Venetoclax Combined with Hag Regimen in Newly Diagnosed ETP-ALL: A Prospective, Multicenter, Phase 2 Trial

Background: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinctive subtype of T cell acute lymphoblastic leukemia (T-ALL), with a unique immunophenotype and genome profile. Patients with ETP-ALL have a relatively poor outcome with standard chemotherapy. Recent studies reported that ETP-ALL cells 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 preclinical data showed that homoharringtonine (HHT) exhibited strong synergistic effect with VEN in ETP-ALL. 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 trial, patients were enrolled at twelve hospitals in China. Eligible patients were newly diagnosed with ETP-ALL (aged ≥14 years) based on the 2016 WHO classification, with an Eastern Cooperative Oncology Group performance status of 0–2. Patients were excluded if they had known central nervous system involvement, uncontrolled systemic infection, uncontrolled tuberculosis, COPD, renal or liver disease, or a history of other malignant tumors excluding melanoma, basal cell carcinoma, and thyroid papillary carcinoma in the past 5 years. The V-HAG regimen included venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14; if the blast cells in the bone marrow (BM) were more than 5% on day 14, the patient continued to receive venetoclax 400 mg until day 28), homoharringtonine (1.4 mg/m², maximum 2 mg daily, intravenously from days 1-10), low-dose cytarabine (10 mg/m² subcutaneously every 12 hours on days 1-14), and G-CSF (200 µg/m² daily on days 1-14 if the WBC <10*10⁹/L). 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 BM minimal residual disease assessed by flow cytometry after one cycle of induction treatment, overall survival (OS), event-free survival (EFS), and adverse events (AEs).

Results: Between July 2022 and March 2024, 34 patients with newly diagnosed ETP-ALL were assessed for eligibility and 31 of whom were enrolled in 12 different hospitals in China. There are 23 male (74.2%) and 8 female (25.8%), with a median age of 54 years (range 18 to 75 years) at enrollment. Except for one patient who experienced acute cerebral infarction on day 26 of treatment and further progressed to multiple organ failure on day 31, all the other 30 patients finished the first cycle of V-HAG treatment and BM were evaluated at the end of cycle 1. Notably, all the 30 patients achieved CRc (100% CRc rate) with CR attained in 25 patients (83.3%) at the end of cycle 1. Then, after one to three cycles of consolidation treatment with V-HAG regimen, 16 of 30 patients (53.3%) proceeded to allogeneic hematopoietic stem cell transplantation(allo-HSCT) so far and 10 patients continued to receive consolidation or maintenance treatment. Another four patients discontinued further consolidation treatment due to personal reasons, and all of them relapsed in one year post CR. Among these 4 patients, one proceeded to salvage allo-HSCT and achieved CR again while the other 3 patients didn’t achieve CR after receiving salvage treatment and passed away later. To date, with a median follow-up of 15.6 months, both the median OS and EFS have not achieved. Six patients died, including the patient who died of acute cerebral infarction and 3 patients who gave up consolidation treatment and relapsed. Additionally, one patient died from disease relapse during consolidation treatment, and another patient died from severe infection following allo-HSCT. The one-year OS was 89.1%. For the adverse events, the most common adverse events of grade 3 or higher included neutropenia, thrombocytopenia, anemia and febrile neutropenia. Tumor lysis syndrome was reported during the ramp-up period (on days 1 through 3 when the dose of venetoclax was increased) in 1 patient (3.3%).

Conclusions: Venetoclax Combined with HAG regimen achieved an 100% CRc rate in newly diagnosed ETP-ALL. This therapy is a promising and well-tolerated regimen in newly diagnosed ETP-ALL patients.