Outcomes of concomitant Philadelphia chromosome-positive and CRLF2-rearranged B-cell ALL

Abstract Background: Ph-like acute lymphoblastic leukemia (Ph-like ALL) represents a high-risk subgroup of B-cell ALL with a very high rate of disease relapse and poor overall survival. Rearrangements of CRLF2 are seen in approximately 50% of patients (pts) with Ph-like ALL. Co-occurrence of Ph+ ALL and CRLF2 rearrangement defines a rare high-risk genomic group (Jain, Haematologica 2017). We report the outcomes of pts with concomitant BCR::ABL1 and CRLF2 fusions. Methods: We retrospectively reviewed database at the MD Anderson Cancer Center between 2014–2022 for pts who were noted to have B-ALL with concomitant Ph+ and CRLF2 rearrangement. Treatment regimen received, including use of chemotherapy, immunotherapy, and ABL1 kinase inhibitors and use of JAK inhibitor ruxolitinib, were recorded. Results: A total of 8 pts were identified. 6 pts were newly diagnosed, and 2 pts had relapsed/refractory (R/R) disease. Median age was 22 years (range, 14-57), 75% were male and 63% were of Hispanic ethnicity. Frequent co-mutations included JAK2 (37%), NRAS (25%), IKZF1 (25%), and PTPN11 (25%). The most common JAK2 mutation was R683G (n=2); one pt had three distinct JAK2 mutations (L884P, R683G, R867Q). BCR::ABL1 transcript was p190 (n=7) and p210 in 1 pt. All newly diagnosed pts (n=6) received ABL1 kinase TKI-based induction (ponatinib, n=4; dasatinib, n=1; imatinib, n=1) with hyper-CVAD (n=3), pediatric-inspired regimens (n=2), and blinatumomab-ponatinib (n=1). 3/6 (50%) pts achieved complete remission (CR) with flow-cytometry MRD negativity at D28; all 6-pts achieved CR with flow-cytometry MRD negativity and complete molecular remission (CMR) for BCR::ABL1 as best response. 1 pt was evaluated for next generation sequencing MRD (clonoSEQ assay) which was negative. 2/6 newly diagnosed pts proceeded to allo-SCT in CR1; one of them received hyper-CVAD + ponatinib as initial therapy and underwent allo-SCT in CR1 5-months from the initial diagnosis while in flow cytometry negative remission and PCR for BCR::ABL1 was 0.01% but died 3-months post-transplant from infectious complications. The other patient who was diagnosed with CML in lymphoid blast phase (prior 6-month history of CML chronic phase on dasatinib) with p210 transcript; pt received hyper-CVAD + ponatinib and underwent allo-SCT in CR1 4 months after the initial diagnosis and remains in MRD negative remission 93 months post-allo-SCT. Of the remaining 4 newly diagnosed pts, 2 remain in long-term remission in CR1, 52 and 89 months without allo-SCT. 1 pt received blinatumomab + ponatinib as initial therapy, relapsed at 8 months with CRLF2+/Ph– extramedullary disease; pt received multiple salvage therapies and died. 1 pt received hyper-CVAD + ponatinib followed by blinatumomab and achieved flow cytometry negative remission and CMR for BCR::ABL1. However, 2-years later, patient developed flow MRD+ disease and received inotuzumab + ponatinib followed by allo-SCT and died 2-months later from post-transplant complications. 1-year EFS and OS for newly diagnosed pts were 66% and 83%, respectively. Among R/R pts (n=2), both had received frontline hyper-CVAD. One was lost to follow-up after 2 cycles, later relapsed, and was treated with hyper-CVAD plus ponatinib but was refractory and died from disease-related complications. The other relapsed 7 months after hyper-CVAD and received blinatumomab plus ponatinib followed by asparaginase-based chemotherapy, but died from intracranial hemorrhage. Both patients also had ruxolitinib added to the salvage treatment. Conclusions: Concomitant Ph+/CRLF2+ B-ALL represents a rare but high-risk subset with inferior outcomes despite TKI- and immunotherapy-based regimens. Notably, relapses often involved loss of the Ph+ clone with persistence of CRLF2+ disease.