Augmented Berlin-Frankfurt-Munster (BFM) Therapy for Adolescent/Young Adults With Acute Lymphoblastic Leukemia or Acute Lymphoblastic Lymphoma

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00866749
• Collaborator: (none)
• Enrollment: 120
• Location: 1
• Arm: 1
• Actual Duration (Months): 142.4
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

Objectives:

A. Primary objective:

1 To assess the feasibility and the effectiveness of pediatric type therapy (augmented BFM) in patients age 12 through 40 with untreated precursor-B or T acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL).

B. Secondary objective:

1. To evaluate the prognostic significance of minimal residual disease in bone marrow samples at the end of induction and at the end of consolidation in this group of patients.

2. To prospectively evaluate gene hypermethylation status in this group of patients.

3. To prospectively analyze asparaginase activity and anti-asparaginase antibody formation in this population of patients.

Condition or Disease	Intervention/Treatment	Phase
Lymphoblastic Leukemia; Lymphoblastic Lymphoma	Drug: Daunorubicin; Drug: Vincristine; Drug: PEG-asparaginase; Drug: Intrathecal Methotrexate; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Doxorubicin; Drug: Thioguanine	Phase 2

Detailed Description

Induction:

During Induction, you will receive augmented Berlin-Frankfurt-Munster chemotherapy, which is made up of a combination of Cerubidine®, Daunorubicin Hydrochloride (daunorubicin), Oncovin® (vincristine), prednisone, dexamethasone, Oncaspar® (PEG Asparaginase), and MTX amethopterin (methotrexate). All of these drugs are designed to interfere with the multiplication of cancer cells to cause them to die and to keep the cancer from coming back.

If you are found to be eligible to take part in this study, on Day 1 or during the spinal tap procedure, you will be given cytarabine as an injection in your spinal fluid. Within 3 days, you will begin the Induction course, which will last for 4 weeks.

Daunorubicin and vincristine will be given through a needle in your vein on Days 1, 8,15, and 22. During the first week of therapy, you will be given 1 infusion of PEG Asparaginase by vein. You will take prednisone by mouth on Days 1-28. Methotrexate will be injected into your spinal fluid on Weeks 2 and 5 during your spinal tap. Cerebrospinal fluid (CSF) studies will be sent with each spinal tap to test the fluid for leukemia. If there is disease in your spinal fluid before starting the treatment, you will be given additional methotrexate doses once a week until there is no disease present. You will continue to receive methotrexate in spinal taps every other week for 8 doses, then monthly for 6 doses.

Blood (about 3 teaspoons) will be drawn multiple times during the study for routine tests. You will have a bone marrow aspirate or biopsy on Days 15 and 29 and then as needed to confirm remission.

If you have less than 5% immature cells in the bone marrow, 1 week after Induction, you will continue treatment with Consolidation 1. If you achieved remission after 4 weeks of Induction treatment, you will then have treatment with Consolidation 1, which will be discussed in a separate informed consent document.

If you have LL and had no bone marrow involvement at screening, you will have a chest x-ray, CT scans, and PET scans to measure the disease. Consolidation 1 and other phases of chemotherapy will be discussed in a separate informed consent document.

If you still have more than 5% leukemia cells in the bone marrow after Induction therapy, you will receive 2 extra weeks of therapy called "Extended Induction" before going to the next phase of therapy. You will receive daunorubicin by vein on Day 1. You will receive vincristine on Weeks 1 and 2 by vein. You will take prednisone by mouth on Days 1-14. You will receive PEG Asparaginase by vein in the first week of the Extended Induction. Blood (about 3 teaspoons) will be drawn weekly during the Extended Induction period for routine tests.

At the end of the Extended Induction period, you will have a physical exam and a bone marrow aspirate or biopsy to learn your response to treatment.

After Extended Induction, if the disease is in remission, then you will have 1 course of Consolidation 1, 2 courses of Consolidation 2, and 2 courses of Consolidation 3 before proceeding to Maintenance therapy. A separate discussion and informed consent document for Consolidation and Maintenance will be provided.

Length of Study:

You may remain on study for as long as you are benefiting. However, if after Extended Induction, the disease is not in remission, you will be taken off study, and your doctor will discuss other treatment options with you.

You may be taken off study if the disease gets worse or comes back during treatment, intolerable side effects occur, new information becomes available to your study doctor, if your doctor thinks it is in your best interest, or if you do not attend your appointments, which are scheduled at least once every 3 months.

This is an investigational study. The chemotherapy drugs used in this study are FDA approved and commercially available. Up to 125 patients will take part in this study. All will be enrolled at MD Anderson.

Consolidation and Maintenance:

During Consolidation, you will receive cyclophosphamide, cytarabine, 6-mercaptopurine, vincristine, PEG asparaginase, methotrexate, doxorubicin, 6-thioguanine, and dexamethasone. During Maintenance, you will receive, vincristine, dexamethasone, 6-mercaptopurine, and methotrexate. All of these drugs are designed to interfere with the multiplication of cancer cells to cause them to die and to keep the cancer from coming back.

If you achieved remission after 4 weeks of induction treatment, you will have treatment with Consolidation 1, Consolidation 2, Consolidation 3 (Parts A and B), and then you will proceed to Maintenance therapy.

If the level of blast cells in your blood is above a certain level at Day 15 of Induction but you achieved complete remission by Day 29, or if you achieved remission after 6 weeks of induction plus extended induction, then you will receive 1 course of Consolidation 1, 2 courses of Consolidation 2, 2 courses of Consolidation 3 (Parts A and B), and then you will proceed to maintenance therapy.

Consolidation 1 will last for 8 weeks (2 months). You will receive cyclophosphamide through a needle in your vein on Weeks 1 and 5. Cytarabine will be given as an injection just beneath the skin or by vein on or around Days 1-4 and Days 8-11 of each month. 6-Mercaptopurine will be taken by mouth on Days 1-14 of each month. Vincristine will be given by vein on Weeks 3-4 of each month. PEG Asparaginase will be given by vein on Week 3 and 6 of each month. You will receive methotrexate through a needle through your spine weekly during Month 1 only. Blood (about 3 teaspoons) will be drawn for routine tests. You will have a spinal tap with spinal fluid tests during the intrathecal methotrexate dose. A spinal tap (also called a lumbar puncture) is when a special needle is inserted into the lower back through the space between the bones to draw a sample of the fluid that surrounds the spinal cord. You will have a bone marrow aspiration at the end of Month 2. To collect a bone marrow aspirate, an area of the hip or chest bone is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle.

Consolidation 2 will last for 7 weeks. You will receive vincristine and methotrexate by vein every 10 plus or minus 2 days for 5 doses. You will receive PEG Asparaginase by vein in Weeks 1 and 4. You will receive intrathecal methotrexate in Weeks 1 and 5. You will have a spinal tap with spinal fluid tests during the intrathecal methotrexate dose. Blood (about 3 teaspoons) will be drawn every 2 weeks for routine tests.

Consolidation 3 (Part A) will last for 4 weeks. You will receive vincristine and Doxorubicin by vein in Weeks 1, 2 and 3. Dexamethasone will be taken by mouth on Days 1-7 and Days 15-21. You will receive PEG Asparaginase by vein on Week 1. You will receive intrathecal methotrexate in Week 1.

Consolidation 3 (Part B) will last for 4 weeks. You will receive cyclophosphamide by vein in Week 1. You will receive cytarabine by vein or as an injection for 4 days in a row in Weeks 1-2. You will take 6-Thioguanine by mouth every day for the first 2 weeks. You will receive intrathecal methotrexate in Weeks 1 and 2. You will receive vincristine by vein on Weeks 3 and 4. You will receive PEG Asparaginase by vein on Week 3.

During Consolidation 3 (Part A and B), blood (about 3 teaspoons) will be drawn at least weekly for routine tests. Spinal fluid tests will be sent with each intrathecal methotrexate dose. Spinal taps will be done during each intrathecal chemotherapy dose

Once you finish Consolidation, you will proceed to maintenance therapy.

The Maintenance period for ALL patients will last for 24 months. If you have ALL, you will receive vincristine by vein every month. You will take dexamethasone by mouth for 5 days every month. You will take 6-Mercaptopurine by mouth once daily. You will take methotrexate by mouth every week. You will receive intrathecal methotrexate every 3 months for the first 12 months of maintenance. You will have a spinal tap with spinal fluid tests during the intrathecal methotrexate dose.

Maintenance for patients with LL will also last for 24 months. If you have LL, you will receive vincristine by vein every month. You will take dexamethasone by mouth for 5 days every month.

You will take 6-Mercaptopurine by mouth once daily. You will take methotrexate by mouth every week.

During the Maintenance period, all participants will have blood samples (about 1 to 3 teaspoons each time) drawn every 3 months for routine tests.

If you have LL, you will have an additional positron emission tomography (PET) scan and computed tomography (CT) scan at the end of the Maintenance period.

Follow-Up Visits:

Your study doctor will inform you of your follow-up visits in the clinic. At each follow-up visit there will be a physical exam and complete blood count. You will be followed-up for the next 3 years after your the last dose of your chemotherapy.

Length of Study:

You may remain on study for as long as you are benefiting. You may be taken off study if the disease gets worse or comes back during treatment, intolerable side effects occur, new information becomes available to your study doctor, if your doctor thinks it is in your best interest, or if you do not attend your appointments, which are scheduled at least once every 3 months.

This is an investigational study. The chemotherapy drugs used in this study are all FDA approved and commercially available. Up to 125 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 120 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Augmented Berlin-Frankfurt-Munster Therapy for Adolescents/Young Adults With Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
• Actual Study Start Date: Sep 12, 2006
• Actual Primary Completion Date: Jul 26, 2018
• Actual Study Completion Date: Jul 26, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Augmented BFM Therapy Induction + Maintenance: Daunorubicin, Vincristine, PEG-asparaginase, Intrathecal Methotrexate, Cyclophosphamide, Cytarabine, Mercaptopurine, Doxorubicin, Thioguanine

Drug: Daunorubicin; Starting Dose 25 mg/m^2 by vein weekly; Other Names: Cerubidine® ; Drug: Vincristine; Starting Dose 2 mg by vein weekly; Other Names: Vincasar® ; Drug: PEG-asparaginase; Starting Dose 2000 International units/m2 by vein in week 1; Other Names: Oncaspar® ; Drug: Intrathecal Methotrexate; Starting Dose 12 mg on week 2 and week 5 injected into spinal fluid; Other Names: Rheumatrex® ; Drug: Cyclophosphamide; Starting Dose 1g/m2 by vein in weeks 1 and 5; Other Names: Cytoxan® ; Drug: Cytarabine; 75 mg/m2 subcutaneous or by vein for four consecutive days on days 1-4 and days 8-11 of both months; Other Names: Cytosar-U® ; Drug: Mercaptopurine; Starting Dose 60 mg/m2 by mouth on days 1-14 of each month; Other Names: Purinethol® ; Drug: Methotrexate; Starting Dose at 100 mg/m2 by vein and escalating by 50 mg/m2/dose every 10 +/- 2 days for 5 doses to toxicity (e.g myelosuppression or mucositis grade 3; Other Names: Rheumatrex® ; Drug: Doxorubicin; 25 mg/m2 by vein in weeks 1, 2 and 3; Other Names: Adriamycin® ; Drug: Thioguanine; 60 mg/m2 by mouth daily for two weeks; Other Names: Thioguanine Tabloid®

Outcome Measures

Primary Outcome Measures

1. 3-Year Event-Free Survival (EFS) [3 Years]

   3-year EFS was calculated based on the participants with a complete response (CR). Study regimen considered successful if it exhibits a 3-year EFS rate greater than 60% and response rate no less than 90% with Grade III-IV infectious toxicity rate in induction no more than 33%.

2. Overall Survival [Up to 12 years]

   Overall Survival defined: Time from date of treatment start until date of death due to any cause or last Follow-up.

3. Participants With a Complete Response (CR) [Up to 1 year]

   Complete Response defined as: Bone Marrow blasts </= 5%, Platelets >/= 100 and an Absolute Neutrophil Count (ANC) >/= 1000

Secondary Outcome Measures

1. Participants Achieving Negative Minimal Residual Disease (MRD) [up to 3 months]

   To evaluate the prognostic significance of minimal residual disease (MRD) in bone marrow samples of participants who achieved a complete response (CR) at the end of induction (day 29) and at the end of consolidation (day 84) in this group of patients.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients must have precursor-B or T-lymphoblastic leukemia or lymphoblastic lymphoma.

2. Patients must be untreated or have had only one prior chemotherapy regimen for ALL or LL . Previously treated patients will be analyzed separately.

3. Age between 12 to 40 years old

4. Patients with Central Nervous System (CNS) disease or testicular disease are eligible.

5. Intrathecal therapy 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. Systemic chemotherapy must begin within 72 hours of the first intrathecal treatment.

6. Signed informed consent prior to the start of systemic therapy. In the event of enrollment of a minor patient, an attempt to obtain assent from the patient must be documented, and parental consent must be signed.

7. Echocardiogram should be done within 72 hours of starting therapy if there are cardiac risk factors (e.g., history of hypertension or of myocardial infarction)

8. Creatinine should be < 3 mg/dL bilirubin < 3 mg/dl unless felt to be due to disease

9. Zubrod Performance status of <3

10. Patients who received steroids more than 72 hours prior to study enrollment are eligible but will be analyzed separately

Exclusion Criteria:

1. Age less than twelve years of age or greater than 40 years.

2. More than one prior treatment regimen for ALL or LL.

3. The patient is pregnant or unwilling to practice appropriate birth control.

4. Presence of the Philadelphia chromosome t(9;22)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Michael E. Rytting, M.D., M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 18, 2014

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00866749
• Other Study ID Numbers: 2006-0375; NCI-2012-01650
• First Posted: Mar 20, 2009
• Last Update Posted: Sep 10, 2019
• Last Verified: Aug 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: acute lymphoblastic leukemia; acute lymphoblastic lymphoma; Leukemia; ALL; 6-Thioguanine; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Methotrexate; PEG-L-Asparaginase; Vincristine; Intrathecal Methotrexate; Mercaptopurine
• Additional relevant MeSH terms: Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Cytarabine; Cyclophosphamide; Doxorubicin; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Thioguanine; Pegaspargase

Study Results

Participant Flow

Recruitment Details	Recruitment Period: October 2006 - March 2014

Arm/Group Title	Augmented BFM Therapy
Arm/Group Description	Induction + Maintenance: Daunorubicin, Vincristine, PEG-asparaginase, Intrathecal Methotrexate, Cyclophosphamide, Cytarabine, Mercaptopurine, Doxorubicin, Thioguanine Daunorubicin: Starting Dose 25 mg/m^2 by vein weekly Vincristine: Starting Dose 2 mg by vein weekly PEG-asparaginase: Starting Dose 2000 International units/m2 by vein in week 1 Intrathecal Methotrexate: Starting Dose 12 mg on week 2 and week 5 injected into spinal fluid Cyclophosphamide: Starting Dose 1g/m2 by vein in weeks 1 and 5 Cytarabine: 75 mg/m2 subcutaneous or by vein for four consecutive days on days 1-4 and days 8-11 of both months Mercaptopurine: Starting Dose 60 mg/m2 by mouth on days 1-14 of each month Methotrexate: Starting Dose at 100 mg/m2 by vein and escalating by 50 mg/m2/dose every 10 +/- 2 days for 5 doses to toxicity (e.g myelosuppression or mucositis grade 3 Doxorubicin: 25 mg/m2 by vein in weeks 1, 2 and 3 Thioguanine: 60 mg/m2 by mouth daily for two weeks
Period Title: Overall Study
STARTED	120
COMPLETED	120
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Augmented BFM Therapy
Arm/Group Description	Induction + Maintenance: Daunorubicin, Vincristine, PEG-asparaginase, Intrathecal Methotrexate, Cyclophosphamide, Cytarabine, Mercaptopurine, Doxorubicin, Thioguanine Daunorubicin: Starting Dose 25 mg/m^2 by vein weekly Vincristine: Starting Dose 2 mg by vein weekly PEG-asparaginase: Starting Dose 2000 International units/m2 by vein in week 1 Intrathecal Methotrexate: Starting Dose 12 mg on week 2 and week 5 injected into spinal fluid Cyclophosphamide: Starting Dose 1g/m2 by vein in weeks 1 and 5 Cytarabine: 75 mg/m2 subcutaneous or by vein for four consecutive days on days 1-4 and days 8-11 of both months Mercaptopurine: Starting Dose 60 mg/m2 by mouth on days 1-14 of each month Methotrexate: Starting Dose at 100 mg/m2 by vein and escalating by 50 mg/m2/dose every 10 +/- 2 days for 5 doses to toxicity (e.g myelosuppression or mucositis grade 3 Doxorubicin: 25 mg/m2 by vein in weeks 1, 2 and 3 Thioguanine: 60 mg/m2 by mouth daily for two weeks
Overall Participants	120
Age (Count of Participants)
<=18 years	24 20%
Between 18 and 65 years	96 80%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	22
Sex: Female, Male (Count of Participants)
Female	44 36.7%
Male	76 63.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	7 5.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	7 5.8%
White	104 86.7%
More than one race	0 0%
Unknown or Not Reported	2 1.7%
Region of Enrollment (participants) [Number]
United States	120 100%

Outcome Measures

1. Primary Outcome

Title	3-Year Event-Free Survival (EFS)
Description	3-year EFS was calculated based on the participants with a complete response (CR). Study regimen considered successful if it exhibits a 3-year EFS rate greater than 60% and response rate no less than 90% with Grade III-IV infectious toxicity rate in induction no more than 33%.
Time Frame	3 Years

Outcome Measure Data

Analysis Population Description

Of the 108 participants who had a complete response, 68 met the definition for 3 year EFS.

Arm/Group Title	Augmented BFM Therapy
Arm/Group Description	Induction + Maintenance: Daunorubicin, Vincristine, PEG-asparaginase, Intrathecal Methotrexate, Cyclophosphamide, Cytarabine, Mercaptopurine, Doxorubicin, Thioguanine Daunorubicin: Starting Dose 25 mg/m^2 by vein weekly Vincristine: Starting Dose 2 mg by vein weekly PEG-asparaginase: Starting Dose 2000 International units/m2 by vein in week 1 Intrathecal Methotrexate: Starting Dose 12 mg on week 2 and week 5 injected into spinal fluid Cyclophosphamide: Starting Dose 1g/m2 by vein in weeks 1 and 5 Cytarabine: 75 mg/m2 subcutaneous or by vein for four consecutive days on days 1-4 and days 8-11 of both months Mercaptopurine: Starting Dose 60 mg/m2 by mouth on days 1-14 of each month Methotrexate: Starting Dose at 100 mg/m2 by vein and escalating by 50 mg/m2/dose every 10 +/- 2 days for 5 doses to toxicity (e.g myelosuppression or mucositis grade 3 Doxorubicin: 25 mg/m2 by vein in weeks 1, 2 and 3 Thioguanine: 60 mg/m2 by mouth daily for two weeks
Measure Participants	108
Count of Participants [Participants]	68 56.7%

2. Primary Outcome

Title	Overall Survival
Description	Overall Survival defined: Time from date of treatment start until date of death due to any cause or last Follow-up.
Time Frame	Up to 12 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Augmented BFM Therapy
Arm/Group Description	Induction + Maintenance: Daunorubicin, Vincristine, PEG-asparaginase, Intrathecal Methotrexate, Cyclophosphamide, Cytarabine, Mercaptopurine, Doxorubicin, Thioguanine Daunorubicin: Starting Dose 25 mg/m^2 by vein weekly Vincristine: Starting Dose 2 mg by vein weekly PEG-asparaginase: Starting Dose 2000 International units/m2 by vein in week 1 Intrathecal Methotrexate: Starting Dose 12 mg on week 2 and week 5 injected into spinal fluid Cyclophosphamide: Starting Dose 1g/m2 by vein in weeks 1 and 5 Cytarabine: 75 mg/m2 subcutaneous or by vein for four consecutive days on days 1-4 and days 8-11 of both months Mercaptopurine: Starting Dose 60 mg/m2 by mouth on days 1-14 of each month Methotrexate: Starting Dose at 100 mg/m2 by vein and escalating by 50 mg/m2/dose every 10 +/- 2 days for 5 doses to toxicity (e.g myelosuppression or mucositis grade 3 Doxorubicin: 25 mg/m2 by vein in weeks 1, 2 and 3 Thioguanine: 60 mg/m2 by mouth daily for two weeks
Measure Participants	120
Median (Full Range) [Months]	121

3. Primary Outcome

Title	Participants With a Complete Response (CR)
Description	Complete Response defined as: Bone Marrow blasts </= 5%, Platelets >/= 100 and an Absolute Neutrophil Count (ANC) >/= 1000
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Augmented BFM Therapy
Arm/Group Description	Induction + Maintenance: Daunorubicin, Vincristine, PEG-asparaginase, Intrathecal Methotrexate, Cyclophosphamide, Cytarabine, Mercaptopurine, Doxorubicin, Thioguanine Daunorubicin: Starting Dose 25 mg/m^2 by vein weekly Vincristine: Starting Dose 2 mg by vein weekly PEG-asparaginase: Starting Dose 2000 International units/m2 by vein in week 1 Intrathecal Methotrexate: Starting Dose 12 mg on week 2 and week 5 injected into spinal fluid Cyclophosphamide: Starting Dose 1g/m2 by vein in weeks 1 and 5 Cytarabine: 75 mg/m2 subcutaneous or by vein for four consecutive days on days 1-4 and days 8-11 of both months Mercaptopurine: Starting Dose 60 mg/m2 by mouth on days 1-14 of each month Methotrexate: Starting Dose at 100 mg/m2 by vein and escalating by 50 mg/m2/dose every 10 +/- 2 days for 5 doses to toxicity (e.g myelosuppression or mucositis grade 3 Doxorubicin: 25 mg/m2 by vein in weeks 1, 2 and 3 Thioguanine: 60 mg/m2 by mouth daily for two weeks
Measure Participants	120
Number [participants]	108 90%

4. Secondary Outcome

Title	Participants Achieving Negative Minimal Residual Disease (MRD)
Description	To evaluate the prognostic significance of minimal residual disease (MRD) in bone marrow samples of participants who achieved a complete response (CR) at the end of induction (day 29) and at the end of consolidation (day 84) in this group of patients.
Time Frame	up to 3 months

Outcome Measure Data

Analysis Population Description

Of the 108 participants who achieved a complete response (CR), 60 participants were MRD negative on day 29 and an additional 27 participants were MRD negative on day 84 for a total 87 MRD negative participants on day 84

Arm/Group Title	Augmented BFM Therapy
Arm/Group Description	Induction + Maintenance: Daunorubicin, Vincristine, PEG-asparaginase, Intrathecal Methotrexate, Cyclophosphamide, Cytarabine, Mercaptopurine, Doxorubicin, Thioguanine Daunorubicin: Starting Dose 25 mg/m^2 by vein weekly Vincristine: Starting Dose 2 mg by vein weekly PEG-asparaginase: Starting Dose 2000 International units/m2 by vein in week 1 Intrathecal Methotrexate: Starting Dose 12 mg on week 2 and week 5 injected into spinal fluid Cyclophosphamide: Starting Dose 1g/m2 by vein in weeks 1 and 5 Cytarabine: 75 mg/m2 subcutaneous or by vein for four consecutive days on days 1-4 and days 8-11 of both months Mercaptopurine: Starting Dose 60 mg/m2 by mouth on days 1-14 of each month Methotrexate: Starting Dose at 100 mg/m2 by vein and escalating by 50 mg/m2/dose every 10 +/- 2 days for 5 doses to toxicity (e.g myelosuppression or mucositis grade 3 Doxorubicin: 25 mg/m2 by vein in weeks 1, 2 and 3 Thioguanine: 60 mg/m2 by mouth daily for two weeks
Measure Participants	108
Participants with CR and MRD negative on Day 29	60 50%
Participants with CR and MRD negative on day 84	87 72.5%

Adverse Events

Time Frame	Participants were assessed through study completion, for up to 3 years.
Arm/Group Title	Augmented BFM Therapy
Arm/Group Description	Induction + Maintenance: Daunorubicin, Vincristine, PEG-asparaginase, Intrathecal Methotrexate, Cyclophosphamide, Cytarabine, Mercaptopurine, Doxorubicin, Thioguanine Daunorubicin: Starting Dose 25 mg/m^2 by vein weekly Vincristine: Starting Dose 2 mg by vein weekly PEG-asparaginase: Starting Dose 2000 International units/m2 by vein in week 1 Intrathecal Methotrexate: Starting Dose 12 mg on week 2 and week 5 injected into spinal fluid Cyclophosphamide: Starting Dose 1g/m2 by vein in weeks 1 and 5 Cytarabine: 75 mg/m2 subcutaneous or by vein for four consecutive days on days 1-4 and days 8-11 of both months Mercaptopurine: Starting Dose 60 mg/m2 by mouth on days 1-14 of each month Methotrexate: Starting Dose at 100 mg/m2 by vein and escalating by 50 mg/m2/dose every 10 +/- 2 days for 5 doses to toxicity (e.g myelosuppression or mucositis grade 3 Doxorubicin: 25 mg/m2 by vein in weeks 1, 2 and 3 Thioguanine: 60 mg/m2 by mouth daily for two weeks
All Cause Mortality
	Augmented BFM Therapy
	Affected / at Risk (%)	# Events
Total	6/120 (5%)
Serious Adverse Events
	Augmented BFM Therapy
	Affected / at Risk (%)	# Events
Total	64/120 (53.3%)
Blood and lymphatic system disorders
Anemia	1/120 (0.8%)	1
Leukocytosis	1/120 (0.8%)	1
Neutropenia	2/120 (1.7%)	2
Cardiac disorders
Congestive Heart Failure	1/120 (0.8%)	1
Tachycardia	2/120 (1.7%)	2
Eye disorders
Double vision	1/120 (0.8%)	1
Gastrointestinal disorders
Abdominal Cramps	1/120 (0.8%)	1
Abdominal Pain	7/120 (5.8%)	15
Colitis	1/120 (0.8%)	1
Constipation	2/120 (1.7%)	2
Dehydration	6/120 (5%)	6
Diarrhea	1/120 (0.8%)	1
Duodenal Ulcer	1/120 (0.8%)	1
Gallbladder Obstruction	1/120 (0.8%)	1
Gastritis	1/120 (0.8%)	1
Gastroparesis	1/120 (0.8%)	1
Ileus	1/120 (0.8%)	1
Mucositis	6/120 (5%)	6
Nausea/Vomiting	5/120 (4.2%)	6
Pancreatitis	7/120 (5.8%)	9
Pneumoperitoneum	1/120 (0.8%)	1
General disorders
Bone Pain	1/120 (0.8%)	1
Cytomegalovirus antigen positive	2/120 (1.7%)	3
Fatigue	1/120 (0.8%)	1
Fever	11/120 (9.2%)	16
Generalized Edema	1/120 (0.8%)	1
Groin Abscess	1/120 (0.8%)	1
Headache	7/120 (5.8%)	10
Hemorrhage	1/120 (0.8%)	1
Knee Pain	1/120 (0.8%)	2
Pain	2/120 (1.7%)	2
Immune system disorders
Allergic Reaction	1/120 (0.8%)	1
Infections and infestations
Herpes Zoster	1/120 (0.8%)	1
Infection	22/120 (18.3%)	29
Neutropenic Fever	30/120 (25%)	51
Investigations
Elevated Alanine Aminotransferase	1/120 (0.8%)	1
Metabolism and nutrition disorders
Hyperbilirubinemia	3/120 (2.5%)	5
Hyperglycemia	2/120 (1.7%)	2
Hyponatremia	1/120 (0.8%)	1
Musculoskeletal and connective tissue disorders
Ankle Fracture	1/120 (0.8%)	1
Avascular Necrosis	3/120 (2.5%)	3
Muscle Weakness	1/120 (0.8%)	1
Osteoprosis	1/120 (0.8%)	1
Nervous system disorders
Central Nervous System, White matter	1/120 (0.8%)	1
Cerebrovascular Ischemia	1/120 (0.8%)	1
Cognitive Disturbance	1/120 (0.8%)	1
Hydrocephalus	1/120 (0.8%)	1
Leukoencephalopathy	1/120 (0.8%)	1
Neuropathy	2/120 (1.7%)	2
Stroke	1/120 (0.8%)	1
Syncope	2/120 (1.7%)	2
Psychiatric disorders
Anxiety/depression	2/120 (1.7%)	2
Renal and urinary disorders
Acute Renal Failure	1/120 (0.8%)	1
Reproductive system and breast disorders
Endometriosis	1/120 (0.8%)	1
Vaginal Herpes	1/120 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	4/120 (3.3%)	4
Pleuritic Chest Pain	1/120 (0.8%)	1
Pulmonary Other	1/120 (0.8%)	1
Respiratory Failure	1/120 (0.8%)	1
Respiratory Syncytial Virus infection	1/120 (0.8%)	1
Skin and subcutaneous tissue disorders
Rash	1/120 (0.8%)	1
Striae	1/120 (0.8%)	1
Vascular disorders
Embolism	3/120 (2.5%)	3
Hypotension	3/120 (2.5%)	3
Thrombosis	1/120 (0.8%)	1
Other (Not Including Serious) Adverse Events
	Augmented BFM Therapy
	Affected / at Risk (%)	# Events
Total	111/120 (92.5%)
Cardiac disorders
Supraventricualr arrhythmia	6/120 (5%)	7
Gastrointestinal disorders
Colitis	6/120 (5%)	6
Dehydration	9/120 (7.5%)	9
Mucositis	22/120 (18.3%)	26
Constipation	11/120 (9.2%)	11
Pancreatitis	11/120 (9.2%)	12
Nausea	19/120 (15.8%)	23
General disorders
Pain	29/120 (24.2%)	38
Immune system disorders
Allergic reaction/hypersensitivity	23/120 (19.2%)	25
Infections and infestations
Neutropenic Fever	12/120 (10%)	15
Infection	70/120 (58.3%)	138
Investigations
Fibrinogen	43/120 (35.8%)	44
Elevated Alanine Aminotransferase	25/120 (20.8%)	78
Metabolism and nutrition disorders
Hypoalbuminemia	9/120 (7.5%)	9
Lipase	9/120 (7.5%)	9
Hypertriglyceridemia	15/120 (12.5%)	15
Hyperglycemia	22/120 (18.3%)	24
Hyperbilirubinemia	57/120 (47.5%)	87
Musculoskeletal and connective tissue disorders
Osteoporosis	11/120 (9.2%)	12
Osteonecrosis	13/120 (10.8%)	13
Nervous system disorders
Neuropathy motor	19/120 (15.8%)	21
Neuropathy sensor	23/120 (19.2%)	24
Skin and subcutaneous tissue disorders
Rash	6/120 (5%)	6
Vascular disorders
Thrombosis	22/120 (18.3%)	29

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.