Pegasparaginase or Asparaginase and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

Condition(s) targeted: Cancer-Related Problem/Condition; Leukemia

Intervention: 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 (Drug); radiation therapy (Procedure)

Phase: Phase 3

Status: Recruiting

Sponsored by: Dana-Farber Cancer Institute

Official(s) and/or principal investigator(s):
Lewis B. Silverman, MD, Principal Investigator, Affiliation: Dana-Farber Cancer Institute

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known whether pegasparaginase is more effective than asparaginase when given together with combination chemotherapy in treating acute lymphoblastic leukemia.

PURPOSE: This randomized phase III trial is studying pegasparaginase to see how well it works compared with asparaginase when given together with combination chemotherapy in treating young patients with newly diagnosed acute lymphoblastic leukemia.

Official title: Treatment of Acute Lymphoblastic Leukemia in Children

Study design: Treatment, Randomized, Open Label

Primary outcome: Toxicity of pegasparaginase vs E. coli asparaginase

Secondary outcome:

Efficacy of pegasparaginase vs E. coli asparaginase

Prognostic significance of asparaginase antibody formation

Correlation of trough enzyme levels with outcome (toxicity and relapse)

Quality of life

Comparison of trough serum asparaginase enzyme levels, asparagine levels, and anti-asparaginase antibody levels

Rate of infections (episodes of bacteremia and disseminated fungal infections) during the remission induction phase of combination chemotherapy

Prognostic significance of response to remission induction chemotherapy as measured by morphology and minimal residual disease (MRD)

Outcome based on MRD status after 28 days of multiagent chemotherapy that intensifies treatment for B-lineage patients with MRD levels > 0.001 at the end of remission induction therapy

Outcome based on MRD status after 14 days of multiagent chemotherapy, every 18 weeks after achieving complete remission, and at the completion of all chemotherapy

Comparison of the outcome of patients (based on bone marrow morphology after 14 days of multiagent chemotherapy) with M2/M3 status vs M1 status or hypoplastic marrows

Efficacy of CNS-directed treatment

CNS-related toxicity of CNS-directed treatment

Relationship between dietary intake and rate of infections and risk of development of fractures during treatment

Detailed description: OBJECTIVES:

Primary

- Compare the relative toxicity of pegasparaginase vs E. coli asparaginase when

administered with combination chemotherapy in children with newly diagnosed acute lymphoblastic leukemia (ALL).

Secondary

- Compare the relative efficacy of these regimens in these patients.

- Determine the prognostic significance of asparaginase antibody formation.

- Correlate trough enzyme levels with outcome (toxicity and relapse).

- Compare the quality of life in patients treated with pegasparaginase vs E. coli

asparaginase.

- Compare trough serum asparaginase enzyme levels, asparagine levels, and

anti-asparaginase antibody levels in patients treated with these regimens.

- Determine the rate of infections (episodes of bacteremia and disseminated fungal

infections) during the remission induction phase of combination chemotherapy in these patients.

- Determine the prognostic significance of response to remission induction chemotherapy as

measured by morphology and minimal residual disease (MRD) measures.

- Determine the outcome of patients based on MRD status after 28 days of multiagent

chemotherapy that intensifies treatment for B-lineage patients with MRD levels greater than 0. 001 at the end of remission induction therapy.

- Determine the outcome of patients based on MRD status after 14 days of multiagent

chemotherapy and at various other time points while on treatment (every 18 weeks after achieving complete remission and at the completion of all chemotherapy).

- Compare the outcome (based on bone marrow morphology after 14 days of multiagent

chemotherapy) of patients with M2/M3 status at that time point vs M1 status or hypoplastic marrows.

- Determine the efficacy and CNS-related toxicity of CNS-directed treatments in these

patients.

- Determine the efficacy and CNS-related toxicity (acute and long-term) of the high-risk

(HR) regimen in which a subset of HR patients are treated with intensive intrathecal (IT) chemotherapy and the remainder are treated with cranial radiation therapy (concurrent with IT chemotherapy).

- Determine the efficacy and CNS-related toxicity (acute and long-term) of intensive IT

therapy in standard-risk patients.

- Correlate dietary antioxidant micronutrient intake (including ascorbic acid, vitamin E,

vitamin A, beta carotene, and total carotenoids) with the rate of infections (episodes of bacteremia and disseminated fungal infections) during remission induction therapy and the consolidation IA phase.

- Correlate dietary calcium intake with risk for development of fractures during the

continuation phase of therapy.

OUTLINE: This is a randomized, multicenter, open-label study. Patients are stratified according to disease risk (standard-risk [SR] vs high-risk [HR] vs very high risk [VHR]).

- 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.

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

- 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.

Patients who are in complete remission (CR) on day 32 proceed to consolidation I. Patients who are not in CR on day 32 receive vincristine IV weekly until CR is achieved. Patients with persistent marrow (greater than 5% leukemic blasts) or those who do not achieve CR by day 53 are removed from the study.

Patients with CSF blasts on cytospin and at least 5 WBC/high-power field (hpf) in the CSF (CNS-3) after remission induction therapy are removed from the study. Patients with CSF blasts and less than 5 WBC/hpf in the CSF (CNS-2) receive 1 course of systemic chemotherapy comprising vincristine IV once a week for 4 weeks; dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes once a day for 2 days; and oral mercaptopurine once a day for 2 weeks. Patients with persistent CNS blasts at day 53 are removed from the study. Patients with no CNS blasts at day 53 proceed to 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.

- Stage 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.

- Stage 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.

- Stage 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 E. coli asparaginase* intramuscularly (IM) weekly beginning on day 48 and continuing for up to 30 weeks OR pegasparaginase* IV 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.

NOTE: *Patients are either randomized to receive E. coli asparaginase or pegasparaginase OR are assigned to receive E. coli asparaginase. Patients continue to receive E. coli asparaginase or pegasparaginase during CNS therapy and consolidation II therapy.

- 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 E. coli asparaginase* OR pegasparaginase* as above beginning on day 1 and continuing for up to 30 weeks. Patients proceed to consolidation II after day 21.

NOTE: *Patients are either randomized to receive E. coli asparaginase or pegasparaginase OR are assigned to receive E. coli asparaginase. Patients continue to receive E. coli asparaginase or pegasparaginase during consolidation II therapy.

- 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 E. coli asparaginase OR pegasparaginase as above beginning on day 1 and continuing for up to 30 weeks. VHR patients continue to receive E. coli asparaginase OR pegasparaginase as per consolidation I treatment. Patients proceed to consolidation II after day 21.

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 (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 E. coli asparaginase or pegasparaginase is completed. Patients also receive MTX IV or IM 1 day after each E. coli asparaginase or pegasparaginase 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 E. coli asparaginase or pegasparaginase 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 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 2 years after achieving CR. Patients continue to receive TIT as in consolidation II for up to 2 years after achieving CR.

Patients complete dietary questionnaires at the time of diagnosis, at day 32, and 12 months after diagnosis.

Quality of life is assessed periodically.

After completion of study therapy, patients are followed periodically for 3 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 544 patients will be accrued for this study.

Minimum age: 1 Year. Maximum age: 17 Years. Gender(s): Both.

Criteria:

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

- Meets criteria for 1 of the following risk groups:

- Standard-risk (SR) disease, defined by the following criteria:

- 1 to 9 years of age

- Highest pretreatment WBC < 50,000/mm³

- No evidence of CNS leukemia, defined by all of the following:

- Diagnostic lumbar puncture without any cerebrospinal fluid (CSF) blast

cells on cytospin (CNS-1) OR < 5 WBC/high-power field (hpf) in CSF with blast cells on cytospin (CNS-2)

- CNS-1 CSF on days 18 and 32 of study treatment

- Absence of cranial nerve palsy at diagnosis

- Absence of T-cell markers on lymphoblasts

- Absence of t(9;22), mixed-lineage leukemia (MLL) gene translocations, and

hypodiploidy < 45 chromosomes by karyotype or fluorescent in situ hybridization (FISH)

- Minimal residual disease (MRD) level < 0. 001 at the end of study remission

induction therapy (day 32) OR end-of-induction MRD status cannot be determined

- High-risk (HR) disease, defined by any of the following criteria:

- 10 to 17 years of age

- Highest pretreatment WBC ≥ 50,000/mm³

- Evidence of CNS leukemia, defined by any of the following:

- Diagnostic lumbar puncture with ≥ 5 WBC/hpf and blast cells on cytospin

(CNS-3)

- CNS-2 CSF on day 18 or 32 of study treatment

- CNS-3 CSF on day 18 of study treatment

- Presence of cranial nerve palsy at diagnosis

- Predominance of T-cell markers on lymphoblasts

- Presence of t(9;22)

- An allogeneic stem cell donor will be sought for transplantation

- These patients will not receive CNS therapy during study treatment

- B-lineage and MRD level < 0. 001 at the end of study remission induction

therapy (day 32) OR end-of-induction MRD status cannot be determined

- Very high-risk (VHR) disease, defined by any of the following criteria:

- Presence of MLL gene translocations (i. e., t[4;11]) by karyotype, FISH, or

molecular analysis

- Presence of hypodiploidy < 45 chromosomes by karyotype or FISH analysis

- MRD level ≥ 0. 001 at the end of study remission induction therapy (day 32)

- 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

San Jorge Children's Hospital, Santurce 00912, Puerto Rico; Recruiting
Luis A. Clavell, MD, Phone: 787-726-0316, Email: luis.clavell@sjcms.com

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States; Recruiting
Clinical Trials Office - Dana-Farber/Harvard Cancer Center, Phone: 617-582-8480

Albert Einstein Cancer Center at Albert Einstein College of Medicine, Bronx, New York 10461, United States; Recruiting
Clinical Trials Office - Albert Einstein Cancer Center at Albe, Phone: 718-904-2730, Email: aecc@aecom.yu.edu

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, New York, New York 10032, United States; Recruiting
Clinical Trials Office - Herbert Irving Comprehensive Cancer C, Phone: 212-305-8615

James P. Wilmot Cancer Center at University of Rochester Medical Center, Rochester, New York 14642, United States; Recruiting
Barbara L. Asselin, MD, Phone: 716-275-2981

McMaster Children's Hospital at Hamilton Health Sciences, Hamilton, Ontario L8N 3Z5, Canada; Recruiting
Uma Athale, MD, Phone: 905-521-2000 ext. 73464

Centre de Recherche du Centre Hospitalier de l'Universite Laval, Sainte Foy, Quebec GIV 4G2, Canada; Recruiting
Yvan Samson, MD, Phone: 418-656-4141

Hopital Sainte Justine, Montreal, Quebec H3T 1C5, Canada; Recruiting
Albert Moghrabi, MD, Phone: 514-345-4969, Email: albert.moghrabi@umontreal.ca

Hasbro Children's Hospital, Providence, Rhode Island 02903, United States; Recruiting
Clinical Trials Office - Hasbro Children's Hospital, Phone: 401-444-8945

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: April 2005
Last updated: October 21, 2008