Treatment of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia using hypercvad with ponatinib is associated with excellent survival with selective use of blinatumomab and allogeneic hematopoietic cell transplantation

Abstract Introduction: Tyrosine Kinase Inhibitors (TKI) are standard additions to first-line therapy for patients (pts) with Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL). Ponatinib offers superior efficacy compared to dasatinib or imatinib when combined with hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) based on outcomes from experience at the MD Anderson Cancer Center. Real-world evidence from other centers evaluating outcomes with this regimen, including measurable residual disease (MRD) responses, may help inform optimal use of this approach. Previous studies primarily utilized flow cytometry to assess MRD. Next-generation sequencing (NGS), a more sensitive and specific method to quantify MRD, has become more commonly utilized and is recommended to more reliability evaluate treatment efficacy. Methods: This retrospective cohort study included pts aged ≥ 18 years with newly diagnosed Ph+ B-ALL who received hyperCVAD with ponatinib at the University of California San Francisco between January 1, 2016, and August 1, 2024. Pts were excluded if they received a non-hyperCVAD chemoimmunotherapy for more than 1 cycle or single agent TKI with or without steroids for more than 4 weeks before starting hyperCVAD (n=7). Use of non-ponatinib TKI was allowed for up to 2 cycles before starting ponatinib. Eight pts started dasatinib before switching to ponatinib. Ponatinib was started at 45mg (n=13) or 30mg (n=10) and decreased to 30mg after achievement of complete remission (CR) for those who started at 45mg. The dose was further decreased to 15mg after the achievement of complete molecular response (CMR). Ponatinib was started at 15mg in 2 pts based on pre-existing hepatic dysfunction. The primary outcomes included overall response rates after induction therapy, including rates of CR, CR with incomplete count recovery, CMR, and MRD negativity assessed by flow cytometry, polymerase chain reaction, and NGS. The secondary outcomes included overall survival (OS), relapse-free survival (RFS), the percentage of pts who received blinatumomab for MRD positivity or chemotherapy intolerance and/or allogenic hematopoietic stem cell transplant (alloHCT) and related outcomes, central nervous system relapse, toxicities, and changes in TKI treatment. Results: Twenty-three pts were included in the study. The median age was 48 (39-55) and 61% were male. Initial white blood cell count was 30.7 x 103/µL (9.9-135) and 10 pts (43.5%) received cytoreductive therapy (typically hydroxyurea or corticosteroids) prior to induction. A median number of 7 cycles of hyperCVAD with a median number of 12 intrathecal chemotherapies for CNS prophylaxis were administered. CD20 positivity ≥20% was present in 18 (78.3%) of whom 14 (77.8%) received Rituximab. All pts achieved complete remission or complete remission with incomplete recovery by the completion of cycle 2. Complete molecular response by BCR-ABL1 PCR was achieved in 36.8% after cycle 1 and 71.4% after cycle 2. Forty percent of pts achieved MRD negativity by NGS after cycle 1, 66.7% by month 3, and 100% by month 6. With the median follow-up of 38.3 months (12.3-82), 2 pts died, resulting in a 3-year OS of 95.5 % (95% confidence interval (CI) 71.9-99.4). Five pts relapsed, including 3 isolated CNS relapses, leading to a 3-year RFS of 81.5% (95 % CI 57.7-92.7). Five pts (22%) received blinatumomab for MRD positivity (median 2.5 cycles), 4 (17.4%) switched to blinatumomab based treatment for chemotherapy intolerance (median 2.5 cycles prior to switch), and 1 (4.3%) switched electively. Four pts (17.4%) received alloHCT — 1 (4.3%) for CR1 consolidation and 3 (13%) in CR2. Six pts (26%) switched ponatinib to a different TKI for adverse events, including thromboembolic events (8.6%), vascular toxicity (8.6%), hepatotoxicity (4.3%), and cardiotoxicity (4.3%). Conclusions: HyperCVAD with ponatinib demonstrated excellent efficacy and safety outcomes that validate findings at the institution that originally explored this approach. A minority of patients (26%) experienced toxicities requiring ponatinib to be changed to an alternative TKI. Furthermore, we demonstrate that the majority of pts can avoid need for alloHCT, with use of blinatumomab reserved for pts with MRD persistence or chemotherapy intolerance. This finding is important for centers that practice in resource-restricted contexts where front-line blinatumomab may not be generally possible.