy) Patients receive standard consolidation therapy, standard interim maintenance therapy, and standard delayed intensification (DI) therapy, followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine
Given IV or SC
Other Names:
Drug: Dexamethasone
Given IV or PO
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV or IT
Other Names:
Drug: Leucovorin Calcium
Given PO
Other Names:
Drug: Mercaptopurine
Given PO
Other Names:
Drug: Methotrexate
Given IM or IT
Other Names:
Drug: Pegaspargase
Given IM
Other Names:
Drug: Thioguanine
Given PO
Other Names:
Drug: Vincristine Sulfate
Given IV
Other Names:
|
| Experimental: Group 1-SR-low ALL, arm II (combination chemotherapy) Patients receive experimental consolidation therapy, experimental interim maintenance therapy, and standard DI therapy, followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. |
Radiation: 3-Dimensional Conformal Radiation Therapy
Some patients undergo cranial radiotherapy
Other Names:
Drug: Dexamethasone
Given IV or PO
Other Names:
Drug: Leucovorin Calcium
Given PO
Other Names:
Drug: Mercaptopurine
Given PO
Other Names:
Drug: Methotrexate
Given IM or IT
Other Names:
Drug: Pegaspargase
Given IM
Other Names:
Drug: Vincristine Sulfate
Given IV
Other Names:
|
| Active Comparator: Group 2-SR-avg ALL, arm I (combination chemotherapy) Patients receive standard consolidation therapy, standard interim maintenance therapy, and standard DI therapy as in group 1, arm I, followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. |
Radiation: 3-Dimensional Conformal Radiation Therapy
Some patients undergo cranial radiotherapy
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine
Given IV or SC
Other Names:
Drug: Dexamethasone
Given IV or PO
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV or IT
Other Names:
Drug: Leucovorin Calcium
Given PO
Other Names:
Drug: Mercaptopurine
Given PO
Other Names:
Drug: Methotrexate
Given IM or IT
Other Names:
Drug: Pegaspargase
Given IM
Other Names:
Drug: Thioguanine
Given PO
Other Names:
|
| Experimental: Group 2-SR-avg ALL, arm II (combination chemotherapy) Patients receive standard consolidation therapy, augmented interim maintenance therapy, augmented DI therapy, followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. |
Radiation: 3-Dimensional Conformal Radiation Therapy
Some patients undergo cranial radiotherapy
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine
Given IV or SC
Other Names:
Drug: Dexamethasone
Given IV or PO
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV or IT
Other Names:
Drug: Leucovorin Calcium
Given PO
Other Names:
Drug: Methotrexate
Given IM or IT
Other Names:
Drug: Pegaspargase
Given IM
Other Names:
Drug: Thioguanine
Given PO
Other Names:
Drug: Vincristine Sulfate
Given IV
Other Names:
|
| Active Comparator: Group 2-SR-avg ALL, arm III (combination chemotherapy) Patients receive intensified consolidation therapy, standard interim maintenance therapy, and standard DI therapy, followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. |
Radiation: 3-Dimensional Conformal Radiation Therapy
Some patients undergo cranial radiotherapy
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine
Given IV or SC
Other Names:
Drug: Dexamethasone
Given IV or PO
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV or IT
Other Names:
Drug: Leucovorin Calcium
Given PO
Other Names:
Drug: Mercaptopurine
Given PO
Other Names:
Drug: Methotrexate
Given IM or IT
Other Names:
Drug: Pegaspargase
Given IM
Other Names:
Drug: Thioguanine
Given PO
Other Names:
Drug: Vincristine Sulfate
Given IV
Other Names:
|
| Active Comparator: Group 2-SR-avg ALL, arm IV (combination chemotherapy) Patients receive intensified consolidation therapy, augmented interim maintenance therapy, and augmented DI therapy, followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. |
Radiation: 3-Dimensional Conformal Radiation Therapy
Some patients undergo cranial radiotherapy
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine
Given IV or SC
Other Names:
Drug: Dexamethasone
Given IV or PO
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV or IT
Other Names:
Drug: Leucovorin Calcium
Given PO
Other Names:
Drug: Mercaptopurine
Given PO
Other Names:
Drug: Methotrexate
Given IM or IT
Other Names:
Drug: Pegaspargase
Given IM
Other Names:
Drug: Thioguanine
Given PO
Other Names:
Drug: Vincristine Sulfate
Given IV
Other Names:
|
| Experimental: Group 3-SR-high ALL, combination chemotherapy Patients receive intensified consolidation therapy, augmented interim maintenance therapy (2 courses), and augmented DI therapy (2 courses), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. |
Radiation: 3-Dimensional Conformal Radiation Therapy
Some patients undergo cranial radiotherapy
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine
Given IV or SC
Other Names:
Drug: Dexamethasone
Given IV or PO
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV or IT
Other Names:
Drug: Leucovorin Calcium
Given PO
Other Names:
Drug: Mercaptopurine
Given PO
Other Names:
Drug: Methotrexate
Given IM or IT
Other Names:
Drug: Pegaspargase
Given IM
Other Names:
Drug: Thioguanine
Given PO
Other Names:
Drug: Vincristine Sulfate
Given IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Event-free Survival (EFS) for SR-Average ALL Patients [6 years]
EFS for SR-Average with standard and Intensified Consolidation. Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
- Event-free Survival (EFS) for SR-Low Patients [6 years]
Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
Secondary Outcome Measures
- Health-related Quality of Life Relative to Physical, Social and Emotional Impairment [At 1, 6 and 12 months after diagnosis and, 3 months post-therapy]
To identify potentially modifiable factors associated with impaired health related quality of life (HRQOL) at different periods of therapy in the patients who are SR-average enrolled on the standard risk ALL study.Standardized scores will be computed for child function using the gender and age-adjusted scores available from normative data from a healthy population of about 10,000 children. The various domains of family functioning will be assessed using well-validated instruments and analyzed as a dichotomous variable (impaired vs. non-impaired family functioning). Multiple regression analysis will be used to test the effect of family functioning (adjusted for therapy given, age at diagnosis, gender, socioeconomic status and other factors) on child function.
- Event-Free Survival Probability According to MRD Status End Induction (Day 29) [MRD at Day 29 of therapy]
Event-Free survival by Day 29 MRD status (negative vs positive), Event Free Probability (time from study entry to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
- Overall Survival Probability (OS) According to Induction Day 29 MRD Status [Overall Survival Probability of 6 years]
Overall survival by Day 29 MRD status (negative vs positive), Overall survival defined as time from study entry to death or date of last contact for patients who are alive.
- Early Marrow Status (EMS) by MRD Status End Induction (Day 29) [Early Marrow Status at Day 15, MRD Status at Day 29 of therapy.]
Early Marrow Status defined as M1 versus M2/M3 marrow is correlated with MRD (Positive vs. Negative)
- Optimal Time Point for Advance Health Related Quality of Life Intervention [At 1 month after diagnosis and 3 months post-therapy.]
Percentage of patients with elevated Anxiety.
- Event-free Survival (EFS) for SR-High Patients. [6 years]
Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
- Event-Free Survival (EFS) for Low MRD (Negative) Subjects by Genetic Subset (TEL/Trisomy Positive vs Negative) [6 years]
Event-free probability where EFS is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
Eligibility Criteria
Criteria
Ages Eligible for Study:
1 Year
to 9 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Patients must be enrolled on AALL03B1 prior to enrollment on AALL0331
-
Initial white blood cells (WBC) < 50,000/ul
-
Newly diagnosed B-precursor acute lymphoblastic leukemia
-
Standard-risk (SR) disease meeting 1 of the following criteria:
-
SR-average by age and WBC
-
No unfavorable features
-
Rapid early responder (RER) by day 15
-
CNS 1 or 2
-
Minimal residual disease (MRD) negative on day 29
-
Trisomies of 4, 10, and 17 or TEL-AML1 translocation and RER and CNS2 allowed
-
SR-low by age and WBC
-
No unfavorable features
-
RER by day 15
-
MRD negative on day 29
-
CNS1
-
Favorable cytogenetics-trisomies of 4, 10, and 17 or TEL-AML translocation
-
SR-high
-
Unfavorable features meeting ≥ 1 of the following criteria:
-
MLL rearrangements and RER
-
Steroid pretreatment
-
CNS3
-
Slow early responder by morphology or MRD
-
Patients with Down syndrome are allowed
-
Patients with overt testicular disease are not eligible for this study, but may be eligible for AALL0232
-
Patients shall have had no prior cytotoxic chemotherapy with the exception of steroids and intrathecal cytarabine; intrathecal chemotherapy with cytarabine is allowed prior to registration for patient convenience; this is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second lumbar puncture; (Note: the central nervous system [CNS] status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment
-
Patients receiving prior steroid therapy may be eligible for AALL0331 study
-
Patients with a contraindication to additional asparaginase therapy, following Induction, are not eligible for the Standard Risk-Low study, and should be removed from protocol therapy at the end of Induction
-
Patients who are assigned to the standard risk-average group following Induction and who meet the HRQOL
-
Age at diagnosis >= 2 years (note that this is a more restrictive age range than for the therapeutic component of the study)
-
At least one parent with reading comprehension of English or Spanish languages for which validated surveys exist
-
Diagnosis at one of the institutions participating in this limited institution correlative study
-
A parent or legal guardian must sign a written informed consent/parental permission for all patients
-
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital of Alabama | Birmingham | Alabama | United States | 35233 |
| 2 | University of Alabama at Birmingham Cancer Center | Birmingham | Alabama | United States | 35233 |
| 3 | USA Health Strada Patient Care Center | Mobile | Alabama | United States | 36604 |
| 4 | Banner Children's at Desert | Mesa | Arizona | United States | 85202 |
| 5 | Phoenix Childrens Hospital | Phoenix | Arizona | United States | 85016 |
| 6 | Banner University Medical Center - Tucson | Tucson | Arizona | United States | 85719 |
| 7 | Arkansas Children's Hospital | Little Rock | Arkansas | United States | 72202-3591 |
| 8 | University of Arkansas for Medical Sciences | Little Rock | Arkansas | United States | 72205 |
| 9 | Kaiser Permanente Downey Medical Center | Downey | California | United States | 90242 |
| 10 | City of Hope Comprehensive Cancer Center | Duarte | California | United States | 91010 |
| 11 | Loma Linda University Medical Center | Loma Linda | California | United States | 92354 |
| 12 | Miller Children's and Women's Hospital Long Beach | Long Beach | California | United States | 90806 |
| 13 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90027 |
| 14 | Cedars Sinai Medical Center | Los Angeles | California | United States | 90048 |
| 15 | Mattel Children's Hospital UCLA | Los Angeles | California | United States | 90095 |
| 16 | UCLA / Jonsson Comprehensive Cancer Center | Los Angeles | California | United States | 90095 |
| 17 | Valley Children's Hospital | Madera | California | United States | 93636 |
| 18 | UCSF Benioff Children's Hospital Oakland | Oakland | California | United States | 94609 |
| 19 | Kaiser Permanente-Oakland | Oakland | California | United States | 94611 |
| 20 | Children's Hospital of Orange County | Orange | California | United States | 92868 |
| 21 | Lucile Packard Children's Hospital Stanford University | Palo Alto | California | United States | 94304 |
| 22 | Sutter Medical Center Sacramento | Sacramento | California | United States | 95816 |
| 23 | University of California Davis Comprehensive Cancer Center | Sacramento | California | United States | 95817 |
| 24 | Rady Children's Hospital - San Diego | San Diego | California | United States | 92123 |
| 25 | UCSF Medical Center-Mount Zion | San Francisco | California | United States | 94115 |
| 26 | UCSF Medical Center-Parnassus | San Francisco | California | United States | 94143 |
| 27 | Santa Barbara Cottage Hospital | Santa Barbara | California | United States | 93102 |
| 28 | Harbor-University of California at Los Angeles Medical Center | Torrance | California | United States | 90502 |
| 29 | Children's Hospital Colorado | Aurora | Colorado | United States | 80045 |
| 30 | Presbyterian - Saint Lukes Medical Center - Health One | Denver | Colorado | United States | 80218 |
| 31 | Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center | Denver | Colorado | United States | 80218 |
| 32 | University of Connecticut | Farmington | Connecticut | United States | 06030 |
| 33 | Connecticut Children's Medical Center | Hartford | Connecticut | United States | 06106 |
| 34 | Yale University | New Haven | Connecticut | United States | 06520 |
| 35 | Alfred I duPont Hospital for Children | Wilmington | Delaware | United States | 19803 |
| 36 | MedStar Georgetown University Hospital | Washington | District of Columbia | United States | 20007 |
| 37 | Children's National Medical Center | Washington | District of Columbia | United States | 20010 |
| 38 | Broward Health Medical Center | Fort Lauderdale | Florida | United States | 33316 |
| 39 | Lee Memorial Health System | Fort Myers | Florida | United States | 33901 |
| 40 | Golisano Children's Hospital of Southwest Florida | Fort Myers | Florida | United States | 33908 |
| 41 | University of Florida Health Science Center - Gainesville | Gainesville | Florida | United States | 32610 |
| 42 | Memorial Regional Hospital/Joe DiMaggio Children's Hospital | Hollywood | Florida | United States | 33021 |
| 43 | Nemours Children's Clinic-Jacksonville | Jacksonville | Florida | United States | 32207 |
| 44 | University of Miami Miller School of Medicine-Sylvester Cancer Center | Miami | Florida | United States | 33136 |
| 45 | Nicklaus Children's Hospital | Miami | Florida | United States | 33155 |
| 46 | Miami Cancer Institute | Miami | Florida | United States | 33176 |
| 47 | AdventHealth Orlando | Orlando | Florida | United States | 32803 |
| 48 | Nemours Children's Clinic - Orlando | Orlando | Florida | United States | 32806 |
| 49 | Orlando Health Cancer Institute | Orlando | Florida | United States | 32806 |
| 50 | Nemours Children's Hospital | Orlando | Florida | United States | 32827 |
| 51 | Nemours Children's Clinic - Pensacola | Pensacola | Florida | United States | 32504 |
| 52 | Sacred Heart Hospital | Pensacola | Florida | United States | 32504 |
| 53 | Johns Hopkins All Children's Hospital | Saint Petersburg | Florida | United States | 33701 |
| 54 | Saint Joseph's Hospital/Children's Hospital-Tampa | Tampa | Florida | United States | 33607 |
| 55 | Saint Mary's Hospital | West Palm Beach | Florida | United States | 33407 |
| 56 | Children's Healthcare of Atlanta - Egleston | Atlanta | Georgia | United States | 30322 |
| 57 | Emory University Hospital/Winship Cancer Institute | Atlanta | Georgia | United States | 30322 |
| 58 | Augusta University Medical Center | Augusta | Georgia | United States | 30912 |
| 59 | Memorial Health University Medical Center | Savannah | Georgia | United States | 31404 |
| 60 | University of Hawaii Cancer Center | Honolulu | Hawaii | United States | 96813 |
| 61 | Tripler Army Medical Center | Honolulu | Hawaii | United States | 96859 |
| 62 | Saint Luke's Cancer Institute - Boise | Boise | Idaho | United States | 83712 |
| 63 | Lurie Children's Hospital-Chicago | Chicago | Illinois | United States | 60611 |
| 64 | University of Illinois | Chicago | Illinois | United States | 60612 |
| 65 | University of Chicago Comprehensive Cancer Center | Chicago | Illinois | United States | 60637 |
| 66 | Loyola University Medical Center | Maywood | Illinois | United States | 60153 |
| 67 | Advocate Children's Hospital-Oak Lawn | Oak Lawn | Illinois | United States | 60453 |
| 68 | Advocate Lutheran General Hospital | Park Ridge | Illinois | United States | 60068 |
| 69 | Saint Jude Midwest Affiliate | Peoria | Illinois | United States | 61637 |
| 70 | Southern Illinois University School of Medicine | Springfield | Illinois | United States | 62702 |
| 71 | Indiana University/Melvin and Bren Simon Cancer Center | Indianapolis | Indiana | United States | 46202 |
| 72 | Riley Hospital for Children | Indianapolis | Indiana | United States | 46202 |
| 73 | Saint Vincent Hospital and Health Care Center | Indianapolis | Indiana | United States | 46260 |
| 74 | Blank Children's Hospital | Des Moines | Iowa | United States | 50309 |
| 75 | University of Iowa/Holden Comprehensive Cancer Center | Iowa City | Iowa | United States | 52242 |
| 76 | University of Kansas Cancer Center | Kansas City | Kansas | United States | 66160 |
| 77 | University of Kentucky/Markey Cancer Center | Lexington | Kentucky | United States | 40536 |
| 78 | Norton Children's Hospital | Louisville | Kentucky | United States | 40202 |
| 79 | Tulane University Health Sciences Center | New Orleans | Louisiana | United States | 70112 |
| 80 | Children's Hospital New Orleans | New Orleans | Louisiana | United States | 70118 |
| 81 | Ochsner Medical Center Jefferson | New Orleans | Louisiana | United States | 70121 |
| 82 | Eastern Maine Medical Center | Bangor | Maine | United States | 04401 |
| 83 | Maine Children's Cancer Program | Scarborough | Maine | United States | 04074 |
| 84 | University of Maryland/Greenebaum Cancer Center | Baltimore | Maryland | United States | 21201 |
| 85 | Sinai Hospital of Baltimore | Baltimore | Maryland | United States | 21215 |
| 86 | Johns Hopkins University/Sidney Kimmel Cancer Center | Baltimore | Maryland | United States | 21287 |
| 87 | Walter Reed National Military Medical Center | Bethesda | Maryland | United States | 20889-5600 |
| 88 | Tufts Children's Hospital | Boston | Massachusetts | United States | 02111 |
| 89 | Massachusetts General Hospital Cancer Center | Boston | Massachusetts | United States | 02114 |
| 90 | Baystate Medical Center | Springfield | Massachusetts | United States | 01199 |
| 91 | UMass Memorial Medical Center - University Campus | Worcester | Massachusetts | United States | 01655 |
| 92 | C S Mott Children's Hospital | Ann Arbor | Michigan | United States | 48109 |
| 93 | Wayne State University/Karmanos Cancer Institute | Detroit | Michigan | United States | 48201 |
| 94 | Ascension Saint John Hospital | Detroit | Michigan | United States | 48236 |
| 95 | Michigan State University Clinical Center | East Lansing | Michigan | United States | 48824-7016 |
| 96 | Hurley Medical Center | Flint | Michigan | United States | 48503 |
| 97 | Helen DeVos Children's Hospital at Spectrum Health | Grand Rapids | Michigan | United States | 49503 |
| 98 | Spectrum Health at Butterworth Campus | Grand Rapids | Michigan | United States | 49503 |
| 99 | Bronson Methodist Hospital | Kalamazoo | Michigan | United States | 49007 |
| 100 | Kalamazoo Center for Medical Studies | Kalamazoo | Michigan | United States | 49008 |
| 101 | Beaumont Children's Hospital-Royal Oak | Royal Oak | Michigan | United States | 48073 |
| 102 | William Beaumont Hospital-Royal Oak | Royal Oak | Michigan | United States | 48073 |
| 103 | Children's Hospitals and Clinics of Minnesota - Minneapolis | Minneapolis | Minnesota | United States | 55404 |
| 104 | University of Minnesota/Masonic Cancer Center | Minneapolis | Minnesota | United States | 55455 |
| 105 | Mayo Clinic in Rochester | Rochester | Minnesota | United States | 55905 |
| 106 | University of Mississippi Medical Center | Jackson | Mississippi | United States | 39216 |
| 107 | Columbia Regional | Columbia | Missouri | United States | 65201 |
| 108 | University of Missouri - Ellis Fischel | Columbia | Missouri | United States | 65212 |
| 109 | Children's Mercy Hospitals and Clinics | Kansas City | Missouri | United States | 64108 |
| 110 | Cardinal Glennon Children's Medical Center | Saint Louis | Missouri | United States | 63104 |
| 111 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
| 112 | Children's Hospital and Medical Center of Omaha | Omaha | Nebraska | United States | 68114 |
| 113 | University of Nebraska Medical Center | Omaha | Nebraska | United States | 68198 |
| 114 | Nevada Cancer Research Foundation NCORP | Las Vegas | Nevada | United States | 89169 |
| 115 | Dartmouth Hitchcock Medical Center | Lebanon | New Hampshire | United States | 03756 |
| 116 | Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
| 117 | Saint Barnabas Medical Center | Livingston | New Jersey | United States | 07039 |
| 118 | Morristown Medical Center | Morristown | New Jersey | United States | 07960 |
| 119 | Saint Peter's University Hospital | New Brunswick | New Jersey | United States | 08901 |
| 120 | Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital | New Brunswick | New Jersey | United States | 08903 |
| 121 | Newark Beth Israel Medical Center | Newark | New Jersey | United States | 07112 |
| 122 | Saint Joseph's Regional Medical Center | Paterson | New Jersey | United States | 07503 |
| 123 | Overlook Hospital | Summit | New Jersey | United States | 07902 |
| 124 | University of New Mexico Cancer Center | Albuquerque | New Mexico | United States | 87102 |
| 125 | Albany Medical Center | Albany | New York | United States | 12208 |
| 126 | Montefiore Medical Center - Moses Campus | Bronx | New York | United States | 10467 |
| 127 | Brooklyn Hospital Center | Brooklyn | New York | United States | 11201 |
| 128 | Brookdale Hospital Medical Center | Brooklyn | New York | United States | 11212 |
| 129 | Maimonides Medical Center | Brooklyn | New York | United States | 11219 |
| 130 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263 |
| 131 | NYU Winthrop Hospital | Mineola | New York | United States | 11501 |
| 132 | The Steven and Alexandra Cohen Children's Medical Center of New York | New Hyde Park | New York | United States | 11040 |
| 133 | Laura and Isaac Perlmutter Cancer Center at NYU Langone | New York | New York | United States | 10016 |
| 134 | Mount Sinai Hospital | New York | New York | United States | 10029 |
| 135 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 136 | NYP/Weill Cornell Medical Center | New York | New York | United States | 10065 |
| 137 | Stony Brook University Medical Center | Stony Brook | New York | United States | 11794 |
| 138 | State University of New York Upstate Medical University | Syracuse | New York | United States | 13210 |
| 139 | New York Medical College | Valhalla | New York | United States | 10595 |
| 140 | Mission Hospital | Asheville | North Carolina | United States | 28801 |
| 141 | UNC Lineberger Comprehensive Cancer Center | Chapel Hill | North Carolina | United States | 27599 |
| 142 | Carolinas Medical Center/Levine Cancer Institute | Charlotte | North Carolina | United States | 28203 |
| 143 | Novant Health Presbyterian Medical Center | Charlotte | North Carolina | United States | 28204 |
| 144 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
| 145 | East Carolina University | Greenville | North Carolina | United States | 27834 |
| 146 | Wake Forest University Health Sciences | Winston-Salem | North Carolina | United States | 27157 |
| 147 | Sanford Broadway Medical Center | Fargo | North Dakota | United States | 58122 |
| 148 | Children's Hospital Medical Center of Akron | Akron | Ohio | United States | 44308 |
| 149 | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229 |
| 150 | Rainbow Babies and Childrens Hospital | Cleveland | Ohio | United States | 44106 |
| 151 | Cleveland Clinic Foundation | Cleveland | Ohio | United States | 44195 |
| 152 | Nationwide Children's Hospital | Columbus | Ohio | United States | 43205 |
| 153 | Dayton Children's Hospital | Dayton | Ohio | United States | 45404 |
| 154 | ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital | Toledo | Ohio | United States | 43606 |
| 155 | Mercy Children's Hospital | Toledo | Ohio | United States | 43608 |
| 156 | University of Toledo | Toledo | Ohio | United States | 43614 |
| 157 | Tod Children's Hospital - Forum Health | Youngstown | Ohio | United States | 44501 |
| 158 | University of Oklahoma Health Sciences Center | Oklahoma City | Oklahoma | United States | 73104 |
| 159 | Natalie Warren Bryant Cancer Center at Saint Francis | Tulsa | Oklahoma | United States | 74136 |
| 160 | Legacy Emanuel Children's Hospital | Portland | Oregon | United States | 97227 |
| 161 | Legacy Emanuel Hospital and Health Center | Portland | Oregon | United States | 97227 |
| 162 | Oregon Health and Science University | Portland | Oregon | United States | 97239 |
| 163 | Lehigh Valley Hospital - Muhlenberg | Bethlehem | Pennsylvania | United States | 18017 |
| 164 | Geisinger Medical Center | Danville | Pennsylvania | United States | 17822 |
| 165 | Penn State Milton S Hershey Medical Center | Hershey | Pennsylvania | United States | 17033-0850 |
| 166 | Penn State Children's Hospital | Hershey | Pennsylvania | United States | 17033 |
| 167 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
| 168 | Children's Oncology Group | Philadelphia | Pennsylvania | United States | 19104 |
| 169 | Saint Christopher's Hospital for Children | Philadelphia | Pennsylvania | United States | 19134 |
| 170 | Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania | United States | 15224 |
| 171 | Rhode Island Hospital | Providence | Rhode Island | United States | 02903 |
| 172 | Medical University of South Carolina | Charleston | South Carolina | United States | 29425 |
| 173 | Prisma Health Richland Hospital | Columbia | South Carolina | United States | 29203 |
| 174 | BI-LO Charities Children's Cancer Center | Greenville | South Carolina | United States | 29605 |
| 175 | Greenville Cancer Treatment Center | Greenville | South Carolina | United States | 29605 |
| 176 | Sanford USD Medical Center - Sioux Falls | Sioux Falls | South Dakota | United States | 57117-5134 |
| 177 | T C Thompson Children's Hospital | Chattanooga | Tennessee | United States | 37403 |
| 178 | East Tennessee Childrens Hospital | Knoxville | Tennessee | United States | 37916 |
| 179 | Vanderbilt University/Ingram Cancer Center | Nashville | Tennessee | United States | 37232 |
| 180 | Texas Tech University Health Sciences Center-Amarillo | Amarillo | Texas | United States | 79106 |
| 181 | Dell Children's Medical Center of Central Texas | Austin | Texas | United States | 78723 |
| 182 | Driscoll Children's Hospital | Corpus Christi | Texas | United States | 78411 |
| 183 | Medical City Dallas Hospital | Dallas | Texas | United States | 75230 |
| 184 | UT Southwestern/Simmons Cancer Center-Dallas | Dallas | Texas | United States | 75390 |
| 185 | Cook Children's Medical Center | Fort Worth | Texas | United States | 76104 |
| 186 | University of Texas Medical Branch | Galveston | Texas | United States | 77555-0565 |
| 187 | Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center | Houston | Texas | United States | 77030 |
| 188 | M D Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 189 | Covenant Children's Hospital | Lubbock | Texas | United States | 79410 |
| 190 | Methodist Children's Hospital of South Texas | San Antonio | Texas | United States | 78229 |
| 191 | University of Texas Health Science Center at San Antonio | San Antonio | Texas | United States | 78229 |
| 192 | Scott and White Memorial Hospital | Temple | Texas | United States | 76508 |
| 193 | Primary Children's Hospital | Salt Lake City | Utah | United States | 84113 |
| 194 | University of Vermont and State Agricultural College | Burlington | Vermont | United States | 05405 |
| 195 | University of Virginia Cancer Center | Charlottesville | Virginia | United States | 22908 |
| 196 | Inova Fairfax Hospital | Falls Church | Virginia | United States | 22042 |
| 197 | Children's Hospital of The King's Daughters | Norfolk | Virginia | United States | 23507 |
| 198 | Naval Medical Center - Portsmouth | Portsmouth | Virginia | United States | 23708-2197 |
| 199 | Virginia Commonwealth University/Massey Cancer Center | Richmond | Virginia | United States | 23298 |
| 200 | Carilion Children's | Roanoke | Virginia | United States | 24014 |
| 201 | Seattle Children's Hospital | Seattle | Washington | United States | 98105 |
| 202 | Providence Sacred Heart Medical Center and Children's Hospital | Spokane | Washington | United States | 99204 |
| 203 | Mary Bridge Children's Hospital and Health Center | Tacoma | Washington | United States | 98405 |
| 204 | Madigan Army Medical Center | Tacoma | Washington | United States | 98431 |
| 205 | West Virginia University Charleston Division | Charleston | West Virginia | United States | 25304 |
| 206 | West Virginia University Healthcare | Morgantown | West Virginia | United States | 26506 |
| 207 | Saint Vincent Hospital Cancer Center Green Bay | Green Bay | Wisconsin | United States | 54301 |
| 208 | University of Wisconsin Hospital and Clinics | Madison | Wisconsin | United States | 53792 |
| 209 | Marshfield Medical Center-Marshfield | Marshfield | Wisconsin | United States | 54449 |
| 210 | Children's Hospital of Wisconsin | Milwaukee | Wisconsin | United States | 53226 |
| 211 | Royal Brisbane and Women's Hospital | Herston | Queensland | Australia | 4029 |
| 212 | Royal Children's Hospital-Brisbane | Herston | Queensland | Australia | 4029 |
| 213 | Women's and Children's Hospital-Adelaide | North Adelaide | South Australia | Australia | 5006 |
| 214 | Royal Children's Hospital | Parkville | Victoria | Australia | 3052 |
| 215 | Princess Margaret Hospital for Children | Perth | Western Australia | Australia | 6008 |
| 216 | Alberta Children's Hospital | Calgary | Alberta | Canada | T3B 6A8 |
| 217 | University of Alberta Hospital | Edmonton | Alberta | Canada | T6G 2B7 |
| 218 | British Columbia Children's Hospital | Vancouver | British Columbia | Canada | V6H 3V4 |
| 219 | CancerCare Manitoba | Winnipeg | Manitoba | Canada | R3E 0V9 |
| 220 | Janeway Child Health Centre | Saint John's | Newfoundland and Labrador | Canada | A1B 3V6 |
| 221 | IWK Health Centre | Halifax | Nova Scotia | Canada | B3K 6R8 |
| 222 | Kingston Health Sciences Centre | Kingston | Ontario | Canada | K7L 2V7 |
| 223 | Children's Hospital | London | Ontario | Canada | N6A 5W9 |
| 224 | Victoria Hospital | London | Ontario | Canada | N6K 1C2 |
| 225 | Children's Hospital of Eastern Ontario | Ottawa | Ontario | Canada | K1H 8L1 |
| 226 | Hospital for Sick Children | Toronto | Ontario | Canada | M5G 1X8 |
| 227 | The Montreal Children's Hospital of the MUHC | Montreal | Quebec | Canada | H3H 1P3 |
| 228 | Centre Hospitalier Universitaire de Sherbrooke-Fleurimont | Sherbrooke | Quebec | Canada | J1H 5N4 |
| 229 | Allan Blair Cancer Centre | Regina | Saskatchewan | Canada | S4T 7T1 |
| 230 | Saskatoon Cancer Centre | Saskatoon | Saskatchewan | Canada | S7N 4H4 |
| 231 | Starship Children's Hospital | Grafton | Auckland | New Zealand | 1145 |
| 232 | Christchurch Hospital | Christchurch | New Zealand | 8011 | |
| 233 | Wellington Children's Hospital | Wellington | New Zealand | 6002 | |
| 234 | Swiss Pediatric Oncology Group - Bern | Bern | Switzerland | 3010 | |
| 235 | Swiss Pediatric Oncology Group - Geneva | Geneva | Switzerland | 1205 | |
| 236 | Swiss Pediatric Oncology Group - Lausanne | Lausanne | Switzerland | 1011 |
Sponsors and Collaborators
- Children's Oncology Group
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Kelly W Maloney, Children's Oncology Group
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00103285
Other Study ID Numbers:
- AALL0331
- NCI-2009-00302
- 05-340
- COG-AALL0331
- CDR0000409589
- AALL0331
- AALL0331
- U10CA098543
First Posted:
Feb 8, 2005
Last Update Posted:
Jun 14, 2021
Last Verified:
Apr 1, 2021
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Group 0 Induction Therapy | Group 1-SR-low ALL, Arm I-combination Chemotherapy | Group 1-SR-low ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm I-combination Chemotherapy | Group 2-SR-avg ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm III-combination Chemotherapy | Group 2-SR-avg ALL, Arm IV-combination Chemotherapy | Group 3-SR-high ALL, Combination Chemotherapy |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine & vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, methotrexate and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, methotrexate. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT 3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine |
| Period Title: Induction | ||||||||
| STARTED | 5377 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| COMPLETED | 4028 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 1349 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: Induction | ||||||||
| STARTED | 0 | 939 | 937 | 503 | 509 | 249 | 248 | 643 |
| COMPLETED | 0 | 807 | 853 | 441 | 425 | 201 | 199 | 523 |
| NOT COMPLETED | 0 | 132 | 84 | 62 | 84 | 48 | 49 | 120 |
Baseline Characteristics
| Arm/Group Title | Group 0 Induction Therapy |
|---|---|
| Arm/Group Description | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV |
| Overall Participants | 5377 |
| Age (Count of Participants) | |
| <=18 years |
5377
100%
|
| Between 18 and 65 years |
0
0%
|
| >=65 years |
0
0%
|
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
4.45
(2.10)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
2489
46.3%
|
| Male |
2888
53.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
1097
20.4%
|
| Not Hispanic or Latino |
4038
75.1%
|
| Unknown or Not Reported |
242
4.5%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
36
0.7%
|
| Asian |
253
4.7%
|
| Native Hawaiian or Other Pacific Islander |
24
0.4%
|
| Black or African American |
326
6.1%
|
| White |
4046
75.2%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
692
12.9%
|
| Region of Enrollment (participants) [Number] | |
| United States |
5377
100%
|
Outcome Measures
| Title | Event-free Survival (EFS) for SR-Average ALL Patients |
|---|---|
| Description | EFS for SR-Average with standard and Intensified Consolidation. Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. |
| Time Frame | 6 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only eligible patients are included in this population. Populations are based on enrollments for all four arms initially, and then only for Arms I and II (standard therapy) once Arms III and IV (intensified therapy) were closed to accrual. |
| Arm/Group Title | Group 2-SR-avg ALL, Arm I-combination Chemotherapy | Group 2-SR-avg ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm III-combination Chemotherapy | Group 2-SR-avg ALL, Arm IV-combination Chemotherapy |
|---|---|---|---|---|
| Arm/Group Description | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV |
| Measure Participants | 500 | 509 | 245 | 246 |
| Standard and Intensified therapy |
83.82
|
88.89
|
88.34
|
90.51
|
| Standard therapy |
87.41
|
88.29
|
| Title | Event-free Survival (EFS) for SR-Low Patients |
|---|---|
| Description | Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. |
| Time Frame | 6 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only eligible patients are included in the analysis. |
| Arm/Group Title | SR-low ALL, Arm I-combination Chemotherapy | SR-low ALL, Arm II-combination Chemotherapy |
|---|---|---|
| Arm/Group Description | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV |
| Measure Participants | 928 | 929 |
| Number (95% Confidence Interval) [Percent probability] |
95.22
|
93.96
|
| Title | Health-related Quality of Life Relative to Physical, Social and Emotional Impairment |
|---|---|
| Description | To identify potentially modifiable factors associated with impaired health related quality of life (HRQOL) at different periods of therapy in the patients who are SR-average enrolled on the standard risk ALL study.Standardized scores will be computed for child function using the gender and age-adjusted scores available from normative data from a healthy population of about 10,000 children. The various domains of family functioning will be assessed using well-validated instruments and analyzed as a dichotomous variable (impaired vs. non-impaired family functioning). Multiple regression analysis will be used to test the effect of family functioning (adjusted for therapy given, age at diagnosis, gender, socioeconomic status and other factors) on child function. |
| Time Frame | At 1, 6 and 12 months after diagnosis and, 3 months post-therapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis is restricted to the 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites, who consented to and completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning). |
| Arm/Group Title | Induction Therapy |
|---|---|
| Arm/Group Description | All patients for induction therapy. |
| Measure Participants | 160 |
| Physical Impairment 1 mth after diagnosis |
76.39
1.4%
|
| Physical Impairment 6 mths after diagnosis |
42.75
0.8%
|
| Physical Impairment 12 mths after diagnosis |
29.41
0.5%
|
| Physical Impairment 3 mths post therapy |
27.84
0.5%
|
| Social Impairment 1 mth after diagnosis |
43.36
0.8%
|
| Social Impairment 6 mths after diagnosis |
23.66
0.4%
|
| Social Impairment 12 mths after diagnosis |
23.53
0.4%
|
| Social Impairment 3 mths post-therapy |
25.77
0.5%
|
| Emotional Impairment 1 mth after diagnosis |
38.89
0.7%
|
| Emotional Impairment 6 mths after diagnosis |
17.56
0.3%
|
| Emotional Impairment 12 mths after diagnosis |
13.97
0.3%
|
| Emotional Impairment 3 mths post-therapy |
8.25
0.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Group 2-SR-avg ALL, Arm I-combination Chemotherapy |
|---|---|---|
| Comments | Physical Functioning: Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post-therapy. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 5.17 | |
| Confidence Interval |
(2-Sided) 95% 1.61 to 16.63 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Odds Ratios in this Statistical Analysis corresponds to all four time points. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Group 2-SR-avg ALL, Arm I-combination Chemotherapy |
|---|---|---|
| Comments | Social Functioning: Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post-therapy. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.99 | |
| Confidence Interval |
(2-Sided) 95% 1.21 to 3.27 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Odds Ratios in this Statistical Analysis corresponds to all four time points | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Group 2-SR-avg ALL, Arm I-combination Chemotherapy |
|---|---|---|
| Comments | Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post-therapy. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.85 | |
| Confidence Interval |
(2-Sided) 95% 1.03 to 3.34 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Odds Ratios in this Statistical Analysis corresponds to all four time points | |
| Title | Event-Free Survival Probability According to MRD Status End Induction (Day 29) |
|---|---|
| Description | Event-Free survival by Day 29 MRD status (negative vs positive), Event Free Probability (time from study entry to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. |
| Time Frame | MRD at Day 29 of therapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| 4981 eligible evaluable patients enrolled on AALL0331 had MRD data at Day 29 |
| Arm/Group Title | Induction Therapy, MRD Negative | Induction Therapy, MRD Positive |
|---|---|---|
| Arm/Group Description | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV |
| Measure Participants | 4614 | 367 |
| Number (95% Confidence Interval) [Percent Probability] |
91.39
|
79.86
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Group 2-SR-avg ALL, Arm I-combination Chemotherapy, Group 2-SR-avg ALL, Arm II-combination Chemotherapy |
|---|---|---|
| Comments | 4981 eligible evaluable patients enrolled on AALL0331 had MRD evaluation at Day 29 of induction. MRD status defined as negative (<0.1%) or positive (>=0.1%). MRD status ( positive vs. negative) was correlated with EFS using Cox regression analysis. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 2.542 | |
| Confidence Interval |
(2-Sided) 95% 1.974 to 3.273 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival Probability (OS) According to Induction Day 29 MRD Status |
|---|---|
| Description | Overall survival by Day 29 MRD status (negative vs positive), Overall survival defined as time from study entry to death or date of last contact for patients who are alive. |
| Time Frame | Overall Survival Probability of 6 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| 4981 eligible evaluable patients enrolled on AALL0331 had MRD data at Day 29. |
| Arm/Group Title | Induction Therapy, MRD Negative | Induction Therapy, MRD Positive |
|---|---|---|
| Arm/Group Description | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV |
| Measure Participants | 4614 | 367 |
| Number (95% Confidence Interval) [percent probability] |
97.07
|
90.47
|
| Title | Early Marrow Status (EMS) by MRD Status End Induction (Day 29) |
|---|---|
| Description | Early Marrow Status defined as M1 versus M2/M3 marrow is correlated with MRD (Positive vs. Negative) |
| Time Frame | Early Marrow Status at Day 15, MRD Status at Day 29 of therapy. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients who had MRD day 29 data but their Bone Marrow (BM) days 8/15 data were missing are excluded. This analysis was done with patients who had both MRD and BM data. There were 5 patients excluded in both MRD Negative and MRD Positive groups due to missing days 8/15 BM. |
| Arm/Group Title | All Patients for Induction, MRD Negative | All Patients for Induction, MRD Positive |
|---|---|---|
| Arm/Group Description | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV |
| Measure Participants | 4609 | 362 |
| Count of Participants [Participants] |
4378
81.4%
|
258
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Group 2-SR-avg ALL, Arm I-combination Chemotherapy, Group 2-SR-avg ALL, Arm II-combination Chemotherapy |
|---|---|---|
| Comments | MRD status ( positive vs. negative) was correlated with Early Marrow Status (M1 vs M2/M3) using Chi Square test. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.131 | |
| Confidence Interval |
(2-Sided) 95% 0.101 to 0.17 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Optimal Time Point for Advance Health Related Quality of Life Intervention |
|---|---|
| Description | Percentage of patients with elevated Anxiety. |
| Time Frame | At 1 month after diagnosis and 3 months post-therapy. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Parents of 159 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the BASC-2 Anxiety Scale at 1 month after diagnosis, and 3 months post-therapy. Of these, 159 patients had data at 1 month after diagnosis and 96 patients had data at 3 months post therapy. |
| Arm/Group Title | Induction Therapy |
|---|---|
| Arm/Group Description | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV |
| Measure Participants | 159 |
| At 1 month after diagnosis |
25.2
0.5%
|
| At 3 months post-therapy |
24.0
0.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Group 2-SR-avg ALL, Arm I-combination Chemotherapy |
|---|---|---|
| Comments | Parents of 159 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the BASC-2 Anxiety Scale at 1 month after diagnosis, and 3 months post-therapy. Of these 159 had data at 1 month after diagnosis and 96 at 3 months post therapy. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 4.1 | |
| Confidence Interval |
(2-Sided) 95% 1.31 to 12.73 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Event-free Survival (EFS) for SR-High Patients. |
|---|---|
| Description | Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. |
| Time Frame | 6 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| CCR: Complete Continuous Remission, where time to event is defined as the time from start of consolidation therapy to first event or date of last follow up for those who did not experience an event. All patients enrolled on the SR-High were used in this analysis regardless of completion of therapy. |
| Arm/Group Title | Group 3-SR-high ALL, Combination Chemotherapy |
|---|---|
| Arm/Group Description | Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium, and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine,MTX. Patients with DS receive (dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT 3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO |
| Measure Participants | 636 |
| Number (95% Confidence Interval) [percent probability] |
85.58
|
| Title | Event-Free Survival (EFS) for Low MRD (Negative) Subjects by Genetic Subset (TEL/Trisomy Positive vs Negative) |
|---|---|
| Description | Event-free probability where EFS is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. |
| Time Frame | 6 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients on the two arms being compared got similar therapy. All patients included in this analysis are MRD negative. SR-Average patients who were CNS2 at diagnosis were excluded in order to have comparable patient cohorts. SR-Low patients are TEL/Trisomy positive while SR-Average patients are TEL/Trisomy negative. |
| Arm/Group Title | Group 1-SR-low ALL, Arm I-combination Chemotherapy | Group 2-SR-avg ALL, Arm I-combination Chemotherapy |
|---|---|---|
| Arm/Group Description | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV |
| Measure Participants | 926 | 422 |
| Number (95% Confidence Interval) [Percent probability] |
95.22
|
88.52
|
Adverse Events
| Time Frame | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Only eligible patients are included in the toxicity analysis. | |||||||||||||||
| Arm/Group Title | Group 0 Induction Therapy | Group 1-SR-low ALL, Arm I-combination Chemotherapy | Group 1-SR-low ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm I-combination Chemotherapy | Group 2-SR-avg ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm III-combination Chemotherapy | Group 2-SR-avg ALL, Arm IV-combination Chemotherapy | Group 3-SR-high ALL, Combination Chemotherapy | ||||||||
| Arm/Group Description | All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV | Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine & vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, methotrexate and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, methotrexate. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT 3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine | ||||||||
All Cause Mortality |
||||||||||||||||
| Group 0 Induction Therapy | Group 1-SR-low ALL, Arm I-combination Chemotherapy | Group 1-SR-low ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm I-combination Chemotherapy | Group 2-SR-avg ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm III-combination Chemotherapy | Group 2-SR-avg ALL, Arm IV-combination Chemotherapy | Group 3-SR-high ALL, Combination Chemotherapy | |||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||||||
Serious Adverse Events |
||||||||||||||||
| Group 0 Induction Therapy | Group 1-SR-low ALL, Arm I-combination Chemotherapy | Group 1-SR-low ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm I-combination Chemotherapy | Group 2-SR-avg ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm III-combination Chemotherapy | Group 2-SR-avg ALL, Arm IV-combination Chemotherapy | Group 3-SR-high ALL, Combination Chemotherapy | |||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 29/1306 (2.2%) | 14/931 (1.5%) | 7/931 (0.8%) | 4/501 (0.8%) | 3/509 (0.6%) | 0/246 (0%) | 1/247 (0.4%) | 12/638 (1.9%) | ||||||||
| Blood and lymphatic system disorders | ||||||||||||||||
| Anemia | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Disseminated intravascular coagulation | 3/1306 (0.2%) | 3 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Febrile neutropenia | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hemolysis | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Cardiac disorders | ||||||||||||||||
| Cardiac arrest | 2/1306 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Myocardial infarction | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Gastrointestinal disorders | ||||||||||||||||
| Abdominal pain | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Ascites | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Cecal hemorrhage | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Colitis | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Colonic perforation | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Diarrhea | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Esophageal perforation | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Esophagitis | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Gastrointestinal disorders - Other, specify | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Mucositis oral | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Oral hemorrhage | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Pancreatitis | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Rectal hemorrhage | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Rectal necrosis | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Rectal pain | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Small intestinal perforation | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Typhlitis | 2/1306 (0.2%) | 2 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| General disorders | ||||||||||||||||
| Death NOS | 4/1306 (0.3%) | 4 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 2/501 (0.4%) | 2 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Edema trunk | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| General disorders and administration site conditions - Other, specify | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Multi-organ failure | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Sudden death NOS | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hepatobiliary disorders | ||||||||||||||||
| Cholecystitis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Hepatic failure | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Hepatobiliary disorders - Other, specify | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Portal hypertension | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Immune system disorders | ||||||||||||||||
| Anaphylaxis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Infections and infestations | ||||||||||||||||
| Appendicitis | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Appendicitis perforated | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Encephalitis infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Encephalomyelitis infection | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Enterocolitis infectious | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Infections and infestations - Other, specify | 6/1306 (0.5%) | 6 | 4/931 (0.4%) | 4 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 7/638 (1.1%) | 7 |
| Lung infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Pleural infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Sepsis | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||||||
| Vascular access complication | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Investigations | ||||||||||||||||
| Activated partial thromboplastin time prolonged | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Alanine aminotransferase increased | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Alkaline phosphatase increased | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Aspartate aminotransferase increased | 0/1306 (0%) | 0 | 3/931 (0.3%) | 3 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Blood bilirubin increased | 0/1306 (0%) | 0 | 3/931 (0.3%) | 3 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| CPK increased | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Fibrinogen decreased | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Investigations - Other, specify | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Lipase increased | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Neutrophil count decreased | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Platelet count decreased | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Serum amylase increased | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| White blood cell decreased | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Metabolism and nutrition disorders | ||||||||||||||||
| Acidosis | 1/1306 (0.1%) | 2 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Dehydration | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hyperglycemia | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hypoalbuminemia | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hypocalcemia | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hypoglycemia | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hypokalemia | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hyponatremia | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Nervous system disorders | ||||||||||||||||
| Depressed level of consciousness | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Encephalopathy | 3/1306 (0.2%) | 3 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Intracranial hemorrhage | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Nervous system disorders - Other, specify | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Peripheral motor neuropathy | 2/1306 (0.2%) | 2 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Seizure | 3/1306 (0.2%) | 3 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Psychiatric disorders | ||||||||||||||||
| Confusion | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||||||
| Acute kidney injury | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Bladder perforation | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||
| Adult respiratory distress syndrome | 3/1306 (0.2%) | 3 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Apnea | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Bronchopulmonary hemorrhage | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Dyspnea | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hypoxia | 3/1306 (0.2%) | 3 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Pleural effusion | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Respiratory failure | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Vascular disorders | ||||||||||||||||
| Hypotension | 4/1306 (0.3%) | 4 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Thromboembolic event | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||||||||||
| Group 0 Induction Therapy | Group 1-SR-low ALL, Arm I-combination Chemotherapy | Group 1-SR-low ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm I-combination Chemotherapy | Group 2-SR-avg ALL, Arm II-combination Chemotherapy | Group 2-SR-avg ALL, Arm III-combination Chemotherapy | Group 2-SR-avg ALL, Arm IV-combination Chemotherapy | Group 3-SR-high ALL, Combination Chemotherapy | |||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 790/1306 (60.5%) | 901/931 (96.8%) | 909/931 (97.6%) | 487/501 (97.2%) | 500/509 (98.2%) | 237/246 (96.3%) | 234/247 (94.7%) | 629/638 (98.6%) | ||||||||
| Blood and lymphatic system disorders | ||||||||||||||||
| Anemia | 86/1306 (6.6%) | 88 | 258/931 (27.7%) | 438 | 232/931 (24.9%) | 356 | 119/501 (23.8%) | 183 | 127/509 (25%) | 213 | 55/246 (22.4%) | 113 | 90/247 (36.4%) | 150 | 213/638 (33.4%) | 466 |
| Blood and lymphatic system disorders - Other, specify | 2/1306 (0.2%) | 2 | 8/931 (0.9%) | 16 | 6/931 (0.6%) | 8 | 1/501 (0.2%) | 1 | 4/509 (0.8%) | 5 | 2/246 (0.8%) | 2 | 1/247 (0.4%) | 1 | 9/638 (1.4%) | 9 |
| Bone marrow hypocellular | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 2 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Disseminated intravascular coagulation | 2/1306 (0.2%) | 2 | 6/931 (0.6%) | 7 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Febrile neutropenia | 130/1306 (10%) | 131 | 531/931 (57%) | 1045 | 555/931 (59.6%) | 1045 | 272/501 (54.3%) | 513 | 330/509 (64.8%) | 733 | 144/246 (58.5%) | 259 | 150/247 (60.7%) | 316 | 475/638 (74.5%) | 1260 |
| Hemolysis | 2/1306 (0.2%) | 2 | 6/931 (0.6%) | 6 | 3/931 (0.3%) | 3 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Hemolytic uremic syndrome | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Leukocytosis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Spleen disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Cardiac disorders | ||||||||||||||||
| Cardiac arrest | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Cardiac disorders - Other, specify | 3/1306 (0.2%) | 3 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Conduction disorder | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Left ventricular systolic dysfunction | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 2/931 (0.2%) | 3 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 4/638 (0.6%) | 4 |
| Mobitz (type) II atrioventricular block | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Myocarditis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Pericardial effusion | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 2 |
| Sinus bradycardia | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Sinus tachycardia | 1/1306 (0.1%) | 1 | 4/931 (0.4%) | 4 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 3 |
| Supraventricular tachycardia | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Ventricular arrhythmia | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Ventricular tachycardia | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Wolff-Parkinson-White syndrome | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Ear and labyrinth disorders | ||||||||||||||||
| Ear and labyrinth disorders - Other, specify | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 3 |
| Ear pain | 0/1306 (0%) | 0 | 2/931 (0.2%) | 4 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 2/509 (0.4%) | 2 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| External ear inflammation | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| External ear pain | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hearing impaired | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Middle ear inflammation | 2/1306 (0.2%) | 2 | 8/931 (0.9%) | 8 | 6/931 (0.6%) | 7 | 4/501 (0.8%) | 4 | 2/509 (0.4%) | 2 | 3/246 (1.2%) | 8 | 5/247 (2%) | 5 | 7/638 (1.1%) | 14 |
| Endocrine disorders | ||||||||||||||||
| Adrenal insufficiency | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 3/501 (0.6%) | 4 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Endocrine disorders - Other, specify | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Eye disorders | ||||||||||||||||
| Blurred vision | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Extraocular muscle paresis | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Eye disorders - Other, specify | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Eye pain | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Glaucoma | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Keratitis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Optic nerve disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Photophobia | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Retinal detachment | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Retinopathy | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Vitreous hemorrhage | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||||||||
| Abdominal distension | 7/1306 (0.5%) | 7 | 10/931 (1.1%) | 10 | 5/931 (0.5%) | 5 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 1/247 (0.4%) | 1 | 5/638 (0.8%) | 5 |
| Abdominal pain | 24/1306 (1.8%) | 24 | 32/931 (3.4%) | 38 | 27/931 (2.9%) | 32 | 27/501 (5.4%) | 32 | 24/509 (4.7%) | 29 | 7/246 (2.8%) | 10 | 15/247 (6.1%) | 19 | 36/638 (5.6%) | 42 |
| Anal mucositis | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 4/638 (0.6%) | 4 |
| Anal necrosis | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Anal pain | 2/1306 (0.2%) | 2 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Ascites | 2/1306 (0.2%) | 2 | 6/931 (0.6%) | 6 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 4/638 (0.6%) | 4 |
| Cecal hemorrhage | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Colitis | 5/1306 (0.4%) | 6 | 7/931 (0.8%) | 7 | 5/931 (0.5%) | 5 | 0/501 (0%) | 0 | 7/509 (1.4%) | 7 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 10/638 (1.6%) | 12 |
| Colonic fistula | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Colonic hemorrhage | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Colonic obstruction | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Colonic perforation | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Colonic ulcer | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Constipation | 12/1306 (0.9%) | 12 | 15/931 (1.6%) | 17 | 12/931 (1.3%) | 12 | 8/501 (1.6%) | 10 | 10/509 (2%) | 11 | 2/246 (0.8%) | 2 | 5/247 (2%) | 5 | 14/638 (2.2%) | 15 |
| Dental caries | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Diarrhea | 24/1306 (1.8%) | 24 | 82/931 (8.8%) | 91 | 63/931 (6.8%) | 67 | 47/501 (9.4%) | 56 | 44/509 (8.6%) | 49 | 17/246 (6.9%) | 20 | 26/247 (10.5%) | 28 | 68/638 (10.7%) | 88 |
| Duodenal hemorrhage | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Duodenal perforation | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Duodenal ulcer | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Dyspepsia | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Dysphagia | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 2/501 (0.4%) | 2 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 4/247 (1.6%) | 4 | 2/638 (0.3%) | 2 |
| Enterocolitis | 0/1306 (0%) | 0 | 4/931 (0.4%) | 4 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 2/509 (0.4%) | 2 | 2/246 (0.8%) | 2 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Esophageal obstruction | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Esophageal pain | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Esophageal stenosis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Esophageal ulcer | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Esophagitis | 0/1306 (0%) | 0 | 6/931 (0.6%) | 6 | 4/931 (0.4%) | 4 | 2/501 (0.4%) | 2 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 4/247 (1.6%) | 4 | 2/638 (0.3%) | 2 |
| Gastric fistula | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Gastric perforation | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Gastritis | 0/1306 (0%) | 0 | 7/931 (0.8%) | 7 | 4/931 (0.4%) | 4 | 1/501 (0.2%) | 1 | 5/509 (1%) | 5 | 2/246 (0.8%) | 2 | 1/247 (0.4%) | 1 | 9/638 (1.4%) | 10 |
| Gastrointestinal disorders - Other, specify | 3/1306 (0.2%) | 3 | 3/931 (0.3%) | 3 | 4/931 (0.4%) | 4 | 0/501 (0%) | 0 | 5/509 (1%) | 5 | 2/246 (0.8%) | 2 | 3/247 (1.2%) | 3 | 5/638 (0.8%) | 6 |
| Gastrointestinal fistula | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Gastrointestinal pain | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Gingival pain | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Ileal hemorrhage | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Ileal perforation | 3/1306 (0.2%) | 3 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Ileal ulcer | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Ileus | 10/1306 (0.8%) | 10 | 8/931 (0.9%) | 9 | 5/931 (0.5%) | 5 | 3/501 (0.6%) | 3 | 7/509 (1.4%) | 7 | 2/246 (0.8%) | 2 | 3/247 (1.2%) | 3 | 4/638 (0.6%) | 4 |
| Intra-abdominal hemorrhage | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Lip pain | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Lower gastrointestinal hemorrhage | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Malabsorption | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Mucositis oral | 9/1306 (0.7%) | 9 | 62/931 (6.7%) | 64 | 53/931 (5.7%) | 61 | 36/501 (7.2%) | 42 | 41/509 (8.1%) | 52 | 19/246 (7.7%) | 28 | 23/247 (9.3%) | 28 | 81/638 (12.7%) | 93 |
| Nausea | 6/1306 (0.5%) | 6 | 14/931 (1.5%) | 14 | 9/931 (1%) | 10 | 14/501 (2.8%) | 16 | 11/509 (2.2%) | 12 | 2/246 (0.8%) | 2 | 4/247 (1.6%) | 4 | 21/638 (3.3%) | 25 |
| Oral hemorrhage | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Oral pain | 3/1306 (0.2%) | 3 | 11/931 (1.2%) | 13 | 5/931 (0.5%) | 5 | 14/501 (2.8%) | 17 | 10/509 (2%) | 12 | 3/246 (1.2%) | 3 | 5/247 (2%) | 5 | 18/638 (2.8%) | 18 |
| Pancreatic hemorrhage | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Pancreatic necrosis | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Pancreatitis | 18/1306 (1.4%) | 19 | 6/931 (0.6%) | 7 | 2/931 (0.2%) | 3 | 5/501 (1%) | 6 | 9/509 (1.8%) | 12 | 3/246 (1.2%) | 3 | 5/247 (2%) | 7 | 20/638 (3.1%) | 28 |
| Proctitis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Rectal fistula | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Rectal hemorrhage | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Rectal mucositis | 0/1306 (0%) | 0 | 3/931 (0.3%) | 3 | 1/931 (0.1%) | 1 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Rectal pain | 1/1306 (0.1%) | 1 | 4/931 (0.4%) | 4 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 3/638 (0.5%) | 3 |
| Small intestinal mucositis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Small intestinal obstruction | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Small intestinal perforation | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Stomach pain | 3/1306 (0.2%) | 3 | 4/931 (0.4%) | 4 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 4/638 (0.6%) | 4 |
| Toothache | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Typhlitis | 6/1306 (0.5%) | 6 | 9/931 (1%) | 9 | 6/931 (0.6%) | 6 | 1/501 (0.2%) | 1 | 8/509 (1.6%) | 8 | 3/246 (1.2%) | 3 | 3/247 (1.2%) | 3 | 11/638 (1.7%) | 13 |
| Upper gastrointestinal hemorrhage | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Vomiting | 11/1306 (0.8%) | 11 | 48/931 (5.2%) | 53 | 37/931 (4%) | 42 | 36/501 (7.2%) | 47 | 33/509 (6.5%) | 40 | 19/246 (7.7%) | 24 | 18/247 (7.3%) | 19 | 52/638 (8.2%) | 65 |
| General disorders | ||||||||||||||||
| Chills | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Edema face | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Edema limbs | 0/1306 (0%) | 0 | 2/931 (0.2%) | 3 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Edema trunk | 3/1306 (0.2%) | 3 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 3/501 (0.6%) | 3 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 3/638 (0.5%) | 3 |
| Facial pain | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Fatigue | 4/1306 (0.3%) | 4 | 16/931 (1.7%) | 16 | 2/931 (0.2%) | 2 | 8/501 (1.6%) | 11 | 8/509 (1.6%) | 9 | 3/246 (1.2%) | 3 | 2/247 (0.8%) | 2 | 11/638 (1.7%) | 11 |
| Fever | 6/1306 (0.5%) | 6 | 84/931 (9%) | 104 | 108/931 (11.6%) | 128 | 49/501 (9.8%) | 58 | 53/509 (10.4%) | 66 | 36/246 (14.6%) | 45 | 20/247 (8.1%) | 23 | 71/638 (11.1%) | 84 |
| Flu like symptoms | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 4/931 (0.4%) | 4 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Gait disturbance | 2/1306 (0.2%) | 2 | 6/931 (0.6%) | 6 | 2/931 (0.2%) | 2 | 3/501 (0.6%) | 4 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 3/638 (0.5%) | 3 |
| General disorders and administration site conditions - Other, specify | 1/1306 (0.1%) | 1 | 5/931 (0.5%) | 6 | 9/931 (1%) | 13 | 4/501 (0.8%) | 4 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 3/247 (1.2%) | 3 | 7/638 (1.1%) | 7 |
| Hypothermia | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Injection site reaction | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Irritability | 2/1306 (0.2%) | 3 | 6/931 (0.6%) | 9 | 4/931 (0.4%) | 6 | 3/501 (0.6%) | 3 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 2 | 1/247 (0.4%) | 1 | 5/638 (0.8%) | 5 |
| Localized edema | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Multi-organ failure | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Non-cardiac chest pain | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Pain | 9/1306 (0.7%) | 9 | 14/931 (1.5%) | 14 | 14/931 (1.5%) | 14 | 2/501 (0.4%) | 2 | 7/509 (1.4%) | 8 | 8/246 (3.3%) | 9 | 2/247 (0.8%) | 2 | 19/638 (3%) | 26 |
| Hepatobiliary disorders | ||||||||||||||||
| Cholecystitis | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 2/931 (0.2%) | 2 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 2/247 (0.8%) | 2 | 0/638 (0%) | 0 |
| Gallbladder obstruction | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 2/247 (0.8%) | 2 | 1/638 (0.2%) | 1 |
| Gallbladder pain | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Hepatic failure | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 3/501 (0.6%) | 3 | 1/509 (0.2%) | 2 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Hepatic necrosis | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hepatic pain | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Hepatobiliary disorders - Other, specify | 1/1306 (0.1%) | 1 | 9/931 (1%) | 10 | 4/931 (0.4%) | 5 | 2/501 (0.4%) | 3 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 4/638 (0.6%) | 4 |
| Portal hypertension | 0/1306 (0%) | 0 | 10/931 (1.1%) | 10 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 8/638 (1.3%) | 8 |
| Immune system disorders | ||||||||||||||||
| Allergic reaction | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Anaphylaxis | 4/1306 (0.3%) | 4 | 76/931 (8.2%) | 83 | 9/931 (1%) | 9 | 5/501 (1%) | 5 | 62/509 (12.2%) | 66 | 31/246 (12.6%) | 32 | 32/247 (13%) | 35 | 92/638 (14.4%) | 102 |
| Autoimmune disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 1/638 (0.2%) | 2 |
| Immune system disorders - Other, specify | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 2/931 (0.2%) | 2 | 1/501 (0.2%) | 1 | 3/509 (0.6%) | 5 | 2/246 (0.8%) | 2 | 2/247 (0.8%) | 4 | 5/638 (0.8%) | 5 |
| Infections and infestations | ||||||||||||||||
| Abdominal infection | 2/1306 (0.2%) | 2 | 8/931 (0.9%) | 9 | 14/931 (1.5%) | 14 | 4/501 (0.8%) | 4 | 5/509 (1%) | 6 | 5/246 (2%) | 5 | 4/247 (1.6%) | 4 | 6/638 (0.9%) | 7 |
| Anorectal infection | 0/1306 (0%) | 0 | 9/931 (1%) | 9 | 2/931 (0.2%) | 2 | 4/501 (0.8%) | 4 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 4/638 (0.6%) | 4 |
| Appendicitis | 2/1306 (0.2%) | 2 | 4/931 (0.4%) | 4 | 4/931 (0.4%) | 5 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Appendicitis perforated | 2/1306 (0.2%) | 2 | 3/931 (0.3%) | 3 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Arteritis infective | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Bladder infection | 3/1306 (0.2%) | 3 | 10/931 (1.1%) | 10 | 10/931 (1.1%) | 12 | 8/501 (1.6%) | 14 | 4/509 (0.8%) | 4 | 5/246 (2%) | 6 | 4/247 (1.6%) | 5 | 12/638 (1.9%) | 19 |
| Bone infection | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 2/931 (0.2%) | 2 | 3/501 (0.6%) | 3 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 2 |
| Bronchial infection | 1/1306 (0.1%) | 1 | 13/931 (1.4%) | 13 | 13/931 (1.4%) | 14 | 8/501 (1.6%) | 9 | 6/509 (1.2%) | 7 | 2/246 (0.8%) | 2 | 3/247 (1.2%) | 3 | 4/638 (0.6%) | 5 |
| Catheter related infection | 8/1306 (0.6%) | 9 | 29/931 (3.1%) | 32 | 37/931 (4%) | 45 | 26/501 (5.2%) | 29 | 21/509 (4.1%) | 27 | 14/246 (5.7%) | 19 | 13/247 (5.3%) | 17 | 34/638 (5.3%) | 40 |
| Conjunctivitis infective | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 2/501 (0.4%) | 2 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Device related infection | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 3/931 (0.3%) | 5 | 2/501 (0.4%) | 2 | 1/509 (0.2%) | 1 | 2/246 (0.8%) | 2 | 0/247 (0%) | 0 | 2/638 (0.3%) | 5 |
| Encephalitis infection | 2/1306 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Encephalomyelitis infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Endocarditis infective | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Enterocolitis infectious | 12/1306 (0.9%) | 12 | 34/931 (3.7%) | 38 | 31/931 (3.3%) | 39 | 14/501 (2.8%) | 15 | 17/509 (3.3%) | 20 | 7/246 (2.8%) | 7 | 14/247 (5.7%) | 17 | 49/638 (7.7%) | 63 |
| Esophageal infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Eye infection | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 6/931 (0.6%) | 7 | 0/501 (0%) | 0 | 2/509 (0.4%) | 2 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Gum infection | 0/1306 (0%) | 0 | 8/931 (0.9%) | 8 | 3/931 (0.3%) | 3 | 2/501 (0.4%) | 2 | 3/509 (0.6%) | 3 | 1/246 (0.4%) | 1 | 3/247 (1.2%) | 3 | 7/638 (1.1%) | 8 |
| Hepatic infection | 2/1306 (0.2%) | 2 | 0/931 (0%) | 0 | 2/931 (0.2%) | 3 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hepatitis viral | 0/1306 (0%) | 0 | 3/931 (0.3%) | 3 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Infections and infestations - Other, specify | 227/1306 (17.4%) | 312 | 489/931 (52.5%) | 962 | 463/931 (49.7%) | 906 | 249/501 (49.7%) | 467 | 298/509 (58.5%) | 643 | 134/246 (54.5%) | 298 | 142/247 (57.5%) | 341 | 434/638 (68%) | 1120 |
| Infective myositis | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Joint infection | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Kidney infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 2/931 (0.2%) | 3 | 4/501 (0.8%) | 4 | 3/509 (0.6%) | 3 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Laryngitis | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Lip infection | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 4/931 (0.4%) | 4 | 3/501 (0.6%) | 3 | 3/509 (0.6%) | 3 | 2/246 (0.8%) | 2 | 3/247 (1.2%) | 3 | 3/638 (0.5%) | 3 |
| Lung infection | 4/1306 (0.3%) | 4 | 74/931 (7.9%) | 91 | 89/931 (9.6%) | 103 | 53/501 (10.6%) | 63 | 53/509 (10.4%) | 59 | 28/246 (11.4%) | 37 | 18/247 (7.3%) | 19 | 73/638 (11.4%) | 92 |
| Lymph gland infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Meningitis | 3/1306 (0.2%) | 3 | 2/931 (0.2%) | 2 | 4/931 (0.4%) | 4 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 2/246 (0.8%) | 2 | 0/247 (0%) | 0 | 5/638 (0.8%) | 5 |
| Mucosal infection | 1/1306 (0.1%) | 1 | 5/931 (0.5%) | 5 | 6/931 (0.6%) | 6 | 4/501 (0.8%) | 4 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 3 |
| Nail infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 2/931 (0.2%) | 2 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Otitis externa | 0/1306 (0%) | 0 | 4/931 (0.4%) | 4 | 1/931 (0.1%) | 1 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 2/246 (0.8%) | 3 | 2/247 (0.8%) | 2 | 2/638 (0.3%) | 2 |
| Otitis media | 0/1306 (0%) | 0 | 41/931 (4.4%) | 50 | 48/931 (5.2%) | 53 | 22/501 (4.4%) | 27 | 25/509 (4.9%) | 27 | 6/246 (2.4%) | 7 | 14/247 (5.7%) | 16 | 44/638 (6.9%) | 52 |
| Papulopustular rash | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Paronychia | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Penile infection | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Peripheral nerve infection | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Peritoneal infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Pharyngitis | 0/1306 (0%) | 0 | 14/931 (1.5%) | 14 | 6/931 (0.6%) | 7 | 9/501 (1.8%) | 9 | 2/509 (0.4%) | 4 | 1/246 (0.4%) | 1 | 4/247 (1.6%) | 5 | 4/638 (0.6%) | 4 |
| Pleural infection | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 2 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Rash pustular | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Salivary gland infection | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 5/509 (1%) | 5 | 2/246 (0.8%) | 2 | 1/247 (0.4%) | 1 | 3/638 (0.5%) | 3 |
| Sepsis | 1/1306 (0.1%) | 1 | 4/931 (0.4%) | 5 | 7/931 (0.8%) | 7 | 4/501 (0.8%) | 4 | 2/509 (0.4%) | 2 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 11/638 (1.7%) | 11 |
| Sinusitis | 0/1306 (0%) | 0 | 44/931 (4.7%) | 51 | 38/931 (4.1%) | 46 | 19/501 (3.8%) | 26 | 26/509 (5.1%) | 29 | 5/246 (2%) | 8 | 8/247 (3.2%) | 8 | 20/638 (3.1%) | 22 |
| Skin infection | 8/1306 (0.6%) | 9 | 32/931 (3.4%) | 36 | 37/931 (4%) | 40 | 22/501 (4.4%) | 24 | 28/509 (5.5%) | 33 | 7/246 (2.8%) | 7 | 7/247 (2.8%) | 8 | 37/638 (5.8%) | 43 |
| Small intestine infection | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 5/931 (0.5%) | 5 | 3/501 (0.6%) | 3 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 3/247 (1.2%) | 3 | 2/638 (0.3%) | 2 |
| Soft tissue infection | 2/1306 (0.2%) | 2 | 5/931 (0.5%) | 6 | 3/931 (0.3%) | 3 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 2/246 (0.8%) | 2 | 0/247 (0%) | 0 | 4/638 (0.6%) | 4 |
| Splenic infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 2 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Tooth infection | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 5/931 (0.5%) | 5 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Tracheitis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Upper respiratory infection | 5/1306 (0.4%) | 5 | 82/931 (8.8%) | 107 | 94/931 (10.1%) | 118 | 59/501 (11.8%) | 69 | 61/509 (12%) | 83 | 17/246 (6.9%) | 24 | 15/247 (6.1%) | 18 | 86/638 (13.5%) | 107 |
| Urethral infection | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Urinary tract infection | 4/1306 (0.3%) | 6 | 31/931 (3.3%) | 34 | 19/931 (2%) | 24 | 22/501 (4.4%) | 30 | 17/509 (3.3%) | 21 | 8/246 (3.3%) | 8 | 8/247 (3.2%) | 11 | 26/638 (4.1%) | 31 |
| Vaginal infection | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Vulval infection | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Wound infection | 3/1306 (0.2%) | 3 | 14/931 (1.5%) | 14 | 6/931 (0.6%) | 6 | 5/501 (1%) | 6 | 9/509 (1.8%) | 10 | 3/246 (1.2%) | 3 | 2/247 (0.8%) | 2 | 11/638 (1.7%) | 11 |
| Injury, poisoning and procedural complications | ||||||||||||||||
| Fall | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Fracture | 1/1306 (0.1%) | 1 | 3/931 (0.3%) | 3 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 4/246 (1.6%) | 4 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Injury, poisoning and procedural complications - Other, specify | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 4/931 (0.4%) | 4 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Intraoperative gastrointestinal injury | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Intraoperative ocular injury | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Intraoperative respiratory injury | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Intraoperative venous injury | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Postoperative hemorrhage | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Prolapse of intestinal stoma | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Spinal fracture | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Vascular access complication | 8/1306 (0.6%) | 8 | 7/931 (0.8%) | 9 | 9/931 (1%) | 13 | 5/501 (1%) | 5 | 3/509 (0.6%) | 3 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 7/638 (1.1%) | 7 |
| Venous injury | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Wound complication | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Wound dehiscence | 2/1306 (0.2%) | 2 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Investigations | ||||||||||||||||
| Activated partial thromboplastin time prolonged | 17/1306 (1.3%) | 17 | 23/931 (2.5%) | 24 | 6/931 (0.6%) | 6 | 9/501 (1.8%) | 12 | 8/509 (1.6%) | 9 | 5/246 (2%) | 5 | 2/247 (0.8%) | 4 | 23/638 (3.6%) | 31 |
| Alanine aminotransferase increased | 174/1306 (13.3%) | 177 | 453/931 (48.7%) | 1316 | 443/931 (47.6%) | 1235 | 207/501 (41.3%) | 500 | 250/509 (49.1%) | 689 | 123/246 (50%) | 362 | 107/247 (43.3%) | 372 | 310/638 (48.6%) | 1009 |
| Alkaline phosphatase increased | 0/1306 (0%) | 0 | 5/931 (0.5%) | 6 | 9/931 (1%) | 10 | 11/501 (2.2%) | 12 | 3/509 (0.6%) | 3 | 1/246 (0.4%) | 1 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 3 |
| Aspartate aminotransferase increased | 59/1306 (4.5%) | 60 | 220/931 (23.6%) | 335 | 188/931 (20.2%) | 278 | 89/501 (17.8%) | 133 | 91/509 (17.9%) | 137 | 54/246 (22%) | 82 | 58/247 (23.5%) | 98 | 164/638 (25.7%) | 288 |
| Blood bilirubin increased | 20/1306 (1.5%) | 20 | 77/931 (8.3%) | 90 | 53/931 (5.7%) | 89 | 28/501 (5.6%) | 42 | 30/509 (5.9%) | 42 | 26/246 (10.6%) | 34 | 16/247 (6.5%) | 19 | 43/638 (6.7%) | 52 |
| CPK increased | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Cholesterol high | 3/1306 (0.2%) | 3 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Creatinine increased | 7/1306 (0.5%) | 7 | 2/931 (0.2%) | 2 | 4/931 (0.4%) | 4 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Electrocardiogram QT corrected interval prolonged | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Fibrinogen decreased | 50/1306 (3.8%) | 50 | 41/931 (4.4%) | 58 | 40/931 (4.3%) | 48 | 31/501 (6.2%) | 35 | 24/509 (4.7%) | 28 | 17/246 (6.9%) | 23 | 12/247 (4.9%) | 17 | 29/638 (4.5%) | 36 |
| GGT increased | 28/1306 (2.1%) | 29 | 49/931 (5.3%) | 79 | 21/931 (2.3%) | 22 | 10/501 (2%) | 13 | 17/509 (3.3%) | 26 | 10/246 (4.1%) | 13 | 12/247 (4.9%) | 17 | 27/638 (4.2%) | 45 |
| INR increased | 5/1306 (0.4%) | 5 | 0/931 (0%) | 0 | 3/931 (0.3%) | 3 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Investigations - Other, specify | 4/1306 (0.3%) | 4 | 8/931 (0.9%) | 10 | 9/931 (1%) | 11 | 12/501 (2.4%) | 15 | 6/509 (1.2%) | 9 | 3/246 (1.2%) | 3 | 0/247 (0%) | 0 | 12/638 (1.9%) | 17 |
| Lipase increased | 28/1306 (2.1%) | 29 | 38/931 (4.1%) | 43 | 7/931 (0.8%) | 10 | 8/501 (1.6%) | 9 | 10/509 (2%) | 15 | 5/246 (2%) | 5 | 14/247 (5.7%) | 17 | 28/638 (4.4%) | 42 |
| Lymphocyte count decreased | 8/1306 (0.6%) | 9 | 56/931 (6%) | 94 | 72/931 (7.7%) | 117 | 24/501 (4.8%) | 39 | 43/509 (8.4%) | 95 | 14/246 (5.7%) | 24 | 23/247 (9.3%) | 50 | 46/638 (7.2%) | 118 |
| Neutrophil count decreased | 166/1306 (12.7%) | 172 | 708/931 (76%) | 2226 | 727/931 (78.1%) | 2182 | 375/501 (74.9%) | 1101 | 429/509 (84.3%) | 1457 | 184/246 (74.8%) | 620 | 201/247 (81.4%) | 731 | 570/638 (89.3%) | 2396 |
| Platelet count decreased | 108/1306 (8.3%) | 111 | 262/931 (28.1%) | 405 | 199/931 (21.4%) | 297 | 108/501 (21.6%) | 143 | 151/509 (29.7%) | 236 | 62/246 (25.2%) | 89 | 79/247 (32%) | 142 | 274/638 (42.9%) | 567 |
| Serum amylase increased | 17/1306 (1.3%) | 17 | 17/931 (1.8%) | 19 | 6/931 (0.6%) | 7 | 5/501 (1%) | 5 | 7/509 (1.4%) | 11 | 4/246 (1.6%) | 4 | 4/247 (1.6%) | 5 | 20/638 (3.1%) | 24 |
| Weight gain | 9/1306 (0.7%) | 9 | 17/931 (1.8%) | 18 | 16/931 (1.7%) | 18 | 10/501 (2%) | 12 | 5/509 (1%) | 7 | 5/246 (2%) | 5 | 3/247 (1.2%) | 3 | 20/638 (3.1%) | 22 |
| Weight loss | 7/1306 (0.5%) | 7 | 11/931 (1.2%) | 12 | 7/931 (0.8%) | 8 | 6/501 (1.2%) | 10 | 5/509 (1%) | 5 | 4/246 (1.6%) | 4 | 5/247 (2%) | 5 | 16/638 (2.5%) | 17 |
| White blood cell decreased | 106/1306 (8.1%) | 110 | 304/931 (32.7%) | 765 | 345/931 (37.1%) | 903 | 160/501 (31.9%) | 354 | 188/509 (36.9%) | 547 | 89/246 (36.2%) | 235 | 113/247 (45.7%) | 337 | 268/638 (42%) | 927 |
| Metabolism and nutrition disorders | ||||||||||||||||
| Acidosis | 4/1306 (0.3%) | 4 | 5/931 (0.5%) | 5 | 4/931 (0.4%) | 4 | 2/501 (0.4%) | 2 | 5/509 (1%) | 6 | 2/246 (0.8%) | 2 | 1/247 (0.4%) | 1 | 6/638 (0.9%) | 6 |
| Alkalosis | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Anorexia | 16/1306 (1.2%) | 16 | 42/931 (4.5%) | 51 | 35/931 (3.8%) | 51 | 23/501 (4.6%) | 41 | 30/509 (5.9%) | 37 | 7/246 (2.8%) | 8 | 22/247 (8.9%) | 26 | 67/638 (10.5%) | 91 |
| Dehydration | 19/1306 (1.5%) | 19 | 54/931 (5.8%) | 67 | 51/931 (5.5%) | 62 | 33/501 (6.6%) | 38 | 45/509 (8.8%) | 55 | 16/246 (6.5%) | 17 | 21/247 (8.5%) | 26 | 83/638 (13%) | 105 |
| Glucose intolerance | 7/1306 (0.5%) | 7 | 4/931 (0.4%) | 5 | 3/931 (0.3%) | 4 | 2/501 (0.4%) | 2 | 6/509 (1.2%) | 6 | 3/246 (1.2%) | 6 | 0/247 (0%) | 0 | 9/638 (1.4%) | 13 |
| Hypercalcemia | 5/1306 (0.4%) | 5 | 5/931 (0.5%) | 5 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 4/638 (0.6%) | 5 |
| Hyperglycemia | 77/1306 (5.9%) | 77 | 52/931 (5.6%) | 57 | 45/931 (4.8%) | 50 | 44/501 (8.8%) | 52 | 37/509 (7.3%) | 44 | 21/246 (8.5%) | 27 | 18/247 (7.3%) | 21 | 71/638 (11.1%) | 102 |
| Hyperkalemia | 22/1306 (1.7%) | 22 | 19/931 (2%) | 19 | 17/931 (1.8%) | 19 | 5/501 (1%) | 5 | 13/509 (2.6%) | 15 | 4/246 (1.6%) | 4 | 4/247 (1.6%) | 4 | 25/638 (3.9%) | 26 |
| Hypermagnesemia | 2/1306 (0.2%) | 2 | 4/931 (0.4%) | 4 | 2/931 (0.2%) | 2 | 7/501 (1.4%) | 7 | 1/509 (0.2%) | 1 | 2/246 (0.8%) | 2 | 2/247 (0.8%) | 2 | 2/638 (0.3%) | 2 |
| Hypernatremia | 0/1306 (0%) | 0 | 4/931 (0.4%) | 4 | 2/931 (0.2%) | 2 | 1/501 (0.2%) | 1 | 4/509 (0.8%) | 4 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 3/638 (0.5%) | 3 |
| Hypertriglyceridemia | 8/1306 (0.6%) | 8 | 8/931 (0.9%) | 9 | 2/931 (0.2%) | 2 | 6/501 (1.2%) | 6 | 2/509 (0.4%) | 2 | 1/246 (0.4%) | 1 | 3/247 (1.2%) | 3 | 7/638 (1.1%) | 8 |
| Hyperuricemia | 6/1306 (0.5%) | 6 | 3/931 (0.3%) | 3 | 3/931 (0.3%) | 3 | 3/501 (0.6%) | 3 | 1/509 (0.2%) | 1 | 2/246 (0.8%) | 2 | 1/247 (0.4%) | 1 | 4/638 (0.6%) | 4 |
| Hypoalbuminemia | 26/1306 (2%) | 26 | 66/931 (7.1%) | 75 | 34/931 (3.7%) | 37 | 17/501 (3.4%) | 17 | 13/509 (2.6%) | 15 | 10/246 (4.1%) | 10 | 12/247 (4.9%) | 12 | 41/638 (6.4%) | 52 |
| Hypocalcemia | 38/1306 (2.9%) | 38 | 35/931 (3.8%) | 36 | 34/931 (3.7%) | 35 | 25/501 (5%) | 25 | 14/509 (2.8%) | 15 | 11/246 (4.5%) | 11 | 13/247 (5.3%) | 14 | 38/638 (6%) | 40 |
| Hypoglycemia | 4/1306 (0.3%) | 4 | 61/931 (6.6%) | 73 | 16/931 (1.7%) | 19 | 17/501 (3.4%) | 21 | 7/509 (1.4%) | 8 | 13/246 (5.3%) | 16 | 10/247 (4%) | 10 | 40/638 (6.3%) | 47 |
| Hypokalemia | 70/1306 (5.4%) | 70 | 107/931 (11.5%) | 127 | 115/931 (12.4%) | 135 | 53/501 (10.6%) | 70 | 64/509 (12.6%) | 80 | 35/246 (14.2%) | 49 | 30/247 (12.1%) | 40 | 138/638 (21.6%) | 191 |
| Hypomagnesemia | 3/1306 (0.2%) | 3 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 2/501 (0.4%) | 2 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Hyponatremia | 77/1306 (5.9%) | 78 | 75/931 (8.1%) | 90 | 62/931 (6.7%) | 68 | 41/501 (8.2%) | 43 | 42/509 (8.3%) | 47 | 19/246 (7.7%) | 20 | 18/247 (7.3%) | 20 | 66/638 (10.3%) | 80 |
| Hypophosphatemia | 20/1306 (1.5%) | 20 | 13/931 (1.4%) | 13 | 21/931 (2.3%) | 21 | 12/501 (2.4%) | 12 | 7/509 (1.4%) | 7 | 4/246 (1.6%) | 4 | 4/247 (1.6%) | 4 | 20/638 (3.1%) | 20 |
| Metabolism and nutrition disorders - Other, specify | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Obesity | 0/1306 (0%) | 0 | 2/931 (0.2%) | 3 | 0/931 (0%) | 0 | 3/501 (0.6%) | 5 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Tumor lysis syndrome | 14/1306 (1.1%) | 14 | 3/931 (0.3%) | 3 | 2/931 (0.2%) | 2 | 4/501 (0.8%) | 4 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||||
| Arthralgia | 4/1306 (0.3%) | 4 | 8/931 (0.9%) | 8 | 0/931 (0%) | 0 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 3/246 (1.2%) | 4 | 0/247 (0%) | 0 | 4/638 (0.6%) | 4 |
| Arthritis | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 2/246 (0.8%) | 2 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Avascular necrosis | 0/1306 (0%) | 0 | 7/931 (0.8%) | 11 | 3/931 (0.3%) | 3 | 2/501 (0.4%) | 5 | 3/509 (0.6%) | 4 | 1/246 (0.4%) | 1 | 1/247 (0.4%) | 2 | 8/638 (1.3%) | 11 |
| Back pain | 8/1306 (0.6%) | 8 | 11/931 (1.2%) | 12 | 12/931 (1.3%) | 12 | 15/501 (3%) | 17 | 6/509 (1.2%) | 6 | 2/246 (0.8%) | 2 | 5/247 (2%) | 6 | 18/638 (2.8%) | 19 |
| Bone pain | 5/1306 (0.4%) | 5 | 10/931 (1.1%) | 11 | 6/931 (0.6%) | 6 | 1/501 (0.2%) | 3 | 8/509 (1.6%) | 8 | 4/246 (1.6%) | 4 | 3/247 (1.2%) | 3 | 8/638 (1.3%) | 8 |
| Buttock pain | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Chest wall pain | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 2 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Generalized muscle weakness | 2/1306 (0.2%) | 2 | 5/931 (0.5%) | 6 | 5/931 (0.5%) | 5 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 2/246 (0.8%) | 2 | 0/247 (0%) | 0 | 3/638 (0.5%) | 3 |
| Joint effusion | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Muscle weakness lower limb | 16/1306 (1.2%) | 16 | 9/931 (1%) | 10 | 7/931 (0.8%) | 7 | 5/501 (1%) | 6 | 7/509 (1.4%) | 7 | 2/246 (0.8%) | 3 | 2/247 (0.8%) | 3 | 12/638 (1.9%) | 12 |
| Muscle weakness right-sided | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Muscle weakness trunk | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Muscle weakness upper limb | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Musculoskeletal and connective tissue disorder - Other, specify | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 3/638 (0.5%) | 3 |
| Myalgia | 3/1306 (0.2%) | 3 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Myositis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 1/247 (0.4%) | 1 | 4/638 (0.6%) | 4 |
| Neck pain | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 2/931 (0.2%) | 2 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Osteoporosis | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 4/509 (0.8%) | 4 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 6/638 (0.9%) | 7 |
| Pain in extremity | 14/1306 (1.1%) | 14 | 34/931 (3.7%) | 38 | 22/931 (2.4%) | 25 | 14/501 (2.8%) | 16 | 18/509 (3.5%) | 25 | 4/246 (1.6%) | 5 | 4/247 (1.6%) | 5 | 24/638 (3.8%) | 32 |
| Soft tissue necrosis lower limb | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Soft tissue necrosis upper limb | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||
| Myelodysplastic syndrome | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Treatment related secondary malignancy | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Tumor pain | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Nervous system disorders | ||||||||||||||||
| Abducens nerve disorder | 0/1306 (0%) | 0 | 2/931 (0.2%) | 3 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Arachnoiditis | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Ataxia | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 6/638 (0.9%) | 6 |
| Cerebrospinal fluid leakage | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 2/501 (0.4%) | 2 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Cognitive disturbance | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| Depressed level of consciousness | 3/1306 (0.2%) | 3 | 3/931 (0.3%) | 3 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 3/509 (0.6%) | 3 | 1/246 (0.4%) | 1 | 2/247 (0.8%) | 2 | 3/638 (0.5%) | 3 |
| Dizziness | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 2/931 (0.2%) | 2 | 1/501 (0.2%) | 1 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Dysphasia | 1/1306 (0.1%) | 1 | 5/931 (0.5%) | 5 | 3/931 (0.3%) | 3 | 2/501 (0.4%) | 3 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Encephalopathy | 5/1306 (0.4%) | 5 | 6/931 (0.6%) | 7 | 7/931 (0.8%) | 7 | 1/501 (0.2%) | 1 | 6/509 (1.2%) | 6 | 2/246 (0.8%) | 2 | 1/247 (0.4%) | 1 | 16/638 (2.5%) | 19 |
| Extrapyramidal disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Facial muscle weakness | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Facial nerve disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 2/501 (0.4%) | 2 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Headache | 10/1306 (0.8%) | 10 | 16/931 (1.7%) | 19 | 21/931 (2.3%) | 24 | 11/501 (2.2%) | 17 | 23/509 (4.5%) | 26 | 6/246 (2.4%) | 6 | 4/247 (1.6%) | 7 | 19/638 (3%) | 30 |
| Hydrocephalus | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Hypoglossal nerve disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 1/638 (0.2%) | 1 |
| IVth nerve disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Intracranial hemorrhage | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 3/638 (0.5%) | 3 |
| Ischemia cerebrovascular | 3/1306 (0.2%) | 3 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Leukoencephalopathy | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 1/247 (0.4%) | 1 | 4/638 (0.6%) | 4 |
| Memory impairment | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Nervous system disorders - Other, specify | 8/1306 (0.6%) | 8 | 3/931 (0.3%) | 3 | 4/931 (0.4%) | 4 | 2/501 (0.4%) | 2 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 10/638 (1.6%) | 10 |
| Neuralgia | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 4/931 (0.4%) | 5 | 0/501 (0%) | 0 | 4/509 (0.8%) | 8 | 1/246 (0.4%) | 1 | 2/247 (0.8%) | 2 | 4/638 (0.6%) | 5 |
| Oculomotor nerve disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Peripheral motor neuropathy | 38/1306 (2.9%) | 38 | 68/931 (7.3%) | 105 | 52/931 (5.6%) | 89 | 43/501 (8.6%) | 76 | 39/509 (7.7%) | 64 | 27/246 (11%) | 46 | 22/247 (8.9%) | 41 | 79/638 (12.4%) | 141 |
| Peripheral sensory neuropathy | 29/1306 (2.2%) | 29 | 57/931 (6.1%) | 94 | 41/931 (4.4%) | 78 | 20/501 (4%) | 42 | 38/509 (7.5%) | 56 | 21/246 (8.5%) | 29 | 9/247 (3.6%) | 14 | 54/638 (8.5%) | 85 |
| Recurrent laryngeal nerve palsy | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Seizure | 12/1306 (0.9%) | 12 | 9/931 (1%) | 9 | 11/931 (1.2%) | 12 | 5/501 (1%) | 5 | 13/509 (2.6%) | 16 | 4/246 (1.6%) | 5 | 7/247 (2.8%) | 7 | 20/638 (3.1%) | 24 |
| Sinus pain | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Somnolence | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Syncope | 0/1306 (0%) | 0 | 3/931 (0.3%) | 4 | 2/931 (0.2%) | 2 | 2/501 (0.4%) | 2 | 5/509 (1%) | 5 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 3/638 (0.5%) | 4 |
| Tremor | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Trigeminal nerve disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 3/246 (1.2%) | 3 | 1/247 (0.4%) | 2 | 1/638 (0.2%) | 1 |
| Vagus nerve disorder | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Vasovagal reaction | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Psychiatric disorders | ||||||||||||||||
| Agitation | 7/1306 (0.5%) | 7 | 8/931 (0.9%) | 11 | 10/931 (1.1%) | 10 | 6/501 (1.2%) | 6 | 6/509 (1.2%) | 6 | 0/246 (0%) | 0 | 2/247 (0.8%) | 2 | 8/638 (1.3%) | 8 |
| Anxiety | 0/1306 (0%) | 0 | 3/931 (0.3%) | 4 | 2/931 (0.2%) | 2 | 3/501 (0.6%) | 3 | 2/509 (0.4%) | 3 | 1/246 (0.4%) | 1 | 3/247 (1.2%) | 3 | 2/638 (0.3%) | 5 |
| Confusion | 2/1306 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 6/509 (1.2%) | 6 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 5/638 (0.8%) | 5 |
| Depression | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 3/931 (0.3%) | 3 | 0/501 (0%) | 0 | 3/509 (0.6%) | 3 | 1/246 (0.4%) | 1 | 3/247 (1.2%) | 5 | 1/638 (0.2%) | 1 |
| Insomnia | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 3/931 (0.3%) | 3 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Personality change | 0/1306 (0%) | 0 | 6/931 (0.6%) | 10 | 8/931 (0.9%) | 11 | 4/501 (0.8%) | 4 | 5/509 (1%) | 7 | 1/246 (0.4%) | 1 | 3/247 (1.2%) | 3 | 6/638 (0.9%) | 7 |
| Psychiatric disorders - Other, specify | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Psychosis | 2/1306 (0.2%) | 2 | 10/931 (1.1%) | 11 | 5/931 (0.5%) | 8 | 0/501 (0%) | 0 | 3/509 (0.6%) | 3 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 5/638 (0.8%) | 5 |
| Suicidal ideation | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||||||
| Acute kidney injury | 7/1306 (0.5%) | 7 | 1/931 (0.1%) | 1 | 3/931 (0.3%) | 3 | 3/501 (0.6%) | 3 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 2/247 (0.8%) | 2 | 2/638 (0.3%) | 2 |
| Bladder spasm | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Cystitis noninfective | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Hematuria | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Proteinuria | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 2 |
| Renal and urinary disorders - Other, specify | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 3/931 (0.3%) | 4 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 3/246 (1.2%) | 3 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Renal calculi | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Renal colic | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Renal hemorrhage | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Urinary retention | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 3/931 (0.3%) | 3 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 2/247 (0.8%) | 4 | 2/638 (0.3%) | 2 |
| Urinary tract obstruction | 4/1306 (0.3%) | 4 | 6/931 (0.6%) | 9 | 3/931 (0.3%) | 3 | 1/501 (0.2%) | 1 | 2/509 (0.4%) | 3 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 4/638 (0.6%) | 4 |
| Urinary tract pain | 0/1306 (0%) | 0 | 2/931 (0.2%) | 3 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 2 | 1/246 (0.4%) | 1 | 3/247 (1.2%) | 3 | 0/638 (0%) | 0 |
| Reproductive system and breast disorders | ||||||||||||||||
| Pelvic pain | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 1/638 (0.2%) | 2 |
| Penile pain | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Scrotal pain | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Testicular pain | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||
| Adult respiratory distress syndrome | 0/1306 (0%) | 0 | 8/931 (0.9%) | 9 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 2/509 (0.4%) | 2 | 1/246 (0.4%) | 4 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Apnea | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 2/509 (0.4%) | 2 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 2/638 (0.3%) | 3 |
| Aspiration | 0/1306 (0%) | 0 | 3/931 (0.3%) | 4 | 2/931 (0.2%) | 2 | 1/501 (0.2%) | 1 | 2/509 (0.4%) | 2 | 2/246 (0.8%) | 2 | 3/247 (1.2%) | 3 | 4/638 (0.6%) | 4 |
| Atelectasis | 2/1306 (0.2%) | 2 | 1/931 (0.1%) | 1 | 2/931 (0.2%) | 2 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Bronchial obstruction | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 2 | 3/931 (0.3%) | 3 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Bronchopulmonary hemorrhage | 2/1306 (0.2%) | 2 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Bronchospasm | 2/1306 (0.2%) | 2 | 11/931 (1.2%) | 11 | 9/931 (1%) | 12 | 5/501 (1%) | 7 | 5/509 (1%) | 5 | 6/246 (2.4%) | 7 | 3/247 (1.2%) | 4 | 2/638 (0.3%) | 3 |
| Cough | 1/1306 (0.1%) | 1 | 13/931 (1.4%) | 13 | 16/931 (1.7%) | 16 | 10/501 (2%) | 14 | 10/509 (2%) | 11 | 2/246 (0.8%) | 2 | 2/247 (0.8%) | 2 | 9/638 (1.4%) | 9 |
| Dyspnea | 0/1306 (0%) | 0 | 4/931 (0.4%) | 4 | 5/931 (0.5%) | 5 | 5/501 (1%) | 7 | 5/509 (1%) | 7 | 1/246 (0.4%) | 1 | 3/247 (1.2%) | 3 | 6/638 (0.9%) | 6 |
| Epistaxis | 0/1306 (0%) | 0 | 4/931 (0.4%) | 4 | 3/931 (0.3%) | 4 | 2/501 (0.4%) | 2 | 2/509 (0.4%) | 3 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 9/638 (1.4%) | 10 |
| Hypoxia | 15/1306 (1.1%) | 15 | 30/931 (3.2%) | 32 | 25/931 (2.7%) | 26 | 11/501 (2.2%) | 14 | 14/509 (2.8%) | 14 | 9/246 (3.7%) | 14 | 10/247 (4%) | 10 | 28/638 (4.4%) | 34 |
| Laryngeal edema | 1/1306 (0.1%) | 1 | 2/931 (0.2%) | 2 | 4/931 (0.4%) | 4 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Laryngeal mucositis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Laryngeal obstruction | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Pharyngeal mucositis | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Pharyngeal stenosis | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Pharyngolaryngeal pain | 0/1306 (0%) | 0 | 4/931 (0.4%) | 4 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Pleural effusion | 9/1306 (0.7%) | 9 | 13/931 (1.4%) | 13 | 4/931 (0.4%) | 4 | 4/501 (0.8%) | 4 | 5/509 (1%) | 5 | 0/246 (0%) | 0 | 4/247 (1.6%) | 5 | 9/638 (1.4%) | 9 |
| Pneumonitis | 6/1306 (0.5%) | 6 | 21/931 (2.3%) | 23 | 20/931 (2.1%) | 21 | 7/501 (1.4%) | 8 | 10/509 (2%) | 10 | 4/246 (1.6%) | 6 | 5/247 (2%) | 6 | 22/638 (3.4%) | 24 |
| Pneumothorax | 2/1306 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Pulmonary edema | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Pulmonary hypertension | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Respiratory failure | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 3/931 (0.3%) | 3 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders - Other, specify | 0/1306 (0%) | 0 | 8/931 (0.9%) | 8 | 15/931 (1.6%) | 16 | 8/501 (1.6%) | 8 | 1/509 (0.2%) | 1 | 2/246 (0.8%) | 2 | 0/247 (0%) | 0 | 11/638 (1.7%) | 12 |
| Sinus disorder | 0/1306 (0%) | 0 | 2/931 (0.2%) | 2 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Sore throat | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Stridor | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Tracheal fistula | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Voice alteration | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 0/638 (0%) | 0 |
| Wheezing | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 3/509 (0.6%) | 3 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Skin and subcutaneous tissue disorders | ||||||||||||||||
| Dry skin | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Erythema multiforme | 1/1306 (0.1%) | 1 | 1/931 (0.1%) | 1 | 2/931 (0.2%) | 3 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 2/638 (0.3%) | 2 |
| Pain of skin | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 1/501 (0.2%) | 1 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Palmar-plantar erythrodysesthesia syndrome | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 2/931 (0.2%) | 2 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Photosensitivity | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Pruritus | 0/1306 (0%) | 0 | 6/931 (0.6%) | 6 | 2/931 (0.2%) | 2 | 1/501 (0.2%) | 1 | 3/509 (0.6%) | 3 | 1/246 (0.4%) | 1 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Purpura | 1/1306 (0.1%) | 1 | 3/931 (0.3%) | 3 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 1/247 (0.4%) | 1 | 2/638 (0.3%) | 2 |
| Rash maculo-papular | 4/1306 (0.3%) | 4 | 10/931 (1.1%) | 11 | 7/931 (0.8%) | 9 | 4/501 (0.8%) | 4 | 12/509 (2.4%) | 13 | 3/246 (1.2%) | 3 | 5/247 (2%) | 6 | 15/638 (2.4%) | 18 |
| Skin and subcutaneous tissue disorders - Other, specify | 2/1306 (0.2%) | 2 | 7/931 (0.8%) | 12 | 4/931 (0.4%) | 4 | 2/501 (0.4%) | 2 | 4/509 (0.8%) | 4 | 1/246 (0.4%) | 1 | 2/247 (0.8%) | 2 | 10/638 (1.6%) | 12 |
| Skin ulceration | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 2/509 (0.4%) | 2 | 0/246 (0%) | 0 | 2/247 (0.8%) | 2 | 3/638 (0.5%) | 3 |
| Stevens-Johnson syndrome | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Urticaria | 0/1306 (0%) | 0 | 7/931 (0.8%) | 7 | 1/931 (0.1%) | 1 | 1/501 (0.2%) | 1 | 3/509 (0.6%) | 3 | 4/246 (1.6%) | 4 | 3/247 (1.2%) | 3 | 5/638 (0.8%) | 5 |
| Surgical and medical procedures | ||||||||||||||||
| Surgical and medical procedures - Other, specify | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Vascular disorders | ||||||||||||||||
| Capillary leak syndrome | 0/1306 (0%) | 0 | 1/931 (0.1%) | 1 | 0/931 (0%) | 0 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
| Hematoma | 1/1306 (0.1%) | 1 | 0/931 (0%) | 0 | 5/931 (0.5%) | 5 | 1/501 (0.2%) | 1 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 1/638 (0.2%) | 1 |
| Hypertension | 30/1306 (2.3%) | 31 | 18/931 (1.9%) | 18 | 29/931 (3.1%) | 31 | 8/501 (1.6%) | 8 | 13/509 (2.6%) | 15 | 6/246 (2.4%) | 12 | 5/247 (2%) | 6 | 30/638 (4.7%) | 35 |
| Hypotension | 10/1306 (0.8%) | 10 | 17/931 (1.8%) | 18 | 10/931 (1.1%) | 10 | 7/501 (1.4%) | 7 | 8/509 (1.6%) | 8 | 2/246 (0.8%) | 2 | 1/247 (0.4%) | 1 | 18/638 (2.8%) | 21 |
| Thromboembolic event | 17/1306 (1.3%) | 17 | 9/931 (1%) | 9 | 6/931 (0.6%) | 6 | 2/501 (0.4%) | 2 | 1/509 (0.2%) | 1 | 0/246 (0%) | 0 | 2/247 (0.8%) | 2 | 5/638 (0.8%) | 6 |
| Vascular disorders - Other, specify | 1/1306 (0.1%) | 1 | 6/931 (0.6%) | 6 | 3/931 (0.3%) | 4 | 2/501 (0.4%) | 2 | 0/509 (0%) | 0 | 2/246 (0.8%) | 4 | 0/247 (0%) | 0 | 3/638 (0.5%) | 3 |
| Vasculitis | 0/1306 (0%) | 0 | 0/931 (0%) | 0 | 1/931 (0.1%) | 1 | 0/501 (0%) | 0 | 0/509 (0%) | 0 | 0/246 (0%) | 0 | 0/247 (0%) | 0 | 0/638 (0%) | 0 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Must obtain prior Sponsor approval.
Results Point of Contact
| Name/Title | Results Reporting Coordinator |
|---|---|
| Organization | Children's Oncology Group |
| Phone | 626-447-0064 |
| resultsreportingcoordinator@childrensoncologygroup.org |
Responsible Party:
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00103285
Other Study ID Numbers:
- AALL0331
- NCI-2009-00302
- 05-340
- COG-AALL0331
- CDR0000409589
- AALL0331
- AALL0331
- U10CA098543
First Posted:
Feb 8, 2005
Last Update Posted:
Jun 14, 2021
Last Verified:
Apr 1, 2021