Background: Many studies have identified various gene aberrations in acute lymphoblastic leukemia (ALL). IKZF1 deletion is frequently observed in Ph-positive ALL, and IKZF1-plus is defined as a poor subgroup when combined with CDKN2, PAX5, or PAR1 deletions. Most findings come from Western pediatric data, and while new gene mutations are being detected, their clinical correlation remains controversial. This study analyzed the prognostic outcomes of genetic abnormalities in Ph+ALL treatment based on allogeneic hematopoietic stem cell transplantation (AlloHSCT).

Methods: We investigated the prognostic relevance of deletions in 11 genes (IKZF1, CDKN2A/B, EBF1, ETV6, PAX5, BTG1, JAK2, RB1, PAR1, ZFY) detected by multiplex ligation-dependent probe amplification (MLPA), and 70 gene mutations additionally checked by high-throughput sequencing (HTS) analysis in 164 adults with Ph-positive ALL. These patients were treated with modified hyper-CVAD and imatinib-based chemotherapy followed by allo-HSCT as post-remission therapy. Among them, 127 underwent allo-HCT (109 in CR1, and 18 ≥CR2), and 69 achieved complete molecular response (CMR, undetectable BCR::ABL1 transcript).

Results: We identified IKZF1 deletion in 132 (80.5%) patients, CDKN2 deletion in 62 (37.8%), and PAX5 deletion in 62 (37.8%), followed by BTG1 deletion (n=38), EBF1 deletion (n=25), JAK2 deletion (n=16), and ETV6 deletion (n=13). Frequently observed mutations included SETD2 (n=11), RUNX1 (n=10), and IKZF1 (n=9). CDKN2 deletion was the only aberration significantly associated with poor outcomes. Among the 132 patients with IKZF1 deletion, 55 (33.54%) had concurrent CDKN2 deletion, and this group showed the worst outcomes. To assess the prognostic impact, we formed three subgroups: Group-1 (no IKZF1 deletion), Group-2 (IKZF1 deletion without CDKN2 deletion), and Group-3 (concurrent IKZF1 and CDKN2 deletions). Baseline clinical characteristics were similar across the groups. All patients achieved complete remission (CR) after chemotherapy, and post-induction CMR rates were not significantly different (31.2%, 24.0%, and 35.2%, p=0.371).

With a median follow-up duration of 27.8 months, overall survival differed significantly among the three groups (p=0.006). The survival difference was mainly attributed to Group 3, with 3-year survival rates of 57.6%, 64.9%, and 38.1% for Groups 1, 2, and 3, respectively. A similar trend was observed in disease-free survival (p=0.004). The differences in survival appeared to be due to higher relapse rates in Group 3. The 3-year cumulative incidence of relapse (CIR) was significantly higher in Group 3 compared to the other groups (37.9%, 24.7%, and 50.7%, respectively, p=0.0246), with no significant difference in non-relapse mortality (p=0.756). These differences were also observed in post-transplant survival among patients who underwent allo-transplantation. The 3-year overall survival rates were 57.6%, 73.0%, and 37.5% for Groups 1, 2, and 3, respectively (p=0.004), and the 3-year disease-free survival rates were 51.0%, 67.1%, and 31.7% (p=0.003). Group 3 had a significantly higher CIR (3-year CIR: 33.4%, 16.8%, and 43.5%, p=0.030), with no difference in non-relapse mortality (p=0.403). This trend was observed even in the subgroup that achieved a major molecular response (MMR) before transplantation.

Conclusion: Our data showed that concurrent IKZF1 and CDKN2 deletions were significantly associated with poor outcomes in Ph-positive ALL due to high relapse rates, regardless of the degree of molecular response before transplantation. No other mutations were found significant, but larger data analysis is needed to determine their clinical relevance

Disclosures

Park:ImpriMed, Inc.: Consultancy, Current holder of stock options in a privately-held company. Kim:BMS & Celgene, Novartis, APLC, AbbVie, Astellas, Janssen, Handok, Pfizer, Sanofi Genzyme, AML-Hub, Daiichi Sankyo and APBMT: Membership on an entity's Board of Directors or advisory committees; AML-Hub, APBMT, ICBMT, APLC, Novartis and BMS: Other: and leadership or fiduciary roles in other board, society, committee or advocacy group ; AbbVie, AIMS Bioscience, AML-Hub, Astellas, BMS & Celgene, Boryung Pharm Co., Daiichi Sankyo, Janssen, Handok, LG Chem, Novartis, Pfizer, SL VaxiGen, VigenCell, Aston Bioscience, Ingenium, Amgen, Sanofi Genzyme, Takeda, Meiji Pharm Co. and GreenCross Phar: Consultancy; Jazz Pharmaceuticals, Takeda, Astellas, AbbVie and APLC: Other: Travel; AbbVie, Astellas, BMS, Handok, Novartis, AML-Hub, Jazz Pharmaceuticals and Takeda: Honoraria, Speakers Bureau; BL&H: Research Funding.

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2024
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