Combination of Venetoclax and Daratumumab Plus CAG Regimen in Adult T-Cell Acute Lymphoblastic Leukemia with Persistent Positive Minimal Residual Disease
Authors: Peng Lijun , Dai Yuting , Ren Jiayi , Liu Weiyang , Xu Jie , Zhang Weiping , Wang Jin , Mi Jian-Qing 
Published: December 2024

Background

T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk disease without good therapeutic options thus far. 50%~70% patients can only achieve complete remission (CR) with positive minimal residual disease (MRD) after intensive therapy, whereas MRD positivity often predicts an ultimate disease relapse. The BCL-2 inhibitor venetoclax has been reported to induce high remission rate in relapsed/refractory T-ALL (R/R T-ALL). CD38 was reported to be constantly expressed on T-ALL blasts even after chemotherapy. Daratumumab (DARA), as a CD38-targeted IgG1κ human monoclonal antibody, has demonstrated efficacy in both preclinical studies of patient-derived xenograft models and clinical cases of T-ALL. Herein, we speculate that the combination of venetoclax and DARA may improve the quality of remission by increasing the rate of MRD negativity.

Objective

In this study, venetoclax combined with DARA regimen was used to treat MRD positive T-ALL. The efficacy and safety profiles were evaluated.

Methods

From December 2022 to November 2023, T-ALL patients（n=7）with MRD positive during first CR (CR1) were analyzed. The median age was 22 (15~33) years old. Venetoclax was given at a dose of 100mg on day1, 200mg on day2, 400mg on day3~14 for the first cycle, then 400mg daily on day1~14 for the proceeding cycles. DARA was administrated at a dose of 16mg/kg on day 1 and day 8. Low-intensity CAG regimen was given as concurrent chemotherapy (Cytarabine 25mg/q12h day1~7, Aclarubicin 20mg/d day1~4, G-CSF 300μg/d day1~7). Every 4 weeks defined as a cycle. Once MRD turned negative, the patient will be scheduled for allogeneic hematopoietic stem cell transplantation (allo-HSCT) as soon as possible.

Multiparameter flow cytometry was employed for MRD monitoring, MRD negativity was defined as less than 0.01%. The expression of CD38 antigen was detected by flow cytometry. Safety assessments included the evaluation of adverse events, which were graded according to CTCAE (version 5.0).

Results

Between 12/2022 and 11/2023, seven patients have been treated by the combination of venetoclax and DARA. The median age was 22 yrs (range, 15~33). At baseline, all patients were remained in CR1, but with positive MRD, and the median MRD level was 0.2% (range, 0.01%~1.36%). All of them had undergone intensive multi-drug chemotherapy (median 2 cycles) as frontline treatment. CD38 expression were positively detected on the surface of leukemia cells in these patients. Five patients received one cycle of venetoclax and DARA, two patients received two cycles of venetoclax and DARA.

In total, 6 out of 7 (85.7%) patients achieved MRD negativity, with 4 of these 7 (57.1%) cases attained MRD negativity soon after one cycle. Subsequently, 5 out of 6 (83.3%) MRD negative patients underwent allo-HSCT. The median time from MRD negative to allo-HSCT was 72.5 days (range, 26~108 days). The rest one with MRD negative is planning to receive allo-HSCT. MRD retention was observed in 1 patient (1/7, 14.3%) after 2 cycles. This case showed partial benefit from this regimen with MRD decreased from 1.36% to 0.07%. After continuing venetoclax contained chemotherapy for 6 months, this patient also successfully bridged to allo-HSCT despite persistent low level MRD (0.01%~0.1%). With a median follow up of 8.6 months (range, 2.7~15.0), all 7 patients remained MRD negative survival. Both overall survival rate and progression free survival rate are 100%.

The most common adverse events of grade 3 or 4 associated with the regimen were leukocytopenia (3/7, 42.9%) and thrombocytopenia (1/7, 14.3%). Infusion-related reactions (IRR) to DARA (grade 1~2) were observed in 5 patients (71.4%) during the first infusion, all ameliorated after symptomatic treatment. No grade 3/4 IRRs were observed. None of the patients in this series developed tumor lysis syndrome related to venetoclax treatment. No life-threatening complications (grade 4) or death were noted. No treatment discontinuation occurred.

Conclusion

The combination of venetoclax and DARA plus CAG regimen is effective and safe in inducing rapid eradication of MRD in T-ALL. Our results suggest that comprehensive management, consisting of small molecular targeted drug, immunotherapy and low intensive chemotherapy followed by allo-HSCT, could be promising curative strategy in high-risk T-ALL. Nevertheless, this warrants further validation on a larger scale of T-ALL.