Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT01700946

Recruitment Status : Completed

First Posted : October 4, 2012

Last Update Posted : August 24, 2021

Sponsor:

Collaborators:

Cookies for Kids' Cancer

Assisi Foundation

Information provided by (Responsible Party):

St. Jude Children's Research Hospital

Study Description

Brief Summary:

The overall objective of this protocol is to improve the cure rate of relapsed precursor B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma.

This phase II trial is studying risk-directed therapy for B-lymphoblastic leukemia or lymphoma in first relapse. Standard risk (SR) and high risk (HR) participants will receive different therapy. Treatment will consist of chemotherapy for SR participants, and chemotherapy followed by hematopoietic stem cell transplant (HSCT) for HR in first relapse. Induction therapy consists of three blocks of chemotherapy. The first block is a novel immunotherapy regimen that includes chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells. SR participants will continue to receive chemotherapy for a total duration of approximately 2 years. HR participants will be candidates for HSCT and will proceed to transplant once a suitable donor is found and their minimal residual disease (MRD) is negative.

Condition or disease	Intervention/treatment	Phase
Recurrent B-Cell Childhood Acute Lymphoblastic Leukemia Recurrent Childhood B-Lymphoblastic Lymphoma	Drug: dexamethasone Drug: vincristine sulfate Biological: rituximab Drug: clofarabine Drug: cyclophosphamide Drug: etoposide Biological: aldesleukin Drug: pegaspargase Drug: methotrexate Drug: mercaptopurine Drug: cytarabine Drug: mitoxantrone Drug: teniposide Drug: vinblastine Biological: natural killer cell infusion Other: laboratory biomarker analysis Drug: therapeutic hydrocortisone Procedure: allogeneic hematopoietic stem cell transplantation Device: CliniMACS	Phase 2

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Detailed Description:

Primary objective

To estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL and lymphoblastic lymphoma treated with risk-directed therapy.

Secondary objectives

To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17
To estimate levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of remission induction therapy for relapsed precursor B-cell ALL.

STUDY DESCRIPTION:

The general treatment plan will consist of chemotherapy for standard-risk participants and chemotherapy followed by HSCT for high risk participants in first relapse of B-precursor ALL or lymphoblastic lymphoma. Remission induction for all participants consists of three blocks of therapy, wherein the first block is a novel immunotherapy regimen that includes cytotoxic chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells. Standard-risk patients will continue to receive chemotherapy for a total duration of approximately 2 years. High-risk patients will be candidates for HSCT and will proceed to transplant once a suitable donor is found and the patient achieves negative MRD.

Participants will be assigned to the standard arm if they experience late relapse (> or = 6 months after completion of frontline therapy) AND maximum residual disease (MRD) is <0.01% at the end of Block II of remission induction therapy. Provisional standard risk participants (i.e., late relapse) will be re-assigned to high risk if MRD is > or = 0.01% at the end of Block II. Participants with lymphoma must be in complete remission at the end of Block III.

High risk participants will meet one of the following criteria:

Early relapse (on therapy or <6 months after completion of frontline therapy), OR
Any relapse after hematopoietic stem cell transplant, OR
MRD > or = 0.01% at the end of Block II of remission induction therapy, OR
Re-emergence of MRD at any time after attaining negative MRD on this clinical trial.

Natural killer (NK) cell collection: Donors who meet eligibility criteria will undergo apheresis once. The cells obtained will be purified for CD56+ cells utilizing the CliniMACS selection system. The NK cell product will undergo quality control testing following standard operating procedures of the St. Jude Human Applications Laboratory.

OUTLINE (STANDARD RISK):

REMISSION INDUCTION:

BLOCK I: Patients receive dexamethasone orally (PO) or intravenously (IV) thrice daily (TID) on days 1-8 and 21-28; vincristine sulfate IV on days 1, 21, 28, and 35; rituximab IV on days 4, 13, 20, and 27; clofarabine, cyclophosphamide, and etoposide IV on days 6-10; aldesleukin subcutaneously (SC) once every other day (QOD) on days 11-19; and pegaspargase IV on days 21 and 35. Patients also undergo natural killer (NK) cell infusion on day 12. Patients may receive triple intrathecal therapy comprising methotrexate, therapeutic hydrocortisone, and cytarabine on days 1, 5, 8, 11, 21, and 28. Patients continue on to Block II after count recovery.

BLOCK II: Patients receive methotrexate IV over 24 hours on days 1 and 8 and mercaptopurine PO on days 1-21. Patients also receive triple intrathecal therapy on day 1. High-risk patients with negative MRD continue on to transplantation. All patients with positive MRD continue on to Block III after count recovery.

BLOCK III: Patients receive cytarabine IV over 2 hours twice daily (BID) on days 1-4 and mitoxantrone hydrochloride IV over 1 hour on days 3-5. Patients also receive triple intrathecal therapy on day 7.

INTERIM CONTINUATION (for patients unable to tolerate dose intensive chemotherapy): Patients receive etoposide and cyclophosphamide IV on day 1, methotrexate IV on day 8, mercaptopurine PO on days 8-14, teniposide and cytarabine IV on day 15, dexamethasone PO TID on days 22-26, and vinblastine IV on day 22.

RE-INDUCTION THERAPY: Patients receive clofarabine, cyclophosphamide, and etoposide IV on days 1-5; dexamethasone PO on days 1-6; and pegaspargase on days 6 and 20 and vincristine sulfate IV on days 6, 13, and 20. Patients may also receive triple intrathecal therapy on days 1 and 15. Patients continue on to continuation treatment after count recovery.

CONTINUATION TREATMENT: Patients receive methotrexate IV over 2 hours on day 1 and mercaptopurine PO on days 1-7 of weeks 1, 2, 5, and 6; teniposide and cytarabine IV on day 1 of weeks 3 and 7; vincristine sulfate IV on day 1 of week 4; dexamethasone PO TID on days 1-5 of weeks 4 and 8; and vinblastine IV on day 1 of week 8. Treatment repeats every 8 weeks for up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients may also receive triple intrathecal therapy on day 1 of week 1 of all courses and day 1 of week 5, courses 1-5.

Due to the unavailability of the drug Teniposide (VM-26), etoposide (VP-16) will be substituted for the remaining doses for patients currently on this study. The protocol Section 5.1.3 allows this substitution.

OUTLINE: GROUP 2 (high risk defined as participants not meeting the standard risk criteria noted above):

Patients receive Remission Induction (Blocks I, II, and III) treatment as described above for Group 1. Patients then undergo allogeneic hematopoietic stem cell transplantation (HSCT) as soon as they have negative MRD. Patients with negative MRD may continue chemotherapy until a suitable donor is found.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 1 year, and then yearly for up to 10 years.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	94 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase II Study of Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma
Actual Study Start Date :	April 15, 2013
Actual Primary Completion Date :	July 24, 2021
Actual Study Completion Date :	July 24, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Chronic Lymphocytic Leukemia Leukemia Lymphoma

Genetic and Rare Diseases Information Center resources: Lymphosarcoma Childhood Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma Acute Graft Versus Host Disease

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Standard Risk Interventions: dexamethasone, vincristine sulfate, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, teniposide, vinblastine, natural killer cell infusion, laboratory biomarker analysis, therapeutic hydrocortisone Cells for infusion are prepared using the CliniMACS System.	Drug: dexamethasone given intravenously or orally Other Name: Decadron(R) Drug: vincristine sulfate given intravenously Other Name: Oncovin(R) Biological: rituximab given intravenously Other Name: Rituxan(R) Drug: clofarabine given intravenously Other Names: Clolar(TM) clofarex Drug: cyclophosphamide given intravenously Other Name: Cytoxan(R) Drug: etoposide given intravenously Other Names: VP-16 Vepesid(R) Biological: aldesleukin given subcutaneously Other Names: IL-2 interleukin-2 Proleukin (R) Drug: pegaspargase given intravenously Other Names: PEG-ASP Peg-L-asparaginase PEG-asparaginase Oncaspar(R) Drug: methotrexate given intrathecally or intravenously Other Names: MTX HDMTX Drug: mercaptopurine given orally Other Names: 6-MP Purinethol(R) Drug: cytarabine given intrathecally or intravenously Other Names: Ara-C Cytosar-U(R) Drug: mitoxantrone given intravenously Other Name: Novantrone(R) Drug: teniposide given intravenously Other Names: VM-26 Vumon(R) Drug: vinblastine given intravenously Other Name: Velban(R) Biological: natural killer cell infusion undergo allogeneic natural killer cell infusion Other Name: NK cell infusion Other: laboratory biomarker analysis correlative studies Drug: therapeutic hydrocortisone given intrathecally Other Name: Cortef Device: CliniMACS The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells. Other Name: Cell Selection System
Active Comparator: High Risk Interventions: dexamethasone, vincristine, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, natural killer cell infusion, allogeneic hematopoietic stem cell transplantation, laboratory biomarker analysis, therapeutic hydrocortisone Cells for infusion are prepared using the CliniMACS System.	Drug: dexamethasone given intravenously or orally Other Name: Decadron(R) Drug: vincristine sulfate given intravenously Other Name: Oncovin(R) Biological: rituximab given intravenously Other Name: Rituxan(R) Drug: clofarabine given intravenously Other Names: Clolar(TM) clofarex Drug: cyclophosphamide given intravenously Other Name: Cytoxan(R) Drug: etoposide given intravenously Other Names: VP-16 Vepesid(R) Biological: aldesleukin given subcutaneously Other Names: IL-2 interleukin-2 Proleukin (R) Drug: pegaspargase given intravenously Other Names: PEG-ASP Peg-L-asparaginase PEG-asparaginase Oncaspar(R) Drug: methotrexate given intrathecally or intravenously Other Names: MTX HDMTX Drug: mercaptopurine given orally Other Names: 6-MP Purinethol(R) Drug: cytarabine given intrathecally or intravenously Other Names: Ara-C Cytosar-U(R) Drug: mitoxantrone given intravenously Other Name: Novantrone(R) Biological: natural killer cell infusion undergo allogeneic natural killer cell infusion Other Name: NK cell infusion Other: laboratory biomarker analysis correlative studies Drug: therapeutic hydrocortisone given intrathecally Other Name: Cortef Procedure: allogeneic hematopoietic stem cell transplantation undergo allogeneic HSCT Other Name: HSCT Device: CliniMACS The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells. Other Name: Cell Selection System

Arm

Intervention/treatment

Active Comparator: Standard Risk

Interventions: dexamethasone, vincristine sulfate, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, teniposide, vinblastine, natural killer cell infusion, laboratory biomarker analysis, therapeutic hydrocortisone

Cells for infusion are prepared using the CliniMACS System.

Drug: dexamethasone

given intravenously or orally

Other Name: Decadron(R)

Drug: vincristine sulfate

given intravenously

Other Name: Oncovin(R)

Biological: rituximab

given intravenously

Other Name: Rituxan(R)

Drug: clofarabine

given intravenously

Other Names:

Clolar(TM)
clofarex

Drug: cyclophosphamide

given intravenously

Other Name: Cytoxan(R)

Drug: etoposide

given intravenously

Other Names:

VP-16
Vepesid(R)

Biological: aldesleukin

given subcutaneously

Other Names:

IL-2
interleukin-2
Proleukin (R)

Drug: pegaspargase

given intravenously

Other Names:

PEG-ASP
Peg-L-asparaginase
PEG-asparaginase
Oncaspar(R)

Drug: methotrexate

given intrathecally or intravenously

Other Names:

MTX
HDMTX

Drug: mercaptopurine

given orally

Other Names:

6-MP
Purinethol(R)

Drug: cytarabine

given intrathecally or intravenously

Other Names:

Ara-C
Cytosar-U(R)

Drug: mitoxantrone

given intravenously

Other Name: Novantrone(R)

Drug: teniposide

given intravenously

Other Names:

VM-26
Vumon(R)

Drug: vinblastine

given intravenously

Other Name: Velban(R)

Biological: natural killer cell infusion

undergo allogeneic natural killer cell infusion

Other Name: NK cell infusion

Other: laboratory biomarker analysis

correlative studies

Drug: therapeutic hydrocortisone

given intrathecally

Other Name: Cortef

Device: CliniMACS

The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.

Other Name: Cell Selection System

Active Comparator: High Risk

Interventions: dexamethasone, vincristine, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, natural killer cell infusion, allogeneic hematopoietic stem cell transplantation, laboratory biomarker analysis, therapeutic hydrocortisone

Cells for infusion are prepared using the CliniMACS System.

Drug: dexamethasone

given intravenously or orally

Other Name: Decadron(R)

Drug: vincristine sulfate

given intravenously

Other Name: Oncovin(R)

Biological: rituximab

given intravenously

Other Name: Rituxan(R)

Drug: clofarabine

given intravenously

Other Names:

Clolar(TM)
clofarex

Drug: cyclophosphamide

given intravenously

Other Name: Cytoxan(R)

Drug: etoposide

given intravenously

Other Names:

VP-16
Vepesid(R)

Biological: aldesleukin

given subcutaneously

Other Names:

IL-2
interleukin-2
Proleukin (R)

Drug: pegaspargase

given intravenously

Other Names:

PEG-ASP
Peg-L-asparaginase
PEG-asparaginase
Oncaspar(R)

Drug: methotrexate

given intrathecally or intravenously

Other Names:

MTX
HDMTX

Drug: mercaptopurine

given orally

Other Names:

6-MP
Purinethol(R)

Drug: cytarabine

given intrathecally or intravenously

Other Names:

Ara-C
Cytosar-U(R)

Drug: mitoxantrone

given intravenously

Other Name: Novantrone(R)

Biological: natural killer cell infusion

undergo allogeneic natural killer cell infusion

Other Name: NK cell infusion

Other: laboratory biomarker analysis

correlative studies

Drug: therapeutic hydrocortisone

given intrathecally

Other Name: Cortef

Procedure: allogeneic hematopoietic stem cell transplantation

undergo allogeneic HSCT

Other Name: HSCT

Device: CliniMACS

Other Name: Cell Selection System

Outcome Measures

Primary Outcome Measures :

3-year overall survival rate of patients with relapsed ALL [ Time Frame: At 3 years of follow-up since the on-study date of the last enrolled patient ]
Estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.
3-year event-free survival rates in patients with relapsed ALL [ Time Frame: At 3 years of follow-up since the on-study date of the last enrolled patient ]
Estimate the 3-year event-free survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.

Secondary Outcome Measures :

Proportion of participants with positive minimal residual disease [ Time Frame: At 3 months after the on-study date of the last enrolled patient ]
To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17.
Mean of CD20 expression levels [ Time Frame: approximately 5 weeks after the on-study date of the last enrolled patient ]
To estimate mean levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of remission induction therapy for relapsed precursor B-cell ALL.
Median CD20 expression levels [ Time Frame: approximately 5 weeks after the on-study date of the last enrolled patient ]
To estimate median levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of remission induction therapy for relapsed precursor B-cell ALL.

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:	up to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

INCLUSION CRITERIA:

Must have relapsed or refractory precursor B-cell acute lymphoblastic leukemia or acute lymphoblastic lymphoma.
Participants with leukemia must meet one of the following:
1. In first hematologic relapse, defined as the reappearance (in a patient who has previously achieved remission) of leukemia blasts in the bone marrow or peripheral blood, OR
2. Refractory to one or two courses of frontline induction therapy (≥ 5% blasts in the bone marrow or peripheral blood confirmed by flow cytometric analysis).
Participant with lymphoma must meet one of the following:
1. In first relapse, OR
2. Refractory to one or two courses of frontline induction therapy with measurable disease
  - Should flow cytometric analyses suggest relapse (by the reappearance of a similar immunophenotype to the original leukemia) in the presence of <5% blasts morphologically, a repeat bone marrow test is recommended to confirm relapse.
  - Molecular or genetic relapse is characterized by the reappearance of a cytogenetic or molecular abnormality.
  - Early relapse is defined as relapse on therapy or < 6 months after completion of frontline therapy. Late relapse is defined as relapse occurring ≥ 6 months after completion of frontline therapy.
Participant's age is < 22 years at time of enrollment (e.g. participant is eligible until 22nd birthday).
Prior therapy:
1. There is no waiting period for participants who relapse while receiving frontline therapy and are free from side effects attributable to such therapy.
2. Emergent radiation therapy, one dose of intrathecal chemotherapy, and up to 7 days of steroids for treatment of relapse are permitted before start of treatment in participants who relapse after completion of frontline therapy.
3. At least 90 days have elapsed since bone marrow transplant and participant is off immune suppression for a minimum of 2 weeks, if applicable. Participants with ALL or NHL who were transplanted in first remission are eligible for this study.

Organ function requirements

Hepatic: Total bilirubin ≤ upper limit of normal (ULN) for age, or if total bilirubin is > ULN, direct bilirubin ≤ 1.4 mg/dl
Cardiac: Shortening fraction ≥ 28%
Renal: Glomerular filtration rate >50cc/min/1.73 m^2, OR maximum serum creatinine (SC) based on age as follows:
- If age is 1 to 2 years, then maximum SC is 0.6 mg/dL
- If age is 2 to 6 years, then maximum SC is 0.8 mg/dL
- If age is 6 to 10 years, then maximum SC is 1 mg/dL
- If age is 10 to <13 years, then maximum SC is 1.2 mg/dL
- If age is 13 to 16 years, then maximum SC is 1.5 mg/dL for males and 1.4 mg/dL for females
- If age is >16 years, then maximum SC is 1.7 mg/dL for males and 1.4 mg/dL for females

EXCLUSION CRITERIA:

Leukemia participants ages 1 to 5 years with induction failure AND favorable cytogenetics (i.e., hyperdiploidy defined as DNA index ≥1.16 or modal chromosome number ≥51, or ETV6-RUNXI).
Hepatitis B or HIV infection.
Pregnant or breast-feeding
Inability or unwillingness or research participant or legal guardian/representative to give written informed consent.

INCLUSION CRITERIA FOR NK CELL DONORS:

Donor is at least 18 years of age.
Donor is a family member.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01700946

Locations

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United States, California
Rady Children's Hospital and Health Center
San Diego, California, United States, 92123
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Cook Children's Medical Center
Fort Worth, Texas, United States, 76104

Sponsors and Collaborators

St. Jude Children's Research Hospital

Cookies for Kids' Cancer

Assisi Foundation

Investigators

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Principal Investigator:	Sima Jeha, MD	St. Jude Children's Research Hospital

More Information

Additional Information:

St. Jude Children's Research Hospital This link exits the ClinicalTrials.gov site

Clinical Trials Open at St. Jude This link exits the ClinicalTrials.gov site

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Responsible Party:	St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:	NCT01700946
Other Study ID Numbers:	ALLR18 NCI-2012-00587 ( Registry Identifier: NCi Clinical Trial Registration Program )
First Posted:	October 4, 2012 Key Record Dates
Last Update Posted:	August 24, 2021
Last Verified:	August 2021

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	Yes
Device Product Not Approved or Cleared by U.S. FDA:	Yes

Keywords provided by St. Jude Children's Research Hospital:


leukemia lymphoma Non-Hodgkins

Additional relevant MeSH terms:

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Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Recurrence Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Disease Attributes Pathologic Processes Cytarabine Aldesleukin	Dexamethasone Hydrocortisone Hydrocortisone 17-butyrate 21-propionate Hydrocortisone acetate Hydrocortisone hemisuccinate Cyclophosphamide Rituximab Methotrexate Etoposide Vincristine Interleukin-2 Asparaginase Mitoxantrone Mercaptopurine Clofarabine

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