Outcomes of Ph-like B-lineage acute lymphoblastic leukemia in the era of novel therapies.

6535 Background: Ph-likeALL) is a high-risk subset of B-ALL with poor treatment response and high relapse rates. We examined outcomes of Ph-like B-ALL pts (pts) treated at a large academic center in the current era of novel therapies. Methods: We retrospectively analyzed 68 adults with Ph-like B-ALL treated at the University of Chicago (2014-2023). Ph-like status was classified per WHO 2022 criteria using FISH, DNA and RNA sequencing. Results: Median age at diagnosis was 34 years (range, 18-74), 68% were male. We found 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 pts with the following distribution: CALGB 10403 in 43%, hyper-CVAD in 28% and other chemo in 9%. The remaining 20% of pts received novel therapies in first-line setting, including C10403 + inotuzumab (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 pts who received novel therapies upfront vs pts who received standard chemo (55% vs 20%, p= 0.02). This is lower than our non-Ph-like B-ALL pts, for whom the MRD-negative CR rate after chemo induction was 62% (p< 0.01). We also observed higher 5-year relapse-free survival (RFS) rate for pts who received novel therapies upfront vs standard chemo alone (65% vs 20%, p< 0.01). We did not detect a significant difference in overall survival (OS) for pts treated with novel therapies vs standard of care (p= 0.52), which is likely due to the utilization of novel therapies as salvage regimens after relapse. Of note, 5 pts received kinase inhibitors (ruxolutinib, dasatinib, imatinib) in salvage setting, but did not achieve remission. There were no differences in OS or RFS outcomes when pts 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 therapy. 7% received anti-CD19 CAR-T cell therapy. 32% had allogeneic transplant (HCT), which was done in CR1 in 31%, while 69% received HCT after salvage (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. Conclusions: Ph-like B-ALL pts treated with standard chemo have lower CR and RFS rates. Adding novel agents (InO, blin, venetoclax) to upfront regimens may improve outcomes. Future studies should focus on optimal first-line combinations and higher-risk groups such as KRAS-mutated Ph-like B-ALL.