Improved MRD Clearance By Incorporating Venetoclax into Pediatric-Inspired Regimen in Newly Diagnosed Adolescent and Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Background

Although most adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph^-ALL) may achieve complete remission (CR) after intensive Berlin Frankfurt Münster (BFM) based regimen, a significant proportion of patients remained minimal residual disease (MRD) positive. Our historical data demonstrated that approximately 50% of patients with Ph^-ALL exhibit persistence of MRD by flow cytometry (FCM) at the end of induction (EOI). In addition to novel immunologic agents, venetoclax (a BCL-2 specific inhibitor) has shown encouraging results in the treatment of ALL. In this study, we explored the efficacy and safety of incorporating venetoclax into pediatric-inspired regimen in newly diagnosed adolescent and adult patients with Ph^-ALL.

Methods

This is a single-arm phase II study (NCT05660473) that enrolled patients (pts) with newly diagnosed Ph^-ALL aged 14-60 years. Based on our previous pediatric-inspired regimen (ChiCTR-OOC-15006328), we add venetoclax to chemotherapy. Induction therapy consists of VCR 1.4 mg/m² (maximum dose 2 mg) on day 1, 8, 15, 22; daunorubicin 30 mg/m² on day 1-3; cyclophosphamide 1200 mg/m² on day 1 and 15; pegylated asparaginase 2500 IU/m² on day 5; prednisone 1 mg/Kg on day 1-14, 0.5 mg/Kg on day 15-28; venetoclax 100 mg on day 6, 200 mg on day 7, 400 mg on day 8-14. On day 14 of induction phase, all patients underwent bone marrow (BM) aspiration. Pts with ≥ 10% BM residual leukemic blasts on day 14 of induction received additional 7 days of venetoclax at a dose of 400 mg per day. After induction therapy, all consolidation and maintenance cycles will be supplemented with an additional 7 days of venetoclax at a dose of 400 mg per day. MRD was measured using BM aspirates with eight-color multiparametric FCM on day 14 of induction, EOI (days 29–42) and throughout the treatment period. MRD levels of < 0.01% and ≥ 0.01% was considered as negative and positive, respectively. The decision on whether to undergo allogeneic hematopoietic stem cell transplantation was determined by a composite of risk stratification, MRD levels and the availability of donors. The primary end point of the study was the MRD negativity rate after induction.

Results

From August 2022 to May 2024, a total of 167 Chinese pts were enrolled. The median age was 31 years (range, 14-60 years) and males accounted for 58.1%. Among them, 126 pts presented with B-cell ALL and 41 with T-cell ALL. These 126 B-ALL cases included 22 (17.5%) with ZNF384-rearranged, 14 (11.1%) with Ph-like, 12 (9.5%) with t(v;11q23.3)/KMT2A rearranged, 11 (8.7%) with t(1;19)(q23.3;p13.3)/TCF3::PBX1, 4 (3.2%) with mutated PAX5 P80R, 3 (2.4%) with MEF2D-rearranged, 3 (2.4%) with DUX4-rearranged, 2 (1.6%) with t(12;21)(p13.2;q22.1)/ETV6::RUNX1 and the remaining 55 (43.7%) cases were B-others. T-ALL patients with ETP‐ALL and non‐ETP‐ALL were 15 (36.6%) and 26 (63.4%), respectively. All pts received induction therapy. In total, 7 pts died during induction therapy, and the induction-related mortality was 4.19%. The primary causes of mortality during induction were infection. Among 160 efficacy-evaluable patients, 152 pts (91.0%, 152/167) achieved CR after induction chemotherapy and 110 pts (72.4%, 110/152) achieved MRD negativity. Compared to our historical cohort (PMID: 38235508), the addition of venetoclax to induction therapy improved MRD clearance from 50% up to over 70%, with the most significant improvement in patients with ETP phenotype (71.4% vs 19.4%). The clearance of MRD for Ph-like patients approximately doubled compared to our prior results, however, more than half of the patients were still persistently MRD positive after CR. After a median follow-up of 10.8 months (range, 1-24 months), the estimated 2-year overall survival and relapse-free survival rates were 83.0% and 81.9%, respectively. The regimen was overall well tolerated. The toxicity profile was similar to our prior regimen. Hematologic toxicity and infections were the most common grade 3 or greater adverse events.

Conclusion

The addition of venetoclax to a pediatric-inspired regimen was safe in adolescent and adult patients with newly diagnosed Ph^-ALL, resulting in a significant improvement in MRD clearance after induction.