Improved Outcomes of Adult Patients with Philadelphia-like Acute Lymphoblastic Leukemia (Ph-Like ALL) Treated within an Integrated Leukemia/Transplant Program with Incorporation of Pediatric Inspired Regimens and Early Allogeneic Transplant

Approximately 10-25% of newly diagnosed B-lineage acute lymphoblastic leukemias have a Philadelphia-like (Ph-like) phenotype. These leukemias lack a BCR-ABL fusion but show similar gene-expression profiling to Ph+ALL. Molecular abnormalities associated with Ph-like include overexpression/rearrangement of CRLF2 with or without JAK-STAT pathway mutations, or fusions involving tyrosine kinases (eg ABL1&2, CSF1R, PDGFRB, JAK2 or EPOR). Patients with Ph-like ALL are typically younger and more likely to be of Hispanic origin than other adult patients with B-lineage ALL and have been associated with a worse overall prognosis (5-year event-free and overall survival < 30%, Jain et al Blood 2017). Since 2017 our program has aimed to identify such patients early using molecular and flow-cytometry profiling and to treat identified Ph-like ALL with age-stratified chemotherapy including pediatric-inspired regimens for patients aged <40. Furthermore, we have aimed to take all eligible patients to allogeneic hematopoietic cell transplantation (AHCT)in a MRD negative state as soon as feasible with routine use of HLA-haploidentical donors when matched donors were unavailable. MRD status was evaluated using the Clonoseq assay and/or fusion specific Q-PCR. We hypothesized that using this approach within an integrated program where the same physicians administer leukemia chemotherapy and AHCT and patients are evaluated for AHCT at the time of diagnosis, that outcomes would improve compared to those observed historically. Of 177 consecutive adult patients with newly diagnosed ALL treated at our center between June 2017 and July 2023 152 (86%) were of B-lineage. Twenty-three patients were identified as Ph-like, comprising 13% of all ALL and 15% of B-lineage ALL patients. Characteristics of Ph-like ALL were: median age 39 (19-72); male (70%); Hispanic ethnicity (61%); race (white 83%, Asian 9%,undeclared 8%), WBC at diagnosis- median 58 x 10e9/L (2-345), cytogenetics (abnormal 48%), molecular abnormality – CRLF2 rearrangement/overexpression (73%), rearrangements of JAK2 (9%), EPOR (5%), ABL1 (5%) PDGFRB (5%); Induction regimen type- Pediatric inspired (50%), HyperCVAD based (36%), Reduced-intensity (14%). Median time from diagnosis to start of induction chemotherapy (excluding pre-phase) was 7d (2-18). Median follow-up of survivors 39 m (12-80m). There were 2 induction deaths (8%). Ninety-one percent of all patients and 100% of evaluable patients achieved a CR in a median of 32 d and 1 cycle (range 1-4). Fifteen patients (65%) proceeded to AHCT in a median of 125 d (23-321 d) from achievement of CR1. Reasons for failure to receive AHCT were: relapse/death pre-AHCT (2), age/KPS/comorbidity (1), lack of caregivers/psychosocial support (2), IEC (2), patient refusal (1). Characteristics of patients receiving AHCT (n=15) were: age - median 35 years (19-68); male (73%), Hispanic ethnicity (73%), donor – haploidentical (53%) matched related (33%) matched unrelated (14%); disease status at AHCT CR1 (93%), CR2 (7%); MRD status at AHCT – negative( 64%) positive (22%), not evaluable (14%); regimen intensity -myeloablative (79%), RIC (7%), non-myeloablative (14%); MRD status pre-AHCT- negative (68%), positive 20%, not evaluable (12%). Median follow-up for surviving transplanted patients is 45 m (17-77m). Kaplan-Meier estimates of overall survival(OS), disease-free survival (DFS) and cumulative incidence of non-relapse mortality (NRM) for all patients following induction are 73%, 41%, 18% at 2 years post induction and 61%, 35% and 25% at 3 years post induction. For patients receiving AHCT, estimated OS, DFS, relapse and non-relapse mortality post-transplant were 80%, 53%, 33% and 13% at 2 years respectively and 64%, 44%, 33% and 22% respectively at 3 years, with no relapses seen after 2 years. These data suggest that the approach described when used in adult patients with Ph-like ALL produces more promising outcomes than historically described. Blinatumomab was not used during consolidation therapy in the reported patients. Its incorporation in the routine therapy of newly diagnosed patients may increase the proportion of patients receiving AHCT in a MRD negative state and further improve outcomes in this historically poor risk patient population.