Incorporation of Nelarabine (NEL), Pegylated Asparaginase (PEG) and Venetoclax (VEN) in the Frontline Therapy of Adult Patients with T-Acute Lymphoblastic Leukemia/T-Lymphoblastic Lymphoma (T-ALL/LBL)

Abstract

Background: NEL is effective for patients (pts) with relapsed T-ALL/LBL, but its incorporation into the front-line therapy has not been investigated extensively in the adult population. In children, the addition of NEL to the induction regimen has shown to improve disease-free survival (DFS) but not the overall survival (OS). VEN has shown preclinical and clinical activity in relapsed T-ALL/LBL. We investigated the addition of NEL and PEG to the hyper-CVAD (HCVAD) regimen in adult pts with T-ALL/LBL. Further on, we explored the safety and efficacy of adding VEN to this regimen. Methods: Pts with previously untreated or minimally pre-treated T-ALL/LBL were eligible if they had an ECOG PS ≤3, creatinine ≤ 2 mg/dL, total bilirubin ≤ 2 mg/dL and ALT/AST ≤ 4 x ULN. Pts received 8 cycles of HCVAD (cycles 1,3, 5, 7) alternating with high dose ara-C and methotrexate (MTX) (cycles 2, 4, 6, 8) at approximately 3-week intervals. Two cycles of NEL (650 mg/m2 daily x 5) were initially administered after cycle 8 (cohort 1). Later, after a protocol amendment, they were administered after cycle 4 and cycle 5 (cohort 2). Subsequently, the protocol was amended to add PEG (1500 IU/m2 capped at 3750 IU) on day 5 of the NEL cycles (cohort 3) and more recently, VEN 400 mg daily was added on the first 7 days of each of 8th cycle of therapy (cohort 4) and this was later modified to be given for 7 days during the induction cycle and reduced to 3 days per cycle post-induction only in pts with ETP-ALL or those with persistent MRD. All other pts did not receive VEN after cycle 1 (cohort 5). Pts with ETP-ALL were referred for allogeneic stem cell transplant in first complete remission (CR). After the completion of the intensive phase, pts in all cohorts received 30 cycles of maintenance therapy with monthly POMP and early intensification with NEL/PEG on cycles 6 and 7 and late intensification with MTX/PEG in cycle 18 and HCVAD on cycle 19. All pts received 8 intrathecal chemotherapy with MTX alternating with ara-C and mediastinal radiation was considered in pts with bulky mediastinal disease. Results: Between 8/2007 and 6/2022, 128 pts were enrolled in the 5 study cohorts sequentially (cohort 1= 30, 2= 49, 3=17, 4=16, 5=16) (Table). Seventy-seven pts had T-ALL, 50 T-LBL and 1 biphenotypic T/myeloid leukemia. Median age was 35 yrs. (range 18-78), 98 pts were male (77%) and 110 pts (86%) had PS 0-1. In pts with T-ALL, median bone marrow blast percentage was 83% (range, 20-97) Six pts (5%) had CNS disease at presentation. Cytogenetics were diploid in 82 pts (64%), abnormal in 36 (28%), and unavailable in 10 pts (8%). Pts were further characterized as early T-cell precursor (ETP; n=24), near ETP (ETP + CD5) (N=19), early-non-ETP (n=3), thymic (n=54), mature (n=12), not otherwise specified (NOS; n=16). Twenty-five pts had received 1-2 cycles of therapy prior to enrollment, with 18 having achieved CR. The 30-day mortality was 0%. One hundred and twelve pts (88%) had ≥ 1 grade 3/4 non-hematological treatment-emergent adverse events (TEAE) with the most frequent grade 3/4 TEAEs being neutropenic infections in 96 pts (75%) and elevated liver enzymes in 25 pts (20%). The overall response rate (CR/CRi/PR) was 98% with CR/CRp in 120/128 pts (94%), PR in 5 (4%), and no response in 3 (2%). The median number of cycles to response (including a negative PET scans) was 1 (range 1-10). CR/CRp rate in T-ALL was 91% and T-LBL was 98%. At a median follow-up of 50 months (1-174), 84 patients (66%) are alive with a 5-year PFS and OS of 60% and 61% (Figure 1) and 79 pts (62%) remain in CR. Conclusion: The addition of NEL/PEG cycles to the HCVAD regimen is feasible. The addition of VEN to each cycle is associated with significant myelosuppression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal