Venetoclax Combined with Hag Regimen in Newly Diagnosed ETP-ALL: Interim Analysis of a Prospective, Multicenter, Phase 2 Trial

Background: Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is identified as a subset of T-lineage ALL with a unique immunophenotype and genome profile in 2009. Patients with ETP-ALL have a relatively poor outcome with standard chemotherapy and studies showed that therapies utilized for myeloid neoplasms may be effective in ETP-ALL given the relatively high frequency of molecular myeloid features. In recent years, targeting of the antiapoptotic protein BCL-2 has emerged as an effective approach in acute myeloid leukemia (AML). Preclinical studies reported that ETP-ALL cells also express high level of BCL-2 and are sensitive to the BCL-2 inhibitor venetoclax (VEN). However, the clinical efficacy of venetoclax combination therapies in ETP-ALL patients is still limited. Our data showed that homoharringtonine (HHT) showed strong synergistic effect with VEN in ETP-ALL (2022 ASH abstract #170604). We therefore conducted a study of combination of VEN and HHT-based HAG regimen (V-HAG regimen) in newly diagnosed ETP-ALL patients. The aim of this study was to investigate the activity and tolerability of V-HAG regimen for newly diagnosed ETP-ALL.

Methods: In this prospective, multicenter, phase 2 clinical trial conducted in 7 different hematological centers in China, eligible patients were newly diagnosed ETP-ALL(aged≥16 years old) based on the 2016 WHO classification with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received venetoclax (100mg on day1, 200mg on day 2 and 400mg on day 3-14, if the blast cells in bone marrow was more than 5% on day 14, the patient continued to receive venetoclax 400mg until day 28), homoharringtonine (1.4 mg/m ²,2mg maximum daily, intravenously daily from on d1-10), Low-dose cytarabine (10 mg/m2 subcutaneously every 12h on d1-14), and G-CSF (100ug/m ² daily on d1-14). Venetoclax dose was reduced by at least 50% in the patients receiving concomitant moderate or strong CYP3A4 inhibitors (such as azole antifungals et al). The primary endpoint was the rate of composite complete remission (CRc) after one cycle of induction treatment, including CR and CR with incomplete count recovery (CRi). Secondary endpoints included bone marrow (BM) minimal residual disease (MRD) by flow cytometry after one cycle of induction treatment, overall survival (OS), event-free survival (EFS), and adverse events (AEs). Here, we report results of the interim analysis.

Results: Between July 2022 and July 2023, we enrolled 18 patients with newly diagnosed ETP-ALL in 7 different hematological centers. 14 of 18 patients (77.8%) were male and 22.2% were female, with a median age of 51 years (range, 29 to 73 years). As of July 31, 2023, 15 patients were available for the assessment of treatment results. Among the 15 patients, 14 patients were given standard V-HAG regimen as showed above and one 73-year-old patient, who had interstitial pneumonia at the onset of ETP-ALL, was given dose-reduced V-HAG regimen. To our surprise, after the first cycle of treatment with V-HAG, all the 15 patients achieved CRc (100% CRc rate), including the 73-year-old patient with dose-reduced regimen. Then, after one to three cycles of consolidation treatment with V-HAG regimen, 7 of 15 patients have proceeded to allo-HSCT so far. With a median follow-up of 7.7 months, both the median OS and EFS were not achieved. In fact, to date, except for the 73-year-old patient who eventually relapsed (6% blasts in BM after receiving a second cycle of dose-reduced V-HAG regimen as consolidation) and died of respiratory failure, all the other 14 patients are remaining alive and event-free. For the adverse events, the most common toxicities were grade 4 neutropenia (93.33%), grade 4 thrombocytopenia (73.33%) and grade 3 febrile neutropenia (26.67%). No early death occurred.

Conclusions: Venetoclax Combined with HAG regimen achieved an 100% CRc rate in newly diagnosed ETP-ALL to date. Enrollment is ongoing to assess its efficacy and safety in treating newly diagnosed ETP-ALL. This therapy is a promising and well-tolerated regimen in newly diagnosed ETP-ALL patients.

Trial registration: The trial was registered in the Chinese Clinical Trial Register with the registration number ChiCTR2200061708.