Venetoclax, Cladribine and Cytarabine for the Treatment of Relapse/Refractory Acute Lymphoblastic Leukemia: Interim Analysis of a Phase 2 Trial
Authors: Li Yan-yan , Zhou Hai-xia , Huang Si-man , Wan Chao-Ling , Xu Ming-zhu , Gong Wen-jie , Qian Chong-Sheng , Wu De-pei , Dai Haiping , Xue Sheng-Li 
Published: December 2023

Venetoclax, cladribine and cytarabine for the treatment of relapse/refractory acute lymphoblastic leukemia: interim analysis of a phase 2 trial
Background: Philadelphia chromosome-negative acute B lymphoblastic leukemia (Ph- B-ALL) accounts for approximately 60-70% of adult B-ALL. Patients with relapse/refractory (R/R) Ph- B-ALL was reported to have a poor prognosis. Immunotherapies such as blinatumomab, CAR T-cell therapy achieved high response rate for Ph- B-ALL. However, salvage chemotherapies are also worth of investigation because many patients can't afford immunotherapies. We found that venetoclax, cladribine and low-dose cytarabine had synergistic cell toxicity against B-ALL cell line RS4;11 in our previously in vitro studies. Based on these findings, we designed a multicenter, phase 2 study utilizing the venetoclax, cladribine and cytarabine (CAV) regimen for the treatment of R/R B-ALL (NCT05657652).
Methods: The CAV regimen consisted of cladribine 5 mg/m 2/day from day 1 to day 3 or day 5, cytarabine 20mg/m 2, q12h, for 7-10 days and venetoclax 100mg d1, 200 mg d2, 400 mg/day from day 3 to day 28. Bone aspiration evaluation was performed at 14-28 days after the completion of CAV regimen. Treatment responses were evaluated according to the NCCN guidelines. The threshold of MRD negativity was defined as less than 0.01% as detected by multiparameter flow cytometry.
Results: Since February 2021, a total of 16 patients with R/R Ph- B-ALL were enrolled in this study. Baseline characteristics of these patients were summarized in Table 1. The median age was 36 years (range, 13-66 years), and 12/16 (75%) patients were male. Among them, 12 patients (75%) had relapsed Ph- B-ALL and 4 patients (25%) had refractory Ph- B-ALL. One patient had concurrent active central nervous system leukemia. One patient had a complex karyotype, and two patients had TP53 mutations. Treatment responses were shown in Table 2. 12/16 (75%) patients responded to CAV regimen after one cycle of CAV regimen, with 3/16 (18.75%) with complete remission (CR), 8/16 (50%) with CRi, and 1/16 (6.25%) with morphology leukemia-free state (MLFS). Among patients who achieved treatment response, 9/12 (75%) patients attained MRD negativity. During the treatment with the CAV regimen, one patient (1/16, 6.3%) developed grade 4 tumor lysis syndrome. 4/16 (25%) patients suffered grade 3 to 4 infections. Grade 1 to 2 gastrointestinal reactions and liver dysfunction were observed in 8/16 (50%) and 5/16 (31.3%) patients, respectively. The 60-day mortality rate was 6.3%. Two patients who relapsed after CAV treatment re-achieved remission after CART therapy. Nine patients received allo-HSCT after CAV regimen. With a median follow-up of 11 months (range, 0.3-28 months), the estimated 1-year overall survival rate was 76.2% and 1-year event-free survival rate was 38.4%. The survival swimming plot was shown in Figure 1. The median OS was not reached and the median EFS was 13 months. The cumulative relapse rate was 31.3% (5/16). At the last follow-up, two patients died of relapse, one patient died of cerebral hemorrhage and one patient died of sepsis.
Conclusion: In summary, our results demonstrated that CAV regimen showed encouraging efficacy and safety in treating R/R Ph- B-ALL patients.