P363: a phase ii study of flumatinib with chemotherapy for newly diagnosed ph/bcr-abl1-positive acute lymphoblastic leukemia in adults: updated results from rj-all2020.2a trial

Background: Tyrosine kinase inhibitors (TKIs) have significantly improved outcomes of patients (pts) with Ph/BCR-ABL1-positive acute lymphoblastic leukemia (Ph/BCR-ABL1+ ALL). Compared to the first-generation TKIs, the second-generation result in a relatively better response rate and survival. Flumatinib is a novel second-generation TKI developed in China and approved in 2019. It has shown better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL. Aims: Herein, we report the updated results of RJ-ALL2020.2A trial, which is the first reported registered clinical trial of flumatinib in Ph/BCR-ABL1+ ALL to evaluate its efficacy and safety in adult pts. Methods: In this prospective phase II study, pt eligibility mainly includes: 18 ≤ age < 65 years; newly diagnosed Ph/BCR-ABL+ ALL; and adequate organ function. Once the diagnosis is confirmed, combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is administered promptly. Allo-HSCT is recommended to all eligible pts. Central nervous system (CNS) prophylaxis is regularly performed after remission induction course. Multiparameter flow cytometry (MFC) and RT-qPCR are used to monitor minimal residual disease (MRD). The primary endpoints are MRD clearance, PFS and OS. (Clinical Trial Registration Number: ChiCTR2100042248) Results: From Dec. 2020 to Dec. 2022, 63 adult pts with de novo Ph/BCR-ABL1+ ALL were enrolled. Median age was 43 years (range, 19-63). Median WBC count at diagnosis was 41.1×109/L (0.6-675.3). And 4 pts had primary CNS leukemia. 60/63 (95.2%) pts achieved CR at the end of induction, with no early death during the induction course. MRD negative (MRD-, <10-4) rates by MFC were 66.1% (39/59) and 80% (44/55), while the CMR (BCR-ABL1 transcript<10-5) rates were 28.1% (16/57) and 51.9% (28/54) at the end of induction and 3 months, respectively. With a median follow-up time of 14 months (range, 2-23), the 1-year PFS and OS rates were 86.1% and 92.5%(Figure 1A, 1B). Among the 58 survived pts, 50 pts were in continuous remission and 8 were relapsed. Among 5 deaths, 4 died of disease progression, and 1 of pulmonary infection post-HSCT. There was a survival superiority in pts who achieved MRD- or CMR at 3 months (PFS: p=0.041, p=0.024; OS: p=0.001, p=0.190). 37 pts received allo-HSCT with a median time of 6 months (range, 1-10) from diagnosis, the median age was 43 years (range, 19-63). Before HSCT, MRD- and CMR rates were 80.6% (29/36) and 72.2% (26/36), respectively. PFS and OS were significantly improved in pts who underwent HSCT (PFS: p=0.008, OS: p=0.02) (Figure 1C, 1D). Among 61 pts evaluable for ABL1 mutations, 21 pts were mutated, and T315I was most frequently identified, accounting for 76.2%. Pts with T315I mutation showed a poorer outcome than non-T315I mutation (PFS: p<0.001, OS: p=0.013) (Figure 1E, 1F). Meanwhile, the combination of flumatinib and chemotherapy was well-tolerated. Non-hematological AEs were mostly grade 1-2, which could be recovered soon after symptomatic management. Most of the G3-4 AEs were hematological, possibly related to induction chemotherapy. No pt discontinued flumatinib due to toxicity.Summary/Conclusion: The combination of the novel second-generation TKI flumatinib and chemotherapy is quite effective and safe in newly-diagnosed Chinese adult pts with Ph/BCR-ABL1+ ALL. This clinical trial is still ongoing, and the long-term follow-up data will be further investigated. Keywords: Acute lymphoblastic leukemia, Tyrosine kinase inhibitor, BCR::ABL