Venetoclax in combination with hypomethylating agents are effective salvage therapy in relapse/refractory ETP-ALL and near-ETP-ALL

Abstract

Abstract Introduction Limited progress has been made in the treatment of T-lymphoblastic leukaemia/lymphoma (T-ALL/LBL) with a paucity of new agents since the approval of nelarabine 20 years ago. Patients with relapsed/refractory T-ALL/LBL have dismal outcomes with survivals of ≤10%. Venetoclax is a BCL-2 inhibitor indicated for the treatment of acute myeloid leukaemia. Preclinical studies showed that BCL-2 and BCL-XL overexpression was observed in ALL, with early T-precursor acute lymphoblastic leukaemia (ETP-ALL) having greater dependence on BCL-2 than BCL-XL. Moreover, ETP-ALL is defined by expression of myeloid antigens, with mutational profiles similar to those of myeloid neoplasms. These findings suggest that venetoclax may have a therapeutic role in this challenging disease. Near-ETP-ALL (nETP-ALL) has a similar immunophenotype to ETP-ALL except for a stronger CD5 expression; with the clinical significance of such a distinction yet to be elucidated. There have been isolated reports and small case series on using venetoclax-based therapy in T-ALL/LBL. However, patient populations were often limited with heterogeneous characteristics, particularly disease immunophenotypes and choices of add-on treatment. Here we report our experience of using venetoclax and hypomethylating agents (HMA) in a cohort of relapsed/refractory T-ALL/LBL patients with ETP or nETP immunophenotype.Methods Adult patients with ETP-ALL/LBL or nETP-ALL who received venetoclax-HMA combination therapy (VEN-HMA) were retrospectively analyzed. Details on patient demographics, clinico-pathologic characteristics, prior therapies, venetoclax and HMA regimens, adverse events, efficacy and death were collected. Complete remission (CR) was defined as bone marrow blasts of ≤5% and resolution of all extramedullary disease. Partial remission (PR) was defined as the presence of 6-25% blasts in the bone marrow and/or ≥50% reduction in extramedullary tumour size assessed by computed tomography. Overall response rate (ORR) included CR and PR. Measurable residual disease (MRD) was determined with multiparameter flow cytometry of marrow blood, with minimum sensitivity of 0.01%. Overall survival (OS) was calculated from the start of VEN-HMA until date of death or last follow-up. Relapse-free survival (RFS) was defined as the interval between achievement of CR to relapse or death. Results Since September 2021, 14 Asian patients with ETP-ALL/LBL or nETP-ALL were treated with VEN-HMA. There was a male predominance (71%). Median age at diagnosis was 41 (range: 23-63) years. The diagnoses were ETP-ALL/LBL (N=9, 64%; 2 being T-LBL) and nETP-ALL (N=5, 36%). Prior allogeneic haematopoietic stem cell transplantation (allo-HSCT) had been performed in 8 patients (57%). Venetoclax was used at 100 mg daily with an azole antifungal prophylaxis (leading to an effective doses of about 400 mg daily) in 13 patients, and 1 patient used venetoclax 200mg daily without concurrent azole. HMA used included azacitadine (75mg/m2 for 7 days/cycle, N=9), decitabine (20mg/m2 for 5 days/cycle, N=4), and sequential decitabine and azacitadine (N=1). VEN-HMA was used as second-line in 6 patients (43%), and as third-line and beyond in 8 patients (57%). The ORR was 71%(CR, N=9, 64%; PR, N=1, 7%), including 6/9 patients with ETP-ALL, and 4/5 patients with nETP-ALL. Notably, all 6 patients treated in second-line responded (CR, N=5; PR, N=1). Undetectable MRD was achieved in 5 out of 8 evaluable patients. The 4 non-responders were heavily pretreated and had allo-HSCT prior to VEN-HMA; including 2 patients who had antecedent exposure to venetoclax used in conjunction with other therapies. Of 9 CR cases, 5 patients were successfully bridged to allo-HSCT. At a median follow-up of 15 months, the median OS was 16 months, with a 12-month OS of 54.2%. Among patients who achieved CR, the 12-month RFS and OS were 76.2% and 88.9%, respectively. The most common adverse events were haematological toxicity (≥grade 3 cytopenia, N=12, 86%), hepatotoxicity (grade 2, N=3, 21%), and sepsis (≥grade 3, N=3, 21%).Conclusions VEN-HMA is an effective salvage option in our cohort of relapsed/refractory ETP-ALL/nETP-ALL, especially in second-line. Haematological toxicities are common but manageable. Patients with prior exposure to venetoclax might have an inferior response to VEN-HMA.