Randomized Precision Medicine Trial of Venetoclax Combination Therapy in Relapsed/Refractory T‑Cell Acute Lymphoblastic Leukemia

The primary objective is to evaluate the benefit of a precision‑medicine strategy using targeted‑therapy combinations on the hematologic response rate in patients with relapsed/refractory T-cell acute lymphoblastic leukemia. Secondary objectives include assessment of the benefit and tolerance of the targeted therapeutic options overall and per option; evaluation of overall survival, relapse‑free survival and event‑free survival; comparison of quality of life and patient‑reported outcomes between strategies and among specific options; exploration of the mechanisms of relapse; and analysis of the allocation of targeted therapeutic options.

The trial enrolled adult and adolescent patients (≥15 years; participants under 18 years were limited to France) of both sexes diagnosed with relapsed/refractory T-cell acute lymphoblastic leukemia. Eligibility required documented disease relapse (first relapse within 24 months of complete remission, second or subsequent relapses, or refractory status after at least two chemotherapy lines) or post‑transplant/CAR‑T failure, and the presence of blast cells suitable for centralized molecular profiling. Participants needed an ECOG performance status of 0‑3, affiliation with a national health system, and no contraindications to the study drugs (venetoclax, tofacitinib, everolimus, enrylaze, or 5‑azacytidine). Women of child‑bearing potential and male participants with partners of child‑bearing potential were required to use effective contraception during the study and for three months thereafter. The sponsor did not provide the total number of participants enrolled.

The study is a phase 4, randomized, controlled trial evaluating precision‑medicine treatment combinations in patients with relapsed/refractory T‑cell acute lymphoblastic leukemia. After obtaining informed consent, eligible participants undergo a screening visit to confirm disease status, ECOG score (0–3), and availability of blast material for central laboratory assessment; those meeting all inclusion criteria are randomized to one of three targeted therapeutic options (venetoclax + tofacitinib; venetoclax + everolimus + enrylaze; venetoclax + azacitidine). The intervention period consists of oral or intravenous administration of the assigned agents according to the predefined dosing schedule, with the primary hematologic remission assessment performed at 3 months post‑randomization. Follow‑up visits are scheduled at baseline (randomization), month 1, month 3, month 6, and an end‑of‑study visit at month 12, during which efficacy endpoints (response rates, survival metrics, minimal residual disease) and safety data (adverse events) are collected. Participants remain in the trial for a maximum of 12 months, unless early termination occurs due to serious adverse events, disease progression, withdrawal of consent, or major protocol violations. Recruitment began on 1 June 2026 and is planned to continue until 1 January 2030.

Venetoclax is supplied as a film‑coated tablet for oral administration. Each tablet contains 400 mg of the active substance. The investigational regimen includes administration of the 400 mg dose according to the protocol‑defined schedule.

Enrylaze (recombinant L‑asparaginase) is provided as a solution for injection/infusion. The dosage is 25 mg/m² administered intravenously. The infusion is performed in accordance with the study dosing calendar.

XELJANZ (tofacitinib) is formulated as a 5 mg film‑coated tablet for oral use. The prescribed dose is 20 mg taken orally as specified by the trial protocol.

Azacitidine (Mylan) is a powder for suspension for injection supplied at a concentration of 25 mg/mL. The dose is 75 mg/m² administered subcutaneously per the study schedule.

Afinitor (everolimus) is a 5 mg tablet for oral administration. The trial specifies a 5 mg oral dose administered according to the protocol‑defined timing.

Efficacy will be evaluated primarily by the hematological remission rate (CRc), defined as the best response observed within three months after randomization and comprising complete remission (CR) or remission with incomplete hematologic recovery (CRi). Secondary efficacy parameters include hematological response rate (CR, CRi, and partial response) at three months, overall survival, stable disease at three months, duration of response, event‑free survival, relapse‑free survival, response per treatment combination at three and six months, bridge to transplant or CAR‑T cell therapy, minimal residual disease in responders at three months, and quality‑of‑life assessments using the HM‑PRO and HADS questionnaires administered monthly through month three.

Response assessments will be performed at predefined timepoints (baseline, three months, and six months where applicable) using standard hematologic criteria to categorize CR, CRi, PR, stable disease, or relapse. Minimal residual disease will be measured in responding patients at the three‑month visit with a validated assay. Quality‑of‑life questionnaires will be collected monthly up to month three. Survival endpoints will be calculated from the date of randomization to the occurrence of the relevant event (death, relapse, or both). All efficacy data will be analyzed according to the predefined statistical analysis plan for the trial.