Frontline HCVAD with Nelarabine and Peg-Asparaginase in T-Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL): Updated Results of a Phase II Trial

Background: Intensive chemotherapy has improved complete remission (CR) rates in T-ALL/LBL. However, long-term overall survival (OS) continues to be suboptimal at about 50%. Nelarabine (NEL) is active in relapsed/refractory T-ALL. PEG-asparaginase (PEG) containing regimens have demonstrated significant activity in the pediatric population (Dunsmore et al. COG AALL0434. J Clin Oncol. 2018 Abstr #10500). We hypothesized that incorporating NEL and PEG in the frontline setting may further improve outcomes in adult T-ALL/LBL (NCT00501826). We had previously reported on the addition of nelarabine to the hyper-CVAD regimen (Abaza Y, Am J Hematol. 2018). Here, we report outcomes with the addition of PEG and longer follow-up.

Methods Pts with T-ALL/LBL, either newly diagnosed or minimally treated (no CR with 1 cycle or CR after ≤2 cycles of induction) were eligible. Pts needed to have ECOG performance status (PS) ≤3, creatinine ≤2 mg/dL, bilirubin ≤2 mg/dL and ALT/AST ≤4 x ULN. The objectives were to determine safety, CR rate, progression-free survival (PFS), and OS with this combination. Pts received 8 cycles of with HCVAD (odd cycles 1,3,5,7) alternating with methotrexate (MTX) and cytarabine (ara-C; even cycles 2,4,6,8) at approximately 3-week intervals. Initially pts received NEL 650 mg/m² IV daily for 5 days after 8 cycles as above. After enrollment of 30 pts, protocol was amended to deliver the 2 courses of NEL after cycle 4 and 5 of therapy in an attempt to reduce risk of early relapse. After enrollment of 79 pts, PEG (1500 IU/m² IV capped at 3750 IU for pts ≤60 yrs and at 2000 IU for pts >60 yrs) was added to NEL courses on day 5. After completion of intensive phase, pts received 30 months of POMP maintenance (6-MP, vincristine, MTX, prednisone) with NEL/PEG replacing cycle 6 and 7 of POMP as early intensification. Late intensification consisted of MTX/PEG replacing cycle 18 and HCVAD replacing cycle 19 of POMP. CNS prophylaxis included 8 intrathecal doses of MTX alternating with ara-C. Pts with bulky mediastinal disease were considered for local radiation therapy prior to starting POMP maintenance.

Results: Between August 16, 2007 and March 6, 2019, we enrolled 96 pts with T-ALL (n=57) and T-LBL (n=39). Median age was 35 yrs (range 18-78), 75 pts were male (78%) and 83 pts (86%) had PS 0-1. In pts with T-ALL, median bone marrow blast % was 79% (range 0-96), 70 pts (73%) had extramedullary disease with mediastinal involvement in 48 pts and CNS involvement in 5 pts. 60 pts (63%) had diploid cytogenetics, 13 pts (14%) had complex cytogenetics, 19 pts had miscellaneous abnormalities and 4 pts had insufficient metaphases. Based on immunophenotype, pts were further characterized as thymic (n=38), early T-cell precursor (ETP; n=38), mature (n=10), not otherwise specified (NOS; n=9), and early-non-ETP (n=3). 12 pts had received prior therapy with HCVAD (n=8), asparaginase-based regimen (n=2), and others (n=2). 30-day mortality was 0%. 9 pts were in CR at enrollment. There were 242 grade 3/4 non-hematological treatment-emergent adverse events (TEAE) with the most frequent grade 3/4 TEAEs being neutropenic infections in 74 pts (77%), hypokalemia in 42 pts (44%), hypophosphatemia in 42 pts (44%) and elevated ALT in 28 pts (29%). Overall response rate was 98% (85/87 pts) with CR in 95% pts (n=83), PR in 2% (n=2), and no response in 2% (n=2). The median no. of cycles to response was 1 (range 1-10) with CR reported based on achieving PET negativity as well as standard response criteria. CR rate in T-ALL was 88% (43/49) and T-LBL was 100% (38/38). At a median follow-up of 58.8 months (mo; 95% CI 42.2, 67.6), 61 pts (63%) are alive with a median PFS and OS of 135.3 and 135.1 mo, respectively (Fig 1a, b) and 55 pts (57%) remain in CR. For pts who received NEL after HCVAD cycle 4, the 7-year OS was 61% compared to 52% who received NEL after cycle 8, hazard ratio 0.91, 95% CI 0.46, 1.82, p=0.7. For pts receiving PEG in addition to NEL, the 2yr OS was 86% (Fig 1c). 30 pts (31%) relapsed and 35 pts (37%) have died including 9 pts who died in CR. 17 pts (18%) pts underwent allogeneic stem cell transplantation, 6 have relapsed, 10 are alive, and 1 pt died in remission. Rate of relapse was 37% with NEL after cycle 8, 33% (16/49) with NEL after cycle 4 and 21% (3/14) with NEL/PEG (p=.38).

Conclusion: HCVAD with NEL with or without PEG is safe and effective as frontline therapy of adults with newly diagnosed T-ALL/LBL. Addition of PEG appears to confer a benefit.