Treatment of Acute Lymphoblastic Leukemia in Children

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00400946
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 800
• Locations: 10
• Arms: 2
• Actual Duration (Months): 170
• Patients Per Site: 80
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

RATIONALE: L-asparaginase is an important component of treatment for childhood acute lymphoblastic leukemia, but is also associated with notable side-effects, including hypersensitivity, pancreatitis, and thrombosis. We have previously reported that patients with acute lymphoblastic leukemia in whom asparaginase treatment was discontinued because of intolerable side-effects had survival outcomes that were inferior to those who received all or nearly all of their intended doses. Two bacterial sources of asparaginase exist: Escherichia coli (E coli) and Erwinia chrysanthemia (Erwinia). Generally, the E coli-derived enzyme has been used as front-line therapy and the Erwinia-derived preparation has been reserved for patients who develop hypersensitivity reactions. Pegylated E coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than native E coli L-asparaginase, and has been used as the initial asparaginase preparation in some pediatric acute lymphoblastic leukemia treatment regimens.

PURPOSE: Although the pharmacokinetics of each of these asparaginase preparations:

intravenous PEG-asparaginase (IV-PEG) and intramuscular native E coli L-asparaginase (IM-EC) have been well characterized, their relative efficacy and toxicity have not been studied extensively.

Condition or Disease	Intervention/Treatment	Phase
Drug/Agent Toxicity by Tissue/Organ; Leukemia	Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: dexamethasone; Drug: dexrazoxane hydrochloride; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: leucovorin calcium; Drug: mercaptopurine; Drug: methotrexate; Drug: methylprednisolone; Drug: pegaspargase; Drug: prednisolone; Drug: therapeutic hydrocortisone; Drug: vincristine sulfate; Radiation: radiation therapy	Phase 3

Detailed Description

RISK CLASSIFICATION:

Patients received were classified into initial risk groups defined as:

High Risk (HR) High risk patients had any of the following features: age 10 years and older, a white blood cell count of 50 000 cells per μL or higher, initial spinal fluid sample with the presence of lymphoblasts and five or more white blood cells per high power field [Central Nervous System (CNS)-3], or a T-cell phenotype.

Standard Risk (SR) All other patients were classified as standard risk.

Patients who achieved complete remission (CR) after 32 days of induction therapy defined as a marrow specimen with less than 5% marrow blasts and evidence of normal haemopoiesis, absence of extramedullary disease, and recovery of peripheral blood counts were randomly assigned in a 1:1 ratio to receive IV-PEG or IM-EC. Randomization was stratified by final risk group assigned based on end-induction minimal residual disease and cytogenetics as follows:

Very High Risk (VHR)

Any initial risk group and any of the following:

• MLL gene rearrangement

• Hypodiploidy (<45 chromosomes)

• B cell-ALL (high) end-induction minimal residual disease (MRD) (>/= 0.001)

High Risk (HR)

No VHR features, plus:

HR initial risk group OR

SR initial risk group with either of the following:

• CNS-2 or CNS-3 on day 18

• CNS-2 on day 32 OR

• t(9;22) Philadelphia chromosome positive (Ph+ ALL)

Standard Risk (SR)

No VHR features, plus:

SR initial risk group AND

• CNS-1 on day 18 and 32

NOTE: CNS-1, Cerebral spinal fluid (CSF) without blasts; CNS-2, CSF with blasts and < 5 WBC per high-power field (HPF); CNS-3, CSF with blasts and ≥ 5 WBC per HPF

THERAPY:

INDUCTION

• Steroid prophase: Patients receive intrathecal (IT) cytarabine on day 1 and methylprednisolone IV every 8 hours on days 1-3. Patients then proceed to remission induction therapy.

Patients with CNS leukemia (CNS-2, CNS-3, or traumatic lumbar puncture [LP] with blasts) on initial LP receive additional IT cytarabine twice weekly beginning on days 4-6 and continuing until cerebrospinal fluid (CSF) is clear, followed by 2 additional doses. Patients with cranial nerve palsy but no leukemia blasts in CSF or leukemic eye infiltrates also receive additional IT cytarabine as above.

NOTE: Patients who received steroids within the past 7 days do not receive steroid prophase treatment; instead they proceed directly to remission induction therapy according to their risk group.

• Remission induction therapy (SR patients): Patients receive oral prednisone or prednisolone 2-3 times daily OR methylprednisolone IV every 8 hours on days 4-32; vincristine IV on days 4, 11, 18, and 25; doxorubicin hydrochloride (DOX) IV over 15 minutes on days 4 and 5; methotrexate (MTX) IV on day 6; pegasparaginase IV over 1 hour on day 7; triple intrathecal therapy (TIT) comprising methotrexate, cytarabine, and hydrocortisone on day 18; and IT MTX on day 32.

• Remission induction therapy (HR and VHR patients): Patients receive prednisone/prednisolone OR methylprednisolone; vincristine; DOX; MTX IV; pegasparaginase; TIT; and IT MTX as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes preceding the DOX infusions on days 4 and 5.

NOTE: Patients who do not receive steroid prophase treatment also receive IT cytarabine on day 4.

NOTE: Patients who are in CR on day 32 proceed to consolidation I. Patients who do not meet protocol definition of CR on day 32 but have no evidence of persistent disease receive vincristine IV weekly until CR is achieved. Patients with persistent marrow disease (greater than 5% leukemic blasts) and/or persistent extramedullary disease or those who do not achieve CR by day 53 are removed from the study.

NOTE: Patients with Ph+ ALL received imatinib (340 mg/m2 PO maximum 600 mg daily starting day 18) in combination with HR chemotherapy until they proceeded to stem cell transplant. Patients with Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive IM-EC during post-induction therapy.

CONSOLIDATION I

• Consolidation I (SR patients): Patients receive vincristine IV and IT MTX on day 1 and oral mercaptopurine once daily on days 1-14. Patients also receive high-dose MTX (HDM) IV continuously over 24 hours on day 1 and leucovorin calcium IV every 6 hours beginning 36 hours after the start of the HDM infusion and continuing until MTX levels are undetectable. Patients proceed to CNS therapy after day 21.

• Consolidation I (HR patients): Patients receive vincristine, IT MTX, and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1 and HDM with leucovorin calcium support as in the SR group beginning 8-24 hours after the completion of the DOX infusion. Patients proceed to CNS therapy after day 21.

• Consolidation I (VHR patients): Patients receive consolidation therapy in 3 stages.

• IA: Patients receive vincristine, IT MTX, and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride, DOX, HDM, and leucovorin calcium as in the HR group.

• IB: Patients receive cyclophosphamide IV over 1 hour and IT MTX on day 22; oral mercaptopurine once daily on days 22-35; and cytarabine IV on days 23-26 and 30-33.

• IC: Patients receive high-dose cytarabine IV over 3 hours every 12 hours on days 43 and 44; etoposide IV over 1 hour on days 45-47; and oral dexamethasone twice daily on days 43-47. Patients also receive IM-EC weekly beginning on day 48 and continuing for up to 30 weeks OR IV-PEG over 1 hour every 2 weeks beginning on day 48 and continuing for up to 30 weeks. Patients proceed to CNS therapy after day 49.

KEY RANDOMIZATION: Patients are randomized 1:1 to receive either IV-PEG or IM-EC post-induction. Those who achieved a complete remission after induction therapy were assigned a final risk group and were eligible to participate in the randomization. The randomization was stratified by final risk group.

NOTE: Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive IM-EC during post-induction therapy. Patients who were eligible but declined randomization were also directly assigned to receive IM-EC. Patients who developed severe pancreatitis (defined as symptoms persisting for >72 h) during induction were not eligible for randomization and received no further doses of asparaginase. Patients who had hypersensitivity to IV-PEG during induction were also ineligible for randomization, but received twice-weekly IM-EC (25 000 IU/m2) during the post-induction treatment phases.

CNS

• CNS therapy (SR patients): Patients receive vincristine IV on day 1; oral mercaptopurine once daily on days 1-14; oral dexamethasone twice daily on days 1-5; and TIT twice weekly for 2 weeks. Patients also receive IV-PEG OR IM-EC as above beginning on day 1 and continuing for up to 30 weeks. Patients proceed to consolidation II after day 21.

• CNS therapy (HR and VHR patients): Patients receive vincristine, mercaptopurine, dexamethasone, and TIT as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1. HR patients also receive IV-PEG OR IM-EC as above beginning on day 1 and continuing for up to 30 weeks. VHR patients continue to receive IV-PEG OR IM-EC as per consolidation I treatment. Patients proceed to consolidation II after day 21.

NOTE: Patients with WBC > 100,000/mm³, T-cell disease, and/or CNS-3 at diagnosis or CNS-2 at end of remission induction therapy also undergo cranial radiation therapy daily for 8 or 10 days.

CONSOLIDATION II

• Consolidation II (SR patients): Patients receive vincristine IV on day 1; oral dexamethasone twice daily on days 1-5; and oral mercaptopurine once daily on days 1-14. Treatment repeats every 21 days until IV-PEG OR IM-EC is completed. Patients also receive MTX IV or IM 1 day after each IV-PEG OR IM-EC dose and TIT every 9 weeks for 6 doses and then every 18 weeks thereafter.

• Consolidation II (HR and VHR patients): Patients receive vincristine, dexamethasone, and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1. Treatment repeats every 21 days until IV-PEG OR IM-EC is completed. Patients also receive MTX IV or IM as in the SR group and TIT every 9 weeks for 6 doses and then every 18 weeks thereafter OR TIT every 18 weeks.

CONTINUATION

• Continuation therapy: After completion of all consolidation therapy, all patients receive vincristine IV on day 1; oral dexamethasone twice daily on days 1-5; oral mercaptopurine once daily on days 1-14; and MTX IV or IM on days 1, 8, and 15. Treatment repeats every 21 days for up to 24 months (102 weeks) after achieving CR. Patients continue to receive TIT as in consolidation II until completion of therapy.

OBJECTIVES:

Primary

• To determine the relative toxicity of IV PEG asparaginase and IM E.coli asparaginase in children with acute lymphoblastic leukemia (ALL)

Secondary (reported)

• To explore the relative efficacy of IV PEG asparaginase and IM E.coliasparaginase

• To determine the rate of infections (episodes of bacteremia and disseminated fungal infections) during the remission induction phase

• To compare trough serum asparaginase enzyme levels, asparagine levels and antiasparaginase antibody levels

• To evaluate the outcome of patients based upon MRD status after 28 days of multiagent chemotherapy within the context of a regimen which intensifies treatment for B-lineage patients with MRD levels >0.001 at the end of remission induction (day 32 MRD status used)

• To evaluate the outcome of patients based upon bone marrow morphology after 14 days of multiagent chemotherapy (day 18 marrow morphology status used)

• To determine the efficacy of CNS-directed treatments

Secondary (not reported)

• To compare antiasparaginase antibody levels (not available due to problems with the assay)

• To correlate trough enzyme levels with outcome (toxicity, relapse)

• To determine CNS-related toxicity of CNS-directed treatments (data is not mature on late neurocognitive impairments in long-term survivors)

• To determine the efficacy and CNS-related toxicity (acute and long-term) of the HR regimen in which a subset of HR patients (B-lineage, CNS-1 or CNS-2, WBC <100,000/m3) are treated with intensive intrathecal chemotherapy and the remainder are treated with 12 Gy cranial radiation (with intrathecal chemotherapy)

• To determine the efficacy and CNS-related toxicity (acute and long-term) of intensive intrathecal therapy in SR patients

• To determine the prognostic significance of asparaginase antibody formation

• To compare randomized treatment groups using health-related quality-of-life analysis (connected with a separate protocol 06-373)

• To investigate the association of dietary antioxidant micronutrient intake with the rate of infections (episodes of bacteremia and disseminated fungal infections) during remission induction therapy and the Consolidation IA phase

• To determine the relationship of dietary calcium intake with risk for development of fractures during the continuation phase of therapy

• To evaluate the association of dietary intake of specific nutrients with treatment-related toxicities during treatment

• To evaluate the outcome of patients based upon MRD status after 14 days of multiagent chemotherapy and at various other timepoints while on treatment every 18 weeks after achieving complete remission and at the completion of all chemotherapy

• To determine the prognostic significance of response to remission induction chemotherapy as measured by morphologic and minimal residual disease (MRD) measures within the context of DFCI ALL Consortium protocol therapy (data limited due to response outcomes)

• To compare rate of infection during remission induction in patients treated with a less intensive induction regimen on Protocol 05-01 (low-dose instead of high-dose methotrexate) with that of patients treated on prior DFCI ALL Consortium Protocol 00-01 (induction regimen included high-dose methotrexate)

• To determine the concordance of MRD quantification using multi-parameter flow cytometry and PCR techniques

• To determine the prognostic significance of gene expression programs in childhood ALL and identify new targets for specific therapies

• To identify clinically relevant gene expression signatures in leukemia cells

• To identify gene expression signature in leukemia cells at diagnosis that predicts peripheral blood response to the steroid prophase

• To identify gene expression changes in leukemia cells induced by steroid treatment

• To determine the frequency and type of tyrosine kinase mutations in childhood ALL and identify new targets for specific therapies

• To explore the potential relationship between abnormal glucose homeostasis during therapy and the development of obesity, as well as the potential relationship between obesity and the age of pubertal onset (assessed in patients treated at DFCI/CHB only)

• To characterize the degree of hyperglycemia and insulin resistance in patients receiving therapy for childhood ALL

• To characterize the degree of insulin resistance and obesity after the completion of therapy for childhood ALL

Study Design

• Study Type: Interventional
• Actual Enrollment: 800 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Acute Lymphoblastic Leukemia in Children
• Actual Study Start Date: Apr 1, 2005
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Jun 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Intramuscular native E coli L-asparaginase (IM-EC) Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: dexamethasone; Drug: dexrazoxane hydrochloride; Drug: doxorubicin hydrochloride; Drug: etoposide; Given IV; Drug: leucovorin calcium; Drug: mercaptopurine; Given orally; Drug: methotrexate; Drug: methylprednisolone; Drug: prednisolone; Drug: therapeutic hydrocortisone; Drug: vincristine sulfate; Radiation: radiation therapy
Experimental: Intravenous PEG-asparaginase (IV-PEG) Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Drug: cyclophosphamide; Drug: cytarabine; Drug: dexamethasone; Drug: dexrazoxane hydrochloride; Drug: doxorubicin hydrochloride; Drug: etoposide; Given IV; Drug: leucovorin calcium; Drug: mercaptopurine; Given orally; Drug: methotrexate; Drug: methylprednisolone; Drug: pegaspargase; Given IV; Drug: prednisolone; Drug: therapeutic hydrocortisone; Drug: vincristine sulfate; Radiation: radiation therapy

Outcome Measures

Primary Outcome Measures

1. Asparaginase-Related Toxicity Rate [30-week post-induction asparaginase treatment period]

   Asparaginase-related toxicity rate is defined as the percentage of patients who experience allergy (all grades), symptomatic pancreatitis (grade 2 or worse), thrombotic or bleeding complications requiring intervention (grade 2 or worse) with treatment attribution of possibly, probably or definite based on CTCAEv3.

Secondary Outcome Measures

1. 5-Year Disease-Free Survival [Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.]

   Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.

2. Post-Induction Nadir Serum Asparaginase Activity Level [Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.]

   Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods.

3. Post-Induction Therapeutic Nadir Serum Asparaginase Activity Rate [Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.]

   Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Post-Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL ever during post-induction therapy.

4. Induction Infection Toxicity Rate [Assessed daily during remission induction days 4-32.]

   Infection toxicity rate is defined as the percentage of patients who experience bacterial or fungal infection of grade 3 or higher with treatment attribution of possibly, probably or definite based on CTCAEv3 during remission induction phase of combination chemotherapy.

5. Induction Serum Asparaginase Activity Level [Samples for serum asparaginase activity analyses were obtained days 4, 11, 18 and 25 post one-dose of IV-PEG on day 7 of the induction phase.]

   Serum asparaginase activity (NSAA) levels were estimated based on established methods.

6. Induction Therapeutic Nadir Serum Asparaginase Activity Rate [Samples for serum asparaginase activity analyses were obtained days 4, 11, 18 and 25 post one-dose of IV-PEG on day 7 of the induction phase.]

   Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL at a given timepoint.

7. 5-Year Disease-Free Survival by MRD Day 32 Status [Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.]

   Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.

8. 5-Year Disease-Free Survival by Bone Marrow Day 18 Status [Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.]

   Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.

9. 5-year Disease-Free Survival by CNS Directed Treatment Group [Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.]

   Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of acute lymphoblastic leukemia (ALL)

• No known mature B-cell ALL, defined by the presence of any of the following:

• Surface immunoglobulin

• L3 morphology

• t(8;14)(q24;q32)

• t(8;22)

• t(2;8)

• T-cell surface markers and t(8;14)(q24;q11) allowed

• No secondary ALL

PATIENT CHARACTERISTICS:

• No known HIV positivity

• Not pregnant or nursing

• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No prior therapy except steroids of ≤ 1 week in duration and/or emergent radiation therapy to the mediastinum

• Patients treated with steroids within the past 7 days will not receive steroid prophase during study treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
2	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York	United States	10461
3	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York	United States	10032
4	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
5	Hasbro Children's Hospital	Providence	Rhode Island	United States	02903
6	INOVA Fairfax Hospital	Fairfax	Virginia	United States	22031
7	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
8	Hopital Sainte Justine	Montreal	Quebec	Canada	H3T 1C5
9	Centre de Recherche du Centre Hospitalier de l'Universite Laval	Sainte Foy	Quebec	Canada	GIV 4G2
10	San Jorge Children's Hospital	Santurce		Puerto Rico	00912

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Lewis B. Silverman, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Lewis B. Silverman, M.D., Silverman, Lewis MD, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00400946
• Other Study ID Numbers: 05-001 / CDR0000513019; P01CA068484; P30CA006516; DFCI-05001; NCT00165165
• First Posted: Nov 17, 2006
• Last Update Posted: Jun 24, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Lewis B. Silverman, M.D., Silverman, Lewis MD, Dana-Farber Cancer Institute: drug/agent toxicity by tissue/organ; untreated childhood acute lymphoblastic leukemia; L1 childhood acute lymphoblastic leukemia; L2 childhood acute lymphoblastic leukemia; T-cell childhood acute lymphoblastic leukemia
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Drug-Related Side Effects and Adverse Reactions; Leucovorin; Cytarabine; Dexamethasone; Methylprednisolone; Prednisolone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Asparaginase; Mercaptopurine; Pegaspargase; Dexrazoxane; Razoxane; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	Patients enrolled from April 22, 2005 to Dec 13, 2011.

Arm/Group Title	Intramuscular Native E Coli L-asparaginase (IM-EC)	Intravenous PEG-asparaginase (IV-PEG)	IM-EC [Directly Assigned]	Ineligible for Randomization	Expansion Cohort
Arm/Group Description	Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive intramuscular E coli L-asparaginase during post-induction therapy. Patients who were eligible but declined randomization were also directly assigned to receive intramuscular E coli L-asparaginase.	All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who did not achieve complete remission and were not assigned a final risk group by the end of the induction phase of treatment were not eligible for randomization. Patients who developed severe pancreatitis (defined as symptoms persisting for >72 h) during induction were not eligible for randomization and received no further doses of asparaginase. Patients who had hypersensitivity to intravenous PEG-asparaginase during induction were also ineligible for randomization, but received twice-weekly IM-EC (25 000 IU/m2) during the post-induction treatment phases.	Patients were enrolled in an expansion cohort to determine the prognostic significance of response to remission induction chemotherapy as measured by morphologic and minimal residual disease (MRD), and to further evaluate the efficacy of patients by final risk classification.
Period Title: Overall Study
STARTED	231	232	42	51	244
Evaluable for CNS Directed-Treatment	231	232	42	21	227
Evaluable for Day 18 Marrow Morphology	158	161	19	13	152
Evaluable for Day 32 MRD	166	167	33	12	168
Eligible and Treated	231	232	42	46	243
COMPLETED	217	221	40	4	206
NOT COMPLETED	14	11	2	47	38

Baseline Characteristics

Arm/Group Title	Intramuscular Native E Coli L-asparaginase (IM-EC)	Intravenous PEG-asparaginase (IV-PEG)	IM-EC [Directly Assigned]	Ineligible for Randomization	Expansion Cohort	Total
Arm/Group Description	Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive intramuscular E coli L-asparaginase during post-induction therapy. Patients who were eligible but declined randomization were also directly assigned to receive intramuscular E coli L-asparaginase.	All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who did not achieve complete remission and were not assigned a final risk group by the end of the induction phase of treatment were not eligible for randomization. Patients who developed severe pancreatitis (defined as symptoms persisting for >72 h) during induction were not eligible for randomization and received no further doses of asparaginase. Patients who had hypersensitivity to intravenous PEG-asparaginase during induction were also ineligible for randomization, but received twice-weekly IM-EC (25 000 IU/m2) during the post-induction treatment phases.	Patients were enrolled in an expansion cohort to determine the prognostic significance of response to remission induction chemotherapy as measured by morphologic and minimal residual disease (MRD), and to further evaluate the efficacy of patients by final risk classification.	Total of all reporting groups
Overall Participants	231	232	42	51	244	800
Age (Count of Participants)
<=18 years	231 100%	232 100%	42 100%	51 100%	244 100%	800 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	111 48.1%	97 41.8%	21 50%	21 41.2%	107 43.9%	357 44.6%
Male	120 51.9%	135 58.2%	21 50%	30 58.8%	137 56.1%	443 55.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	40 17.3%	48 20.7%	3 7.1%	13 25.5%	48 19.7%	152 19%
Not Hispanic or Latino	165 71.4%	170 73.3%	35 83.3%	34 66.7%	180 73.8%	584 73%
Unknown or Not Reported	26 11.3%	14 6%	4 9.5%	4 7.8%	16 6.6%	64 8%
Age Classification (Count of Participants)
< 10 years old	176 76.2%	165 71.1%	35 83.3%	26 51%	196 80.3%	598 74.8%
>/= 10 years old	55 23.8%	67 28.9%	7 16.7%	25 49%	48 19.7%	202 25.3%

Outcome Measures

1. Primary Outcome

Title	Asparaginase-Related Toxicity Rate
Description	Asparaginase-related toxicity rate is defined as the percentage of patients who experience allergy (all grades), symptomatic pancreatitis (grade 2 or worse), thrombotic or bleeding complications requiring intervention (grade 2 or worse) with treatment attribution of possibly, probably or definite based on CTCAEv3.
Time Frame	30-week post-induction asparaginase treatment period

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all randomized patients.

Arm/Group Title	Intramuscular Native E Coli L-asparaginase (IM-EC)	Intravenous PEG-asparaginase (IV-PEG)
Arm/Group Description	Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.
Measure Participants	231	232
Number (95% Confidence Interval) [percentage of participants]	26 11.3%	28 12.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intramuscular Native E Coli L-asparaginase (IM-EC), Intravenous PEG-asparaginase (IV-PEG)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.60
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	5-Year Disease-Free Survival
Description	Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.
Time Frame	Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all randomized patients.

Arm/Group Title	Intramuscular Native E Coli L-asparaginase (IM-EC)	Intravenous PEG-asparaginase (IV-PEG)
Arm/Group Description	Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.
Measure Participants	231	232
Number (95% Confidence Interval) [probability]	.89	.90

3. Secondary Outcome

Title	Post-Induction Nadir Serum Asparaginase Activity Level
Description	Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods.
Time Frame	Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all randomized patients who consented to research studies with an evaluable sample for analysis of serum asparaginase activity at the respective post-induction assessment timepoints.

Arm/Group Title	Intramuscular Native E Coli L-asparaginase (IM-EC)	Intravenous PEG-asparaginase (IV-PEG)
Arm/Group Description	Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.
Measure Participants	231	232
Week 5 NSAA Level	0.129 (0.108)	0.726 (0.322)
Week 11 NSAA Level	0.143 (0.131)	0.773 (0.231)
Week 17 NSAA Level	0.159 (0.161)	0.787 (0.303)
Week 23 NSAA Level	0.180 (0.261)	0.757 (0.255)
Week 29 NSAA Level	0.123 (0.102)	0.806 (0.313)

4. Secondary Outcome

Title	Post-Induction Therapeutic Nadir Serum Asparaginase Activity Rate
Description	Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Post-Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL ever during post-induction therapy.
Time Frame	Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all randomized patients who consented to research studies with a one post-induction evaluable sample for analysis of serum asparaginase activity.

Arm/Group Title	Intramuscular Native E Coli L-asparaginase (IM-EC)	Intravenous PEG-asparaginase (IV-PEG)
Arm/Group Description	Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.
Measure Participants	170	168
Number (95% Confidence Interval) [percentage of participants]	71 30.7%	99 42.7%

5. Secondary Outcome

Title	Induction Infection Toxicity Rate
Description	Infection toxicity rate is defined as the percentage of patients who experience bacterial or fungal infection of grade 3 or higher with treatment attribution of possibly, probably or definite based on CTCAEv3 during remission induction phase of combination chemotherapy.
Time Frame	Assessed daily during remission induction days 4-32.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of eligible and treated patients. This excludes the 6 enrolled but ineligible patients. Rates in this overall study cohort will be compared against historical controls (in particular patients treated with a more intensive induction regimen).

Arm/Group Title	Overall
Arm/Group Description	Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization wherein patients received either E. coli L-asparaginase or peg-asparaginase. Standard risk and high-risk patients began post-induction randomized asparaginase therapy at the start of the CNS phase, whereas very high-risk patients began asparaginase therapy on day 8 of consolidation phase IC. Patients who did not achieve complete remission by the end of the induction phase were not eligible for randomization, were removed from protocol treatment, and received alternative therapy according to the discretion of their treating physician. Further details are provided in the study description section.
Measure Participants	794
Number (95% Confidence Interval) [percentage of participants]	26 11.3%

6. Secondary Outcome

Title	Induction Serum Asparaginase Activity Level
Description	Serum asparaginase activity (NSAA) levels were estimated based on established methods.
Time Frame	Samples for serum asparaginase activity analyses were obtained days 4, 11, 18 and 25 post one-dose of IV-PEG on day 7 of the induction phase.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all randomized patients who consented to research studies with an evaluable sample for analysis of serum asparaginase activity at the respective induction assessment timepoints.

Arm/Group Title	Overall
Arm/Group Description	Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization wherein patients received either E. coli L-asparaginase or peg-asparaginase. Standard risk and high-risk patients began post-induction randomized asparaginase therapy at the start of the CNS phase, whereas very high-risk patients began asparaginase therapy on day 8 of consolidation phase IC. Patients who did not achieve complete remission by the end of the induction phase were not eligible for randomization, were removed from protocol treatment, and received alternative therapy according to the discretion of their treating physician. Further details are provided in the study description section.
Measure Participants	794
Day 4 NSAA Level	.694
Day 11 NSAA Level	.505
Day 18 NSAA Level	.211
Day 25 NSAA Level	.048

7. Secondary Outcome

Title	Induction Therapeutic Nadir Serum Asparaginase Activity Rate
Description	Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL at a given timepoint.
Time Frame	Samples for serum asparaginase activity analyses were obtained days 4, 11, 18 and 25 post one-dose of IV-PEG on day 7 of the induction phase.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all randomized patients who consented to research studies with an evaluable sample for analysis of serum asparaginase activity at the respective induction assessment timepoints.

Arm/Group Title	Overall
Arm/Group Description	Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization wherein patients received either E. coli L-asparaginase or peg-asparaginase. Standard risk and high-risk patients began post-induction randomized asparaginase therapy at the start of the CNS phase, whereas very high-risk patients began asparaginase therapy on day 8 of consolidation phase IC. Patients who did not achieve complete remission by the end of the induction phase were not eligible for randomization, were removed from protocol treatment, and received alternative therapy according to the discretion of their treating physician. Further details are provided in the study description section.
Measure Participants	794
Day 4 NSAA Rate	97 42%
Day 11 NSAA Rate	96 41.6%
Day 18 NSAA Rate	87 37.7%
Day 25 NSAA Rate	12 5.2%

8. Secondary Outcome

Title	5-Year Disease-Free Survival by MRD Day 32 Status
Description	Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.
Time Frame	Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of B cell ALL patients who achieved an induction complete remission with an evaluable sample at day 32 for analysis of MRD.

Arm/Group Title	Low Day 32 MRD Level	High Day 32 MRD Level
Arm/Group Description	Low end-induction (day 32) minimal residual disease (MRD) evaluated was defined as <0.001. This MRD classification was one component of determining final risk classification. Peripheral blood samples were collected for evaluation of MRD using PCR methods.	High end-induction (day 32) minimal residual disease (MRD) evaluated was defined as >/=0.001. This MRD classification was one component of determining final risk classification. Peripheral blood samples were collected for evaluation of MRD using PCR methods
Measure Participants	50	496
Number (95% Confidence Interval) [probability]	.79	.90

9. Secondary Outcome

Title	5-Year Disease-Free Survival by Bone Marrow Day 18 Status
Description	Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.
Time Frame	Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of patients who achieved an induction complete remission with an evaluable sample at day 18 (optional submission) for analysis of marrow morphology.

Arm/Group Title	M1 Day 18 Bone Marrow Status	M2/M3 Day 18 Bone Marrow Status	Hypocellular Day 18 Bone Marrow Status
Arm/Group Description	M1 marrow morphology at day 18 was defined as <5% blasts.	M2 marrow morphology at day 18 was defined as 5-24% blasts. M3 marrow morphology at day 18 was defined as >25% blasts.	Hypocellular marrow morphology at day 18 was defined as empty blasts.
Measure Participants	284	26	193
Number (95% Confidence Interval) [probability]	.89	.78	.88

10. Secondary Outcome

Title	5-year Disease-Free Survival by CNS Directed Treatment Group
Description	Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.
Time Frame	Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of patients who achieved an induction complete remission with an evaluable sample at diagnosis for analysis of CNS-directed therapy .

Arm/Group Title	CNS-1	CNS-2	CNS-3	Traumatic Tap With Blasts	Traumatic Tap Without Blasts
Arm/Group Description	CNS-1: no blast cells in cytospin, regardless of cerebrospinal fluid (CSF) count	CNS-2: 5 or fewer WBC on CSF cell count, with blasts on cytospin	CNS-3: more than 5 WBC on CSF cell count, with blasts on cytospin	Traumatic Tap with Blasts: with blast cells and >100 RBCs on a wet prep	Traumatic Tap without Blasts: without blast cells and >100 RBCs on a wet prep
Measure Participants	579	114	9	32	19
Number (95% Confidence Interval) [probability]	.89	.89	1.00	.84	.87

Adverse Events

Time Frame	Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups.
Adverse Event Reporting Description	Reporting included (trt-related, all grades [G] unless specified): asparaginase-related allergy, symptomatic pancreatitis (>G1), thrombotic or bleeding complications requiring intervention (>G1), infections (>G2), symptomatic osteonecrosis (>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Arm/Group Title	Intramuscular Native E Coli L-asparaginase (IM-EC)		Intravenous PEG-asparaginase (IV-PEG)		Overall
Arm/Group Description	Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.		Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.		Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization wherein patients received either E. coli L-asparaginase or peg-asparaginase. Standard risk and high-risk patients began post-induction randomized asparaginase therapy at the start of the CNS phase, whereas very high-risk patients began asparaginase therapy on day 8 of consolidation phase IC. Patients who did not achieve complete remission by the end of the induction phase were not eligible for randomization, were removed from protocol treatment, and received alternative therapy according to the discretion of their treating physician. Further details are provided in the study description section.
All Cause Mortality
	Intramuscular Native E Coli L-asparaginase (IM-EC)		Intravenous PEG-asparaginase (IV-PEG)		Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/231 (0.4%)		1/232 (0.4%)		2/794 (0.3%)
Serious Adverse Events
	Intramuscular Native E Coli L-asparaginase (IM-EC)		Intravenous PEG-asparaginase (IV-PEG)		Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	132/231 (57.1%)		142/232 (61.2%)		574/794 (72.3%)
Blood and lymphatic system disorders
Hematologic-other	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Hemolysis	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Hemoglobin	4/231 (1.7%)		0/232 (0%)		12/794 (1.5%)
Febrile neutropenia	6/231 (2.6%)		7/232 (3%)		18/794 (2.3%)
Cardiac disorders
Atrial flutter	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Cardiac-other	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Left ventricular systolic dysfunction	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Sinus tachycardia	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Ventricular tachycardia	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Gastrointestinal disorders
Cecum/appendix- hemorrhage	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Enteritis	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Nausea	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Necrosis- pancreas	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Oral cavity- pain	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Perforation- stomach	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Ulcer- anus	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Ulcer- duodenum	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Ulcer- esophagus	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Ulcer- gastric	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Varices (esophageal)- hemorrhage	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Colitis	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Duodenum- hemorrhage	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Esophagitis	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Lower GI- hemorrhage NOS	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Oral gums- pain	1/231 (0.4%)		1/232 (0.4%)		2/794 (0.3%)
Perforation- small bowel NOS	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Vomiting	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Constipation	1/231 (0.4%)		0/232 (0%)		3/794 (0.4%)
Diarrhea w/o prior colostomy	1/231 (0.4%)		0/232 (0%)		3/794 (0.4%)
Upper GI- hemorrhage NOS	0/231 (0%)		0/232 (0%)		3/794 (0.4%)
Abdomen- pain	0/231 (0%)		2/232 (0.9%)		4/794 (0.5%)
Ileus	0/231 (0%)		0/232 (0%)		4/794 (0.5%)
Muco/stomatitis (symptom) oral cavity	2/231 (0.9%)		2/232 (0.9%)		7/794 (0.9%)
Typhlitis	0/231 (0%)		2/232 (0.9%)		16/794 (2%)
Pancreatitis	3/231 (1.3%)		9/232 (3.9%)		26/794 (3.3%)
Muco/stomatitis by exam- oral cavity	15/231 (6.5%)		21/232 (9.1%)		100/794 (12.6%)
General disorders
Death - multiorgan failure	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Death - sudden death	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Edema limb	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Pain NOS	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Fatigue	1/231 (0.4%)		1/232 (0.4%)		2/794 (0.3%)
Fever w/o neutropenia	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Pain-other	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Extremity-lower (gait/walking)	1/231 (0.4%)		1/232 (0.4%)		6/794 (0.8%)
Hepatobiliary disorders
Liver dysfunction/failure	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Immune system disorders
Allergic reaction	6/231 (2.6%)		14/232 (6%)		33/794 (4.2%)
Infections and infestations
Infection Gr0-2 neut- bladder	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- bronchus	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- cervix	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- dental-tooth	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- middle ear	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- muscle	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection Gr0-2 neut- soft tissue	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection Gr0-2 neut- spleen	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- brain	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection w/ gr3-4 neut- brain + spinal	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- dental-tooth	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- eye NOS	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- lens	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- lip/perioral	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection w/ gr3-4 neut- liver	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection w/ gr3-4 neut- paranasal	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection w/ gr3-4 neut- pleura	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- sinus	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- spinal cord	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- spleen	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection w/ gr3-4 neut- trachea	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- vein	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC abdomen NOS	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC colon	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC lymphatic	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC meninges	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC skin (cellulitis)	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC ungual (nails)	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC upper airway NOS	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC urinary tract NOS	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- abdomen	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Infection Gr0-2 neut- catheter	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Infection Gr0-2 neut- eye NOS	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Infection Gr0-2 neut- liver	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection Gr0-2 neut- peritoneal	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection Gr0-2 neut- wound	2/231 (0.9%)		0/232 (0%)		2/794 (0.3%)
Infection w/ gr3-4 neut- anal/perianal	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection w/ gr3-4 neut- kidney	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Infection w/ gr3-4 neut- meninges	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection w/ gr3-4 neut- middle ear	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Infection w/ gr3-4 neut- peritoneal	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection w/ gr3-4 neut- urinary tract	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Infection w/ unk ANC bladder	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection w/ unk ANC lung	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection w/ unk ANC wound	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection Gr0-2 neut- urinary tract	2/231 (0.9%)		0/232 (0%)		4/794 (0.5%)
Infection w/ gr3-4 neut- catheter relate	0/231 (0%)		0/232 (0%)		4/794 (0.5%)
Infection w/ gr3-4 neut- upper airway	2/231 (0.9%)		1/232 (0.4%)		4/794 (0.5%)
Infection w/ gr3-4 neut- wound	0/231 (0%)		1/232 (0.4%)		4/794 (0.5%)
Infection w/ gr3-4 neut- lung	0/231 (0%)		1/232 (0.4%)		7/794 (0.9%)
Infection Gr0-2 neut- skin	3/231 (1.3%)		2/232 (0.9%)		8/794 (1%)
Infection-other	1/231 (0.4%)		3/232 (1.3%)		9/794 (1.1%)
Infection Gr0-2 neut- lung	5/231 (2.2%)		2/232 (0.9%)		10/794 (1.3%)
Infection w/ gr3-4 neut- skin	6/231 (2.6%)		1/232 (0.4%)		12/794 (1.5%)
Colitis- infectious (e.g. C.diff)	1/231 (0.4%)		2/232 (0.9%)		13/794 (1.6%)
Opportunistic infection lymphopenia>=gr1	5/231 (2.2%)		6/232 (2.6%)		15/794 (1.9%)
Infection Gr 0-2 neut- blood	33/231 (14.3%)		30/232 (12.9%)		103/794 (13%)
Infection w/ gr 3-4 neut- blood	25/231 (10.8%)		29/232 (12.5%)		234/794 (29.5%)
Injury, poisoning and procedural complications
Intra-op injury Other (Specify)	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Intra-op injury Pleura	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Surgical hemorrhage	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Wound - non-infectious	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Fracture	5/231 (2.2%)		1/232 (0.4%)		11/794 (1.4%)
Investigations
ADH secretion abnormality (eg SIADH)	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Alkaline phosphatase	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Coagulation-other	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Creatinine	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
INR	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
PTT	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Hypercholesterolemia	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Fibrinogen	0/231 (0%)		0/232 (0%)		3/794 (0.4%)
Leukocytes	0/231 (0%)		0/232 (0%)		3/794 (0.4%)
Metabolic/Laboratory-other	0/231 (0%)		1/232 (0.4%)		4/794 (0.5%)
Neutrophils	1/231 (0.4%)		2/232 (0.9%)		6/794 (0.8%)
Platelets	1/231 (0.4%)		0/232 (0%)		6/794 (0.8%)
GGT	1/231 (0.4%)		1/232 (0.4%)		7/794 (0.9%)
Bilirubin	1/231 (0.4%)		4/232 (1.7%)		16/794 (2%)
AST- SGOT	4/231 (1.7%)		8/232 (3.4%)		28/794 (3.5%)
Amylase	5/231 (2.2%)		6/232 (2.6%)		37/794 (4.7%)
ALT- SGPT	9/231 (3.9%)		10/232 (4.3%)		48/794 (6%)
Lipase	12/231 (5.2%)		10/232 (4.3%)		49/794 (6.2%)
Metabolism and nutrition disorders
Hypoalbuminemia	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Iron overload	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Urinary electrolyte wasting	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Hyperkalemia	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Hyperuricemia	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Anorexia	2/231 (0.9%)		0/232 (0%)		4/794 (0.5%)
Dehydration	1/231 (0.4%)		0/232 (0%)		4/794 (0.5%)
Hypophosphatemia	1/231 (0.4%)		1/232 (0.4%)		4/794 (0.5%)
Tumor lysis syndrome	0/231 (0%)		0/232 (0%)		4/794 (0.5%)
Hypocalcemia	0/231 (0%)		0/232 (0%)		7/794 (0.9%)
Hypoglycemia	4/231 (1.7%)		1/232 (0.4%)		7/794 (0.9%)
Hyponatremia	1/231 (0.4%)		2/232 (0.9%)		11/794 (1.4%)
Hypokalemia	8/231 (3.5%)		5/232 (2.2%)		22/794 (2.8%)
Hyperglycemia	6/231 (2.6%)		1/232 (0.4%)		25/794 (3.1%)
Hypertriglyceridemia	12/231 (5.2%)		20/232 (8.6%)		69/794 (8.7%)
Musculoskeletal and connective tissue disorders
Back- pain	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Joint- pain	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Muscular/skeletal hypoplasia	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Nonneuropathic lower extr muscle weak	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Osteoporosis	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Soft tissue necrosis- extremity lower	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Bone- pain	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Extremity-limb- pain	1/231 (0.4%)		1/232 (0.4%)		5/794 (0.6%)
Osteonecrosis (avascular necrosis)	6/231 (2.6%)		6/232 (2.6%)		15/794 (1.9%)
Nervous system disorders
CNS cerebrovascular ischemia	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Head/headache	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Speech impairment	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Syncope	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Myelitis	0/231 (0%)		1/232 (0.4%)		3/794 (0.4%)
Neurologic-other	1/231 (0.4%)		1/232 (0.4%)		3/794 (0.4%)
Neuropathy-sensory	2/231 (0.9%)		0/232 (0%)		4/794 (0.5%)
CNS- hemorrhage	2/231 (0.9%)		1/232 (0.4%)		6/794 (0.8%)
Encephalopathy	2/231 (0.9%)		0/232 (0%)		6/794 (0.8%)
Neuropathy-motor	2/231 (0.9%)		3/232 (1.3%)		14/794 (1.8%)
Seizure	6/231 (2.6%)		6/232 (2.6%)		22/794 (2.8%)
Psychiatric disorders
Anxiety	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Insomnia	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Personality	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Agitation	0/231 (0%)		2/232 (0.9%)		2/794 (0.3%)
Confusion	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Depression	1/231 (0.4%)		1/232 (0.4%)		3/794 (0.4%)
Psychosis	0/231 (0%)		1/232 (0.4%)		3/794 (0.4%)
Renal and urinary disorders
Kidney- pain	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Obstruction-ureteral	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Perforation- appendix	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Renal failure	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Reproductive system and breast disorders
Pelvic- pain	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary- hemorrhage	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Cough	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Lung- hemorrhage	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
(ARDS)	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Dyspnea	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Pleural effusion (non-malignant)	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Pulmonary/Upper Respiratory-other	0/231 (0%)		1/232 (0.4%)		3/794 (0.4%)
Hypoxia	0/231 (0%)		0/232 (0%)		6/794 (0.8%)
Pneumonitis/pulmonary infiltrates	3/231 (1.3%)		1/232 (0.4%)		9/794 (1.1%)
Skin and subcutaneous tissue disorders
Pruritus/itching	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Skin breakdown/decubitus ulcer	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Skin-other	1/231 (0.4%)		0/232 (0%)		3/794 (0.4%)
Vascular disorders
Acute vascular leak syndrome	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Chyle or lymph leakage	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Peripheral arterial ischemia	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Hypotension	2/231 (0.9%)		3/232 (1.3%)		10/794 (1.3%)
Vascular access-Thrombosis/embolism	8/231 (3.5%)		2/232 (0.9%)		15/794 (1.9%)
Hypertension	2/231 (0.9%)		3/232 (1.3%)		39/794 (4.9%)
Thrombosis/thrombus/embolism	10/231 (4.3%)		12/232 (5.2%)		55/794 (6.9%)
Other (Not Including Serious) Adverse Events
	Intramuscular Native E Coli L-asparaginase (IM-EC)		Intravenous PEG-asparaginase (IV-PEG)		Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/231 (17.3%)		38/232 (16.4%)		118/794 (14.9%)
Blood and lymphatic system disorders
Hemoglobin	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Febrile neutropenia	3/231 (1.3%)		2/232 (0.9%)		7/794 (0.9%)
Cardiac disorders
Sinus tachycardia	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Left ventricular systolic dysfunction	0/231 (0%)		0/232 (0%)		3/794 (0.4%)
Ear and labyrinth disorders
Otitis- middle ear (non-infectious)	0/231 (0%)		3/232 (1.3%)		3/794 (0.4%)
Gastrointestinal disorders
Enteritis	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Muco/stomatitis (symptom) anus	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Oral cavity- pain	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Perforation- stomach	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Diarrhea w/o prior colostomy	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Ulcer- anus	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Colitis	0/231 (0%)		1/232 (0.4%)		4/794 (0.5%)
Constipation	0/231 (0%)		0/232 (0%)		4/794 (0.5%)
Typhlitis	0/231 (0%)		0/232 (0%)		4/794 (0.5%)
Muco/stomatitis (symptom) oral cavity	0/231 (0%)		1/232 (0.4%)		5/794 (0.6%)
Muco/stomatitis by exam- oral cavity	7/231 (3%)		7/232 (3%)		31/794 (3.9%)
Pancreatitis	15/231 (6.5%)		17/232 (7.3%)		61/794 (7.7%)
General disorders
Chest/thoracic pain NOS	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Extremity-lower (gait/walking)	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Fatigue	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Hypothermia	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Fever w/o neutropenia	1/231 (0.4%)		4/232 (1.7%)		5/794 (0.6%)
Pain-other	1/231 (0.4%)		1/232 (0.4%)		5/794 (0.6%)
Immune system disorders
Allergy-other	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Allergic reaction	8/231 (3.5%)		13/232 (5.6%)		33/794 (4.2%)
Infections and infestations
Infection Gr0-2 neut- bladder	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- bronchus	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- external ear	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- eye NOS	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- kidney	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection Gr0-2 neut- lung	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection Gr0-2 neut- lymphatic	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- meninges	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- bronchus	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection w/ gr3-4 neut- catheter relate	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- eye NOS	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection w/ gr3-4 neut- larynx	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- middle ear	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- peritoneal	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- pharynx	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- urinary tract	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ gr3-4 neut- wound	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Infection w/ unk ANC catheter related	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC skin (cellulitis)	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC ungual (nails)	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC upper airway NOS	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection w/ unk ANC wound	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Infection Gr0-2 neut- conjunctiva	1/231 (0.4%)		1/232 (0.4%)		2/794 (0.3%)
Infection Gr0-2 neut- middle ear	1/231 (0.4%)		1/232 (0.4%)		2/794 (0.3%)
Infection Gr0-2 neut- mucosa	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection Gr0-2 neut- ungual	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection Gr0-2 neut- upper airway	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection Gr0-2 neut- wound	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Infection w/ unk ANC lung	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Infection w/ unk ANC urinary tract NOS	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Infection Gr0-2 neut- nose	2/231 (0.9%)		0/232 (0%)		3/794 (0.4%)
Infection Gr0-2 neut- sinus	0/231 (0%)		1/232 (0.4%)		3/794 (0.4%)
Infection Gr0-2 neut- skin	1/231 (0.4%)		1/232 (0.4%)		3/794 (0.4%)
Infection Gr0-2 neut- urinary tract	0/231 (0%)		1/232 (0.4%)		3/794 (0.4%)
Infection w/ gr 3-4 neut- blood	0/231 (0%)		1/232 (0.4%)		3/794 (0.4%)
Infection Gr0-2 neut- oral cavity	0/231 (0%)		2/232 (0.9%)		4/794 (0.5%)
Infection-other	2/231 (0.9%)		0/232 (0%)		4/794 (0.5%)
Colitis- infectious (e.g. C.diff)	1/231 (0.4%)		1/232 (0.4%)		6/794 (0.8%)
Opportunistic infection lymphopenia>=gr1	5/231 (2.2%)		1/232 (0.4%)		10/794 (1.3%)
Infection Gr 0-2 neut- blood	12/231 (5.2%)		9/232 (3.9%)		32/794 (4%)
Injury, poisoning and procedural complications
Chemoradiation dermatitis	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Fracture	37/231 (16%)		38/232 (16.4%)		118/794 (14.9%)
Investigations
Creatinine	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Lipase	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Neutrophils	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Weight loss	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
ALT- SGPT	1/231 (0.4%)		0/232 (0%)		4/794 (0.5%)
Amylase	1/231 (0.4%)		2/232 (0.9%)		4/794 (0.5%)
AST- SGOT	2/231 (0.9%)		0/232 (0%)		6/794 (0.8%)
Metabolism and nutrition disorders
Dehydration	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Hypoglycemia	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Hyperglycemia	0/231 (0%)		0/232 (0%)		2/794 (0.3%)
Hypertriglyceridemia	3/231 (1.3%)		7/232 (3%)		14/794 (1.8%)
Musculoskeletal and connective tissue disorders
Muscle- pain	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Musculoskeletal/soft tissue-other	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Nonneuropathic lower extr muscle weak	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Back- pain	0/231 (0%)		1/232 (0.4%)		2/794 (0.3%)
Joint- pain	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Bone- pain	1/231 (0.4%)		0/232 (0%)		3/794 (0.4%)
Extremity-limb- pain	2/231 (0.9%)		1/232 (0.4%)		4/794 (0.5%)
Osteonecrosis (avascular necrosis)	15/231 (6.5%)		15/232 (6.5%)		45/794 (5.7%)
Nervous system disorders
Neurologic-other	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Speech impairment	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Syncope	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
CNS- hemorrhage	4/231 (1.7%)		0/232 (0%)		4/794 (0.5%)
Neuropathy-sensory	1/231 (0.4%)		0/232 (0%)		4/794 (0.5%)
Neuropathy-motor	0/231 (0%)		0/232 (0%)		5/794 (0.6%)
Seizure	5/231 (2.2%)		5/232 (2.2%)		17/794 (2.1%)
Psychiatric disorders
Agitation	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Psychosis	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Personality	1/231 (0.4%)		0/232 (0%)		2/794 (0.3%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Cough	1/231 (0.4%)		0/232 (0%)		1/794 (0.1%)
Hypoxia	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Pulmonary/Upper Respiratory-other	0/231 (0%)		1/232 (0.4%)		1/794 (0.1%)
Pneumonitis/pulmonary infiltrates	0/231 (0%)		2/232 (0.9%)		2/794 (0.3%)
Skin and subcutaneous tissue disorders
Erythema multiforme	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Ulceration	0/231 (0%)		0/232 (0%)		1/794 (0.1%)
Skin-other	2/231 (0.9%)		3/232 (1.3%)		5/794 (0.6%)
Vascular disorders
Hypotension	1/231 (0.4%)		1/232 (0.4%)		2/794 (0.3%)
Vascular access-Thrombosis/embolism	1/231 (0.4%)		3/232 (1.3%)		6/794 (0.8%)
Thrombosis/thrombus/embolism	9/231 (3.9%)		4/232 (1.7%)		22/794 (2.8%)
Hypertension	8/231 (3.5%)		4/232 (1.7%)		58/794 (7.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.