P378: chemo-free treatment of vaf induce a early and deep molecular responsein in patients with newly diagnosed philadelphia chromosome-positive acute leukemia: a prospective, single arm, phase ii study

Background: The 3-month complete molecular response(CMR) is a favourable prognostic factor for overall survival(OS), even negating the need for allogeneic haematopoietic stem cell transplant (allo-HSCT). The overall 3-month CMR of standard chemotherapy with TKIs is 57%. Preclinical data have suggested Bcl-2 inhibitors strongly induce apoptosis in Ph+ cells, and highly synergistic with TKIs, identifying BCL2 as a new therapeutic target of particular relevance in Ph+ ALL. Aims: We evaluated the efficacy and safety of a chemo-free combination of venetoclax, azacitidine and flumatinib (VAF) in patients with ND Ph+AL and accelerated or blast phase chronic myeloid leukemia(CML). The primary endpoint was CMR rate at end of two cycles of VAF. Secondary endpoints included relapse-free survival(RFS), overall survival(OS), and safety. Methods: We designed a single-arm phase 2 study in adults with ND Ph+ AL and CML-AP/BP. Patients received two cycles of VAF induction. Administration of the VAF regimen was as follows: venetoclax,100 mg d1, 200 mg d2,400 mg d3-21, orally; azacitidine,75 mg/m2, d1-7, subcutaneously; flumatinib, 600 mg once daily continuously from d4. Once patients reached CMR after two cycles of VAF induction, they received one cycle of high-dose cytarabine based-regime consolidation and proceed to allo-HSCT if eligible. VAF were repeated for patients ineligible for allo-HSCT every 4 weeks as maintenance therapy until disease progression. Twelve doses of prophylactic intrathecal chemotherapy were administered. Results: Between May 2022 and February 2023, a total of 20 ND patients were enrolled (14 Ph+ALL, 2 Ph+ B/M mixed phenotype acute leukemia(MPAL) and 4 CML-AP/BP). As of 28 February 2023, 13 patients had received two cycles of the VAF regimen (include 11 Ph+ ALL, 1 Ph+ B/M MPAL and 1 CML-BP), and 12 of them were evaluable for the primary endpoint (except for one with Ph+ ALL withdrew from this trial after discontinuing cycle2 due to severe COVID‐19 pneumonia). Patient characteristics and outcomes of VAF are summarised in table 1. After one cycle of VAF, CR/CRi rate was 100% (13/13). Of the 13 patients, 92.3% had a molecular response with 76.9% CMR and 15.4% MMR, and another one achieved a CCyR. The CMR rate at end of two cycles of VAF, the primary endpoint, increased to 83.3%. The median time from induction to CMR was 21d (range, 14-70d). No early death within 4 weeks was observed. The median duration of follow-up was 7.6 (3-9) months. The 6-month RFS and OS of all 12 patients was both 100%. The treatment was well-tolerated, the most common adverse hematological events reported were febrile neutropenia (grade 1-2,3 [23%] of 13). The median recovery time of neutropenia and thrombocytopenia was 11 and 5 days, respectively. The median number of red blood cell and platelet infusions were 5U and 15U. Mild non-hematological toxicities were reported. The average time of hospitalization was 22 days and 7 days of cycle1 and cycle2, respectively. All patients received cycle2 treatment in Day Ward. No patient discontinued due to toxicity. Summary/Conclusion: VAF is a highly effective and safe strategy to achieve early and deep molecular response in patients with ND Ph+AL in the frontline setting, providing a potential Day ward/Out-patient treatment strategyfor Ph+AL.Keywords: Philadelphia chromosome, Azacitidine, Venetoclax, Acute lymphoblastic leukemia