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1457 Low-Risk Group Identified By a Refined Prognostic System Integrating Both IKZF1plusgenotyping and MRD Assessment in Adult BCR::ABL1-Positive Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Biomarkers, Molecular Markers, and Minimal Residual Disease in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Translational Research, Patient-reported outcomes, Diseases, Lymphoid Malignancies, Measurable Residual Disease
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Cheng Wang, MAS1*, Jianfeng Li, PhD2*, Weiyang Liu, MD3*, Han Yan2*, Yuchen Yan2*, Lingling Zhao2*, Jiayi Ren, MD2*, Lijun Peng2*, Jiaojiao Zhang2*, Yuanfang Liu, MD, PhD2*, Xiangqin Weng, Master2*, Yongmei Zhu, PhD2*, Weiping Zhang, MD, PhD2*, Jie Xu, MD, PhD2, Duohui Jing2*, Jian-Qing Mi2* and Jin Wang, MD, PhD2*

1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, TX, China
2Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
3Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, AL, China

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 (< 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 < 0.001), event-free survival (P = 0.003 or P < 0.001), and lower cumulative incidence of relapse (P = 0.005 or P < 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 < 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 < 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.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH