P354: multi-institutional study evaluating the impact on survival of newer treatment combinations and allogeneic stem cell transplantation in philadelphia chromosome positive acute lymphoblastic leukemia

Background: Prior to the era of tyrosine kinase inhibitors (TKI) the outcome of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) was poor. With the introduction of TKI in combination with chemotherapy, especially ponatinib, the outcome has remarkably improved with 5-year overall survival (OS) up to 75%. Furthermore, the concept of “chemotherapy free” induction using a combination of blinatumomab (Blina) plus (+) TKI has minimized the toxicity associated with chemotherapy without compromising the clinical outcome. Aims: We conducted a retrospective multicenter study to analyze the long-term outcome of adult (> 18 years) Ph+ ALL patients (pts) with evolving first line therapies and the clinical significance of allogeneic hematopoietic stem cell transplantation (allo-HCT) in improving survival in the era of newer treatment combinations. Methods: A total of 395 adult Ph+ ALL pts from 9 US academic institutions, who were diagnosed between May 2003 and June 2022 were evaluated to assess for response and survival with different first line treatment combinations. We also assessed the survival benefit of allo-HCT among pts who achieved undetectable BCR::ABL1 (uBCR::ABL1) at 3 months (mo) from the time of induction therapy. Results: The median age of the pts was 52 years (range [R] 19-85), 56% of pts had additional cytogenetic (CG) abnormalities, and 32 (8%) pts had CNS disease at diagnosis. A higher proportion of pts received TKI in combination with intensive chemotherapy (IC) (67%), than TKI + steroids (16%), TKI + low intensity chemotherapy (LC; combination of vincristine, steroids +/- rituximab) (10%), TKI + Blina (3%) and IC without TKI (4%) during induction. During induction, the highest proportion of pts received 2nd generation TKI combinations (68.5%), compared to 1st generation (21.5%) or 3rd generation (5%): 5% of pts did not receive TKI (Table 1). The complete remission (CR) rate was 94%; measurable residual disease (MRD) negative by flow cytometry 51% and 53% were in uBCR::ABL1 at 3 mo from induction. A total of 189 (49%) pts received allo-HCT in CR1, among them 61% of pts received TKI maintenance post allo-HCT. The median relapse free survival (RFS) for the entire cohort was 49.7 mo: TKI + IC (54 mo), TKI + LC (18.3 mo), TKI + steroids (38.1 mo), IC without TKI (20.3 mo) and TKI + Blina (NR, 90% at 63 mo), (p= 0.01; Fig 1A). The median OS for the entire cohort was 72.8 mo: TKI + IC (112 mo), TKI + LC (24.8 mo), TKI + steroids (94 mo), IC without TKI (28.8 mo) and TKI + Blina (NR, 90% at 63 mo)), (p= 0.01; Fig 1B). Among pts who achieved uBCR::ABL1 at 3 mo: RFS was significantly better among pts receiving allo-HCT vs no allo-HCT (135 vs 29.3 mo; p= 0.01, Fig 1C). However, OS was not significantly different with or without allo-HCT (135.2 vs 149.3 mo; p= 0.01, Fig 1D), respectively. RFS (38.9, 54.2, NR [60% at 50 mo]; p= 0.78) and OS (50.4, 94, NR [71% at 50 mo]; p= 0.23) were not significantly different between 1st, 2nd and 3rd generation TKI, respectively. In univariate analysis, additional CG abnormality (p= 0.9/p=0.13), CNS disease at diagnosis (p= 0.93/p=0.80), WBC > 100 x109/L (p= 0.65/p= 0.93), p190 vs p210 fusion protein (p= 0.69/p= 0.18) ponatinib vs other TKI based induction (p= 0.94/p= 0.94), uBCR::ABL1 at 3 mo (p=0.36/p=0.19) did not significantly impact RFS/OS, respectively. Summary/Conclusion: Our real world analysis suggests significantly better RFS but not OS among Ph+ ALL pts with uBCR::ABL1 at 3 mo receiving allo-HCT. Albeit with small numbers of pts, the data suggest better RFS and OS with Blina + TKI combination.Keywords: ALL, Ph+ ALL, Allo-SCT