Flumatinib with Low-Intensity Chemotherapy in Elderly Patients with Newly Diagnosed BCR::ABL1-Positive Acute Lymphoblastic Leukemia
Authors: Liu Weiyang , Liu Yuanfang , Zhu Yongmei , Weng Xiangqin , Wang Cheng , Ouyang Wanyan , Xu Jie , Zhang Weiping , Wang Jin , Mi Jian-Qing 
Published: December 2024

Background

Second-generation Tyrosine kinase inhibitors (TKIs) further improved outcomes in BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). Flumatinib, an approved alternative second-generation TKI in China since 2019, has demonstrated favorable efficacy and safety profiles in chronic myeloid leukemia. However, limited studies have specifically investigated the utilization of flumatinib in BCR::ABL1+ ALL, particularly among elderly patients (pts). Herein, we present the clinical findings of flumatinib combined with a low-intensity chemotherapy regimen for ALL pts aged 65 years and older.

Methods

In this observational study, newly diagnosed BCR::ABL1+ ALL pts aged ≥ 65 years with adequate organ function were analyzed. All pts received flumatinib (600mg/day) and VP-based (Vincristine/Prednisone) chemotherapy; dose reduction was permitted according to the discretion of physicians. Central nervous system (CNS) prophylaxis is regularly performed by intrathecal injection of methotrexate, cytarabine, and dexamethasone after the induction course. No pts underwent allogeneic hematopoietic stem cell transplantation. Minimal residual disease (MRD) was monitored by both multiparameter flow cytometry at a sensitivity of at least 0.01% and real-time quantitative PCR at a sensitivity of 0.001%. Complete molecular remission (CMR) was defined as the absence of quantifiable BCR::ABL1 transcripts. IKZF1plus (IKZF1 deletions with CDKN2A, CDKN2B, PAX5, or PAR1 region deletions, in the absence of ERG deletion) was identified by multiplex ligation-dependent probe amplification. Adverse events (AEs) were assessed according to CTCAE v5.0.

Results

From January 2021 to April 2024, 25 pts with de novo BCR::ABL1+ ALL underwent flumatinib combined with VP-based chemotherapy. The median age was 68 years (range, 65-78), 56.0% of pts were females, and the median WBC count was 49.0 ×109/L (IQR, 16.0-105.2). BCR::ABL1 p190 fusion transcript was detected in 16 pts, while p190 and p210 were simultaneously found in 7 pts. For karyotype analysis and DNA sequencing, poor-risk cytogenetic and molecular alterations were identified in 17/24 pts, and additional cytogenetic aberrations were identified in 18/23 pts. With the MLPA method, 10/23 pts were found to have IKZF1plus. Besides, one pt had primary CNS leukemia.

All 25 pts achieved CR/CRi at the end of induction, with no early death during the induction course. The MRD flow negative rate and the CMR rate were 72.0% (18/25) and 12.5% (3/24) at the end of induction and 72.7% (16/22) and 31.8% (7/22) at 3 months, respectively. With a median follow-up time of 22.3 months (range, 2.6-43.6), the estimated 2-year OS and PFS rates were 64.8% and 50.2%, with a median OS and PFS of 26.0 and 24.1 months, respectively. Among the 15 survived pts, 13 were in continuous remission, and 2 were relapsed. Among 10 deaths, 9 died of disease progression and 1 of pulmonary infection. There was a survival superiority in pts who achieved MRD flow negativity at 3 months ( OS: p=0.002, PFS: p=0.027).

Among 24 pts evaluable for ABL1 mutations, one or more known mutations were found in 15 pts. T315I was most frequently identified, accounting for 66.7% (10/15), followed by Y253H of 53.3% (8/15). Among 11/24 pts with relapsed disease, 10 were associated with ABL1 mutations, including 8 with T315I and 4 with Y253H, and 8 with multiple mutations successively or simultaneously. Pts with T315I mutation showed a poorer outcome than non-T315I mutation (OS: p=0.022, PFS: p=0.033).

Finally, the safety profiles of the flumatinib-based therapy were acceptable. Non-hematological AEs were primarily G1-2, reversible rapidly after symptomatic management. Most of the G3-4 AEs were hematological and infectious, possibly related to chemotherapy. No G3-4 pleural effusion, pericardial effusion, cardiovascular adverse events, or pancreatitis were found. No permanent discontinuation or death related to flumatinib was observed.

Conclusion

This study firstly reports the efficacy and safety of the second-generation TKI flumatinib combined with low-dose chemotherapy in newly-diagnosed elderly pts with BCR::ABL1+ ALL. The clinical outcomes observed for flumatnib were comparable to those reported for the classical second-generation TKI dasatinib. These findings will be further validated through long-term follow-up with an expanded sample size.