Outcomes of BCR::ABL1-like B-Lineage Acute Lymphoblastic Leukemia in the Era of Novel Therapies
Authors: Rahmani Youshanlouei Hamed , Shah Syed , Anazco Francisca , Patel Anand Ashwin , Duvall Adam S. , Roloff Gregory W , Drazer Michael W , Kosuri Satyajit , Nawas Mariam T. , Lager Angela , Fitzpatrick Carrie , Wang Peng , Tjota Melissa , Gurbuxani Sandeep , Venkataraman Girish , Cheng Jason Xiaojun , Segal Jeremy , Odenike Olatoyosi , Larson Richard A. , Stock Wendy , Saygin Caner 
Published: December 2024

Introduction: BCR::ABL1–like acute lymphoblastic leukemia (BCR::ABL1-like B-ALL) is a high-risk subset of ALL that represents 15-20% of newly diagnosed adults with B-lineage ALL. Standard chemotherapy-based (chemo) regimens are associated with inferior response and high relapse rates in this disease. Due to its high frequency in Hispanic patients (pts), BCR::ABL1-like B-ALL is a major contributor to racial disparities in ALL outcomes. There is no consensus on recommending allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR) for this disease, especially in the era of novel antibody-based and cellular targeted therapies. We aimed to investigate the outcomes of BCR::ABL1-like B-ALL patients treated at a large academic center in the current era of novel therapies.

Methods: We retrospectively analyzed clinical outcomes of 68 consecutive adult pts with BCR::ABL1-like B-ALL who were treated at the University of Chicago between 2014 and 2023. Classification of BCR::ABL1-like status was made according to the WHO 2022 criteria using accumulative results from FISH, DNA sequencing, and RNA sequencing studies performed at our CLIA-certified cytogenetics and molecular diagnostics laboratories.

Results: Median age at diagnosis was 34.5 years (range, 18-74), 68% were male. Genomic studies revealed CRLF2 rearrangements (CRLF2-r) in 75%, JAK2-r in 10%, ABL1-r in 6%, FGFR-r in 3%, and rearrangements in ABL2, CSF1R, PDGFR and ROS1 at 1.5% each. Most common co-occurring somatic gene mutations involved IKZF1 (41%), CDKN2A (37%), JAK2 (37%), KRAS (16%), PAX5 (12%) and NRAS (10%). First-line therapy was chemo alone in 80% of patients with the following distribution: CALGB 10403 (C10403) in 43%, hyper-CVAD in 28% and other chemo in 9%. The remaining 20% of patients received novel therapies in first-line setting, including C10403 + inotuzumab ozogamicin (InO) in 7%, ino + blinatumomab (blin) in 6%, hyperCVD + venetoclax in 4% and C10403 + imatinib in 3%. Post-induction flow cytometry-based measurable residual disease (MRD) negativity rate was significantly higher in patients who received novel therapies upfront vs patients who received standard chemo (55% vs 20%, p= 0.02). This is significantly lower than our non-BCR::ABL1-like B-ALL patients, for whom the flow cytometry-based MRD-negative CR rate after chemo induction was 62% (p&lt; 0.01). We also observed higher 5-year relapse-free survival (RFS) rate for patients who received novel therapies upfront vs those who received standard chemo alone (65% vs 20%, p&lt; 0.01). We did not detect a significant difference in overall survival (OS) for patients treated with novel therapies vs standard of care (median, not reached vs 37 months, p= 0.52), which is likely due to the utilization of novel therapies as salvage regimens after relapse. Of note, 5 patients received tyrosine kinase inhibitors (ruxolutinib, dasatinib, imatinib) in salvage setting, but did not achieve remission. There were no differences in OS or RFS outcomes when patients were stratified based on CRLF2-r vs non-CRLF2-r. Among co-occurring gene alterations, we observed higher risk for relapse in cases with KRAS mutations (HR= 4.29, 95% CI= 1.3-13.4), which was independent from the type of first-line treatment received.

7% of pts received anti-CD19 chimeric antigen receptor (CAR-T) cell therapy for relapsed disease. 32% of pts received allogeneic HCT, which was done in CR1 in 31% of cases due to MRD positivity, while 69% received HCT after salvage therapy (CR2 or CR3). 64% received myeloablative conditioning (TBI-based regimens) with the following distribution of donors: 46% matched unrelated, 27% mismatched unrelated, 18% matched related, 9% haplo-cord. Median OS after HCT was 10 months. We did not identify RFS or OS differences between patients who did or did not receive allogeneic HCT.

Conclusion: Collectively, standard chemo (pediatric-inspired or others) is associated with inferior response rates and RFS in patients with BCR::ABL1-like B-ALL. Incorporation of novel agents (InO, blin, venetoclax) in upfront chemotherapy regimens may close the gap between BCR::ABL1-like and non-BCR::ABL1-like disease. Future studies should focus on optimal first-line combination regimens and higher-risk subsets such as KRAS-mutated BCR::ABL1-like B-ALL.