Nelarabine (NEL), Pegylated Asparginase (PEG) and Venetoclax (VEN) Incorporated to HCVAD Chemotherapy in the Frontline Treatment of Adult Patients with T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (T-ALL/T-LBL)
Authors: Senapati Jayastu , Kantarjian Hagop M. , Jabbour Elias , Babakhanlou Rodrick , Kadia Tapan M. , Borthakur Gautam , Konopleva Marina Y. , Wierda William G. , Burger Jan A. , Issa Ghayas C. , Maiti Abhishek , Balkin Hayley S. , Kelly Mary , Garris Rebecca , Ferrajoli Alessandra , Garcia-Manero Guillermo , Alvarado Valero Yesid , Kebriaei Partow , Short Nicholas J. , Jain Nitin , Ravandi Farhad 
Published: December 2023

Background:

The incorporation of novel agents such as NEL and PEG to frontline therapy has been associated with improved outcomes in pediatric patients (pts) with T-ALL/LBL, but has not been extensively studied in the adult pts. BCL-2 upregulation has been demonstrated in T-lymphoblasts, especially of the early T-cell precursor (ETP) ALL and addition of VEN (BCL-2 inhibitor) may be beneficial.

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 (C) of HCVAD (C 1,3, 5, 7) alternating with high dose Ara-C and methotrexate (MTX) (C 2, 4, 6, 8) at approximately 3-week intervals. Two cycles of NEL (650 mg/m 2 daily x 5) were initially administered after C8 (cohort 1). Later, after a protocol amendment, they were administered after C4 and C5 (cohort 2). Subsequently, the protocol was amended to add PEG (1500 IU/m 2 capped at 3750 IU; for pts age 60 or older, dose was 1000 IU/m 2, capped at 2000 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 8 cycles of therapy (cohort 4); this was later modified to be given for 7 days during the induction cycle to all pts and reduced to 3 days per post-induction cycle only in pts with ETP-ALL or those with persistent measurable residual disease (MRD) and all other pts did not receive VEN after C1 (cohort 5). Pts with ETP-ALL were referred for allogeneic stem cell transplant (allo-SCT) 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 (prednisone, vincristine, MTX, prednisone) and early intensification with NEL/PEG on C6 and 7 and late intensification with MTX/PEG in C18 and HCVAD on C19. 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 7/2007 and 12/2022, 133 pts were enrolled in the 5 study cohorts sequentially (cohort 1= 30, 2= 49, 3=17, 4=16, 5=21) (Table 1). Eighty pts (60%) had T-ALL, 52 T-LBL (39%) and 1 pt had ETP/myeloid bi-phenotypic leukemia. The median age for the entire cohort was 35 years (yrs) (range 18-78), 102 pts were male (77%), 83 pts (62%) were white and 18 pts (14%) had PS ≥2. Overall, 24 pts (18%) had an ETP phenotype and another 19 pts (14%) had a near-ETP phenotype. Six pts (5%) had central nervous system disease at diagnosis, 72 pts (54%) had mediastinal disease, 49 of 80 (61%) T-ALL pts had extramedullary disease and 20 pts (15%) were in complete remission (CR) at trial enrollment after minimal pre-enrollment therapy. Overall response (CR+CRp+CRi+PR) on trial was attained in 109/113 (95%) pts [CR= 101 (89%), CRi/CRp= 3 (3%), PR=5 (4%)]. CR/CRi/CRp was attained in 36/41 (88%) pts with ETP/near-ETP ALL and 60/64 (94%) of confirmed near-ETP ALL pts ( p=0.31). At a median follow-up of 62 months (mos), the median overall survival (OS) was not reached (NR), 3-yr OS was 71% and 5-yr OS was 64% . The 3-yr OS for pts treated with HCVAD+NEL (cohort 1+2), HCVAD+NEL+PEG (Cohort 3) and HCVAD+NEL+PEG+VEN (Cohort 4+5) were 66%, 88% and 76% respectively (Figure 1). Median OS was not reached for both VEN cohorts, while 3-yr OS was 72% in cohort 4 compared to 88% in cohort 5 ( p=0.51), with significantly shorter follow-up for the latter (33 mos vs. 15 mos). Amongst the 124 pts who had CR/CRp/CRi, the median RFS was NR and 5-yr RFS was 68%. 24 (18%) pts underwent SCT in first remission, including 20 (83%) with ETP or near-ETP ALL. The median OS was shorter in the 44 ETP/near-ETP pts compared to the 77 pts with non-ETP phenotype (71 mos vs. NR, p=0.08). 30 and 60-day mortality was 0% and 1%. 10 pts (7.5%) died in remission (3, 5 and 2 pts in cohorts 1, 2 and 4 respectively) including 1 after SCT, 4 after developing therapy-related acute myeloid leukemia and 5 from infectious complications.

Conclusion: The ongoing phase 2 trial of NEL, ASP, VEN added to the HCVAD regimen shows promising long-term survival in adult pts with T-ALL/LBL with 3-yr OS of 76%-88% in pts treated with HCVAD+NEL+PEG +/- VEN. Larger prospective trials and longer follow-up are needed to demonstrate further benefit.