Risk-Directed Therapy in Treating Young Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. 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 ALLR17.

II. To estimate levels of cluster of differentiation (CD)20 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.

EXPLORATORY OBJECTIVES:

I. To assess donor natural killer (NK) cell immunoglobulin-like receptor (KIR) repertoire and explore the efficacy of NK cell infusions followed by rituximab in relapsed ALL.

II. To study whether pre-existing or emerging development of serum antibodies to asparaginase is related to hypersensitivity reactions or exposure to asparaginase or to anti-leukemic or adverse effects of therapy, in participants with relapsed ALL.

III. To describe the effect of prophylactic antibiotics on: a) the evolution of antibiotic resistance in peri-rectal swab isolates of Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Streptococcus mitis and enterococci; b) resistance patterns of bacterial isolates from all sterile site cultures.

IV. To characterize global gene expression and copy number changes in leukemic cells at relapse and to compare to initial diagnosis (when available) to improve knowledge of mechanisms of relapse.

V. To determine in vitro sensitivity of pretreatment relapsed leukemic cells to anti-leukemic agents and compare to in vitro sensitivity at diagnosis (when available).

VI. To engraft freshly harvested relapsed ALL cells into murine models of ALL to gain insights into therapy resistance.

VII. To study the development of resistant clones during therapy for relapsed ALL.

OUTLINE:

GROUP 1 (standard risk defined as patients with late relapse [complete cytogenetic response (CCR) > 6 months] AND MRD negative after Block II):

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 IV, cyclophosphamide IV, 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 transplant 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.

*NOTE: Day 35 chemotherapy (vincristine + pegaspargase) may be skipped for patients whose blood counts recover before day 35.

**NOTE: Patients who do not receive NK cells for any reason do not receive aldesleukin, and subsequent chemotherapy is moved up by 7 days (day 21 to day 14).

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.

* NOTE: Patients with high-risk relapse who require cranial irradiation prior to transplant will not receive this block of therapy.

BLOCK III: Patients receive cytarabine IV over 2 hours every 12 hours 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 IV, cyclophosphamide IV, and methotrexate IV on day 1, mercaptopurine PO on days 1-7, teniposide IV and cytarabine IV on day 1, dexamethasone PO TID on days 1-5, and vinblastine IV on day 1. Patients also receive triple intrathecal therapy on day 1 of week 1.

RE-INDUCTION THERAPY: Patients receive clofarabine IV, cyclophosphamide IV, and etoposide IV on days 1-5; dexamethasone PO on days 1-6; and pegaspargase IV 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 or intramuscularlly (IM) on day 1 and mercaptopurine tablet PO on days 1-7 of weeks 1, 2, 5, and 6; teniposide IV 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.

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 transplant (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.