Low-Risk Group Identified By a Refined Prognostic System Integrating Both IKZF1plusgenotyping and MRD Assessment in Adult BCR::ABL1-Positive Acute Lymphoblastic Leukemia
Authors: Wang Cheng , Li Jianfeng , Liu Weiyang , Yan Han , Yan Yuchen , Zhao Lingling , Ren Jiayi , Peng Lijun , Zhang Jiaojiao , Liu Yuanfang , Weng Xiangqin , Zhu Yongmei , Zhang Weiping , Xu Jie , Jing Duohui , Mi Jian-Qing , Wang Jin 
Published: December 2024

Background: The integration of tyrosine kinase inhibitors (TKIs) into multiagent chemotherapy regimens has markedly improved the prognosis of patients with BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a backbone of contemporary curative treatments for adult BCR::ABL1+ ALL. IKZF1plus genotype and minimal residual disease (MRD) are well-recognized independent prognostic factors to evaluate treatment response of BCR::ABL1+ ALL. However, so far, there have been no studies on the synergy of these two prognostic factors [IKZF1plus genotyping (IKZF1plus or non-IKZF1plus) and MRD assessment (MRD positivity or negativity)] in risk stratification of adult BCR::ABL1+ ALL. Meanwhile, increasing evidence suggests that allo-HSCT may not benefit all adult patients, but the stratification criteria for identifying fit adult patients undergoing or sparing from transplantation remain elusive.
Objectives: This study aimed to refine the risk stratification by integrating both IKZF1plus genotyping and MRD assessment, and explored the necessity of allo-HSCT for different risk groups, in order to improve the management of allo-HSCT in BCR::ABL1+ ALL therapy.
Methods: 187 newly diagnosed adult BCR::ABL1+ ALL patients (aged ≥18) treated in our institute between June 2014 and August 2023 were analyzed, among which 155 patients (aged 18-64) were included in the survival analysis. The patients were treated with a TKI-based [imatinib or flumatinib (a second-generation TKI)] standardized VDP regimen(vincristine/daunorubicin/prednisone), and eligible patients were recommended to undergo allo-HSCT (Clinical Trial Registration Number: ChiCTRONRC-14004968, ChiCTR2100042248 and ChiCRT2100044308). Multiplex ligation-dependent probe amplification (MLPA) was used for IKZF1plus genotyping, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to routinely monitor MRD. MRD negativity (MRD-), equivalent to complete molecular remission in this study, was defined as the absence of detectable BCR::ABL1 transcript (&lt; 0.001%) at three months of treatment.
Results: Till July 15, 2024, the overall median follow-up period was 36.3 months (range, 7.5-123.1). There was no significant difference in baseline characteristics and survival outcomes between imatinib (n = 67) and flumatinib (n = 120) cohorts. Based on IKZF1plus genotype and MRD status at 3 months, 155 patients (aged 18-64) with available data were stratified into three risk groups: low-risk (non-IKZF1plus/MRD-, n = 45), intermediate-risk (non-IKZF1plus/MRD+, n = 49) and high-risk (IKZF1plus, n = 61). Compared to intermediate-risk or high-risk group, the low-risk group had better overall survival (OS) (P = 0.07 or P &lt; 0.001), event-free survival (P = 0.003 or P &lt; 0.001), and lower cumulative incidence of relapse (P = 0.005 or P &lt; 0.001), respectively.
Next, we analyzed the impacts of allo-HSCT for three risk groups. Without allo-HSCT, OS of the low-risk group was significantly superior to the other groups (P &lt; 0.001). However, allo-HSCT failed to further improve OS of the low-risk group (P = 0.85), but improved OS of the intermediate (P = 0.08) and high-risk (P &lt; 0.001) groups. After allo-HSCT, OS of the three groups reached similar levels (P = 0.55).
Conclusions: This study is the largest cohort to date focusing on IKZF1plus aberration and MRD simultaneously in adult BCR::ABL1+ ALL. Integrating both IKZF1 genotype and MRD status at 3 months, BCR::ABL1+ ALL could be further classified into three distinct risk groups: low-risk, intermediate-risk and high-risk. The low-risk group (non-IKZF1plus/MRD-), for the first time, was identified in adult BCR::ABL1+ ALL. In the era of TKI combined with chemotherapy, it also suggested that allo-HSCT should be spared for the low-risk group, but is recommended for intermediate-risk and high-risk groups if eligible.