To Nelarabine or Not for Pediatric T-cell Acute Lymphoblastic Leukemia

Kristin Held Wheatley, PharmD, BCOP
Clinical Pharmacy Specialist, Pediatric Oncology and Infectious Diseases Program Director, PGY1 Pharmacy Residency
Lehigh Valley Health Network, Allentown, PA

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of pediatric leukemias and patients are generally characterized by unfavorable clinical features including older age, male predominance, higher presenting leukocyte count, higher frequency of mediastinal mass and central nervous system (CNS) involvement at diagnosis.^1,2 Survival has improved markedly with risk-directed therapy and has reached 80-85% though outcomes remain poor for patients who experience relapse.¹

An agent with potential for targeted benefit in T-cell malignancies is the purine nucleoside analogue, nelarabine. Accumulation of intracellular deoxyguanosine (dGuo) triphosphate (dGTP) was noted to be specifically toxic to T-cells in patients with purine nucleoside phosphorylase (PNP) deficiency. Arabinofuranosylguanine (ara-G) is a PNP-resistant dGuo analogue, but its clinical use was limited by solubility challenges. Nelarabine is available as a prodrug and is rapidly metabolized by adenosine deaminase to ara-G which is transported into leukemic cells and phosphorylated to the triphosphate form (ara-GTP), the main intracellular metabolite, where it accumulates and inhibits DNA synthesis. The selective T-cell toxicity demonstrated by nelarabine reflects inherently higher phosphorylation that occurs within T-cells compared with B-cells. Further, cytotoxicity occurs to a greater extent in T-lymphoblasts than in mature T-cells which may explain preferential utility in T-ALL compared to T-cell lymphoblastic lymphoma (T-LLy). Nelarabine has not been associated with toxicities commonly reported with more traditional cytotoxic chemotherapy; however, neurotoxicity is dose limiting and is thought to occur as a result of greater accumulation of ara-GTP within CNS tissue. CNS effects predominate with primarily reversible somnolence though seizures are also reported. Peripheral neuropathies may be severe, cumulative and gradually reversible and range from numbness and paresthesias to motor weakness and paralysis.^3-6

Nelarabine received accelerated approval as a single agent in relapsed/refractory T-ALL and T-LLy following initial phase I and II studies. A phase I study enrolled 93 adult and pediatric patients with relapsed/refractory hematologic malignancies of which 66% of patients had T-cell malignancies. Doses ranged from 5 mg/kg to 75 mg/kg IV and responses were seen at all dose levels. Overall response rate (ORR) was reported as 31% in all disease subtypes with complete or partial response achieved in 54% of patients with T-ALL or T-LLy after one to two courses. Reversible toxicity was noted in 50% of pediatric patients with an onset of symptoms within 12 days of the start of therapy. No neurotoxicity was identified at a dose of 40 mg/kg within pediatric patients (roughly equivalent to 1200 mg/m2) and this dose was recommended for initial phase II trials.5 Pediatric Oncology Group (POG) P9673 enrolled 153 patients younger than 21 years with relapsed or refractory T-cell malignancies. Two dose de-escalations were required from the initial starting dose of 1200 mg/m2. Patients in first relapse experienced an ORR of 55% and tolerated 650 mg/m2 daily for five days. Grade 3 or 4 neurologic toxicities occurred in 18% of patients with 12% experiencing CNS toxicity and 9% peripheral nerve toxicity.⁶

The Children’s Oncology Group (COG) added nelarabine, administered as five or six 5-day courses of 400 mg/m2 or 650 mg/m2, to an intensive modified Berlin-Frankfurt Münster (BFM) 86 regimen in children with newly diagnosed higher-risk T-ALL within AALL00P2. Five-year event-free survival (EFS) in slow early responders who received nelarabine was 69%, which was equivalent to rapid early responders who did not receive nelarabine. Grade 3 or 4 peripheral neuropathy occurred in 15% of patients who received nelarabine and in no patients who did not receive nelarabine (P = 0.203). Whereas, central neurotoxicity, excluding seizures, occurred in 4% of patients treated with nelarabine compared to 25% of patients who did not receive nelarabine (P = 0.019). Four patients treated with nelarabine experienced five seizure episodes – none occurred in conjunction with nelarabine administration. Nelarabine was reported as tolerable, safe and feasible when combined with intensive chemotherapy.⁷

The subsequent protocol, AALL0434, was a phase III trial evaluating nelarabine in patients with newly diagnosed intermediate risk (IR) or high risk (HR) T-ALL. Additional questions to be answered included whether cranial radiotherapy (CRT) could be minimized in low risk (LR) patients as well as the safety and efficacy of escalating dose (Capizzi) methotrexate (C-MTX) compared to high-dose methotrexate (HD-MTX). AALL0434 enrolled 1562 patients and 5-year EFS and overall survival (OS) were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. All patients received a 28-day, prednisone-based, four-drug induction and were subsequently risk stratified as LR, IR, HR or induction failure. LR patients did not participate in the nelarabine randomization. Of note, 24% of patients were taken off protocol during induction prior to randomization at investigator discretion. Six hundred fifty-nine IR or HR patients were randomized to receive treatment with or without nelarabine given as six 5-day courses of 650 mg/m2 incorporated within consolidation (days 1-5 and 43-47), delayed intensification (days 29-33), and the first three maintenance cycles (days 29-33). All IR and HR patients received 12 Gy of prophylactic CRT. Patients randomized to nelarabine were reported to have superior disease-free survival (DFS) of 88.2% ± 2.4% compared to 82.1% ± 2.7% (P = 0.029) for those who did not receive nelarabine. OS was not statistically different between groups (90.3% ± 2.2% vs. 87.9% ± 2.3%, P = 0.168, respectively). Nelarabine was associated with a decrease in CNS relapses with 5-year cumulative incidence rates (isolated and combined) of 1.3% ± 0.6% in patients who received nelarabine (4 events) compared to 6.9% ± 1.4% in patients without nelarabine (23 events), P = 0.001. Day 29 minimal residual disease (MRD) < 0.1% was prognostic when compared to MRD ≥ 0.1% with or without nelarabine (92.3% ± 2.9% vs. 83.5% ± 3.9%, P = 0.01 compared to 89% ± 3.1% vs. 73.4% ± 4.3%, P = 0.0003). Peripheral motor and sensory neuropathy and central neurotoxicity rates were similar in the nelarabine and no nelarabine arms.⁸

The successor T-ALL study, AALL1231, incorporated bortezomib within a modified augmented BFM backbone. Notably, dexamethasone was used during induction and two additional doses of pegaspargase were added to eliminate CRT in the majority of patients. The modified induction was noted to result in improved end of induction MRD < 0.1% when compared with AALL0434 (69.6% [no bortezomib] and 72.2% [bortezomib] vs. 64.6%, respectively; P = 0.02). The 4-year EFS and OS were reported as 81.9% ± 1.5% and 87% ± 1.3%, respectively. The inferior OS when compared to AALL0434 was noted to be related to increased toxic deaths and poor outcomes of the very high risk (VHR) group. Induction mortality was higher in AALL1231 compared to AALL0434 (1.5% vs. 0.4%; P = 0.002) likely due to incorporation of dexamethasone as rates were similar to Associazione Italiana di Ematologia e Oncologia Pediatrica (AEIOP)-BFM ALL 2000.9,10 Though improvements in EFS and OS with bortezomib were specifically noted in patients with T-LLy, the adjustments made to therapy allowed elimination of CRT in more than 90% of patients.⁹

In the midst of completion and publication of the above North American trials, UKALL-2003, which enrolled between 2003 and 2011, demonstrated a 3-year EFS and OS for patients with T-cell phenotype of 86% ± 3.3% and 90% ± 2.8%, respectively. Notable differences in treatment included use of dexamethasone, restriction of CRT for overt CNS disease at presentation (CNS3) and utilization of C-MTX.10 Current treatment approaches for T-ALL in the United Kingdom reserve nelarabine for patients with poor initial response, MRD ≥ 5%, and/or relapsed disease.^11,12

Addition of nelarabine comes at a cost including, at a minimum, 30 days of drug and extension of consolidation by 21 days. A recent commentary highlights the discrepancy in calculating the potential benefit based on the chemotherapy backbone. If the larger 6-percentage point advantage associated with the greater effect of nelarabine on the HD-MTX arm on AALL0434 was utilized to calculate a number needed to treat, 17 patients would need to be treated to avoid one relapse compared to 50 patients for the reportedly superior C-MTX arm.^{13, 14}

Though nelarabine is a potentially beneficial intervention in certain patient groups, the available data is not conclusive and incorporation should be as part of rational decision making between the medical team, patients and families.

REFERENCES

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