Olverembatinib-mediated deep remission improves allogeneic stem cell transplantation outcome in patients with blast crisis chronic myeloid leukemia: First real-world practice report

Abstract

Abstract Introduction: Despite therapeutic advances, blast crisis chronic myeloid leukemia (BC-CML) remains poor outcomes. Long-term survival depends on achieving a second chronic phase (CP) followed by allogeneic hematopoietic stem-cell transplantation (allo-HSCT). We aimed to investigate whether the novel tyrosine-kinase inhibitor (TKI) olverembatinib improves responses and optimizes allo-HSCT outcomes compared to the first-/second-generation TKIs (1/2G-TKIs) in BC-CML. Methods: This real-world practice analysis captured data from ​​consecutively enrolled​​ BC-CML patients aged ≥14 years undergoing allo-HSCT at the Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences between November 2021 and January 2025, including both de novo and chronic phase-transformed cases. Collected data ​​included​​ demographic and clinical characteristics, treatment responses, and transplant-related outcomes. Cumulative incidences of complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response (CMR) were calculated using the Fine-Gray test. Categorical variables were analyzed by Fisher's exact test, continuous variables by Mann-Whitney U test. Overall survival (OS) and progression-free survival (PFS) were calculated according to Kaplan Meier. Institutional Review Board (IRB) approval was obtained in accordance with the Declaration of Helsinki. Results: A total of 64 patients with BC-CML receiving pre-transplant TKIs treatment were included in the study (median age 33 years, range 14–61). At BC diagnosis, 43.8% (n=28) exhibited additional cytogenetic abnormality, including 20 complex karyotype. Twenty patients (31.3%) harbored ABL1 mutations, predominantly E255K and Y253K. T315I was seen in 5 cases. Thirty (46.9%) patients carried additional genetic mutations, including myeloid neoplasm-associated mutations (e.g., ASXL1, RUNX1) and IKZF1 deletions. Extramedullary involvement occurred in 11 patients (17.2%). All patients received TKIs+chemotherapy before transplantation and were stratified by pre-transplant TKIs exposure: 1/2G-TKI cohort (n=42, imatinib, nilotinib, flumatinib or dasatinib) versus olverembatinib (n=21, HQP1351), with balanced baseline characteristics. The olverembatinib cohort demonstrated advanced pre-transplantation treatment responses: higher hematologic remission rates (100% vs 81%, p<0.05) and CCyR rate (76.2% vs 55.8%, p=0.17). Notably, olverembatinib achieved significantly improved molecular remission at transplantation: MMR 61.9% vs 16.3% (p<0.001) and CMR 23.8% vs 4.7% (p<0.05). Haploidentical transplants were the predominant HSCT type (olverembatinib 81% vs 1/2G TKI 58%) with no graft failure documented. Both cohorts showed a high incidence of grade II-IV aGVHD (57.1% vs 76.7%) and infections (23.8% vs 69.8%). The median follow-up post HSCT was 775 days in olverembatinib cohort and 3232 days in the control cohort, respectively. Olverembatinib cohort showed clinically meaningful improved survival, including trends toward improved two-year OS (87.1% vs 57.2%) and two-year PFS (75.8% vs 52.6%), lower NRM (12.9% vs 34.0%), and reduced relapse incidence (12.5% vs 19.3%). Safety analysis revealed treatment-related adverse events in olverembatinib cohort 52.4% (11/21) of patients. Six (28.6%) developed grade 3/4 neutropenia. Cardiovascular Events were observed in two patients, including deep vein thrombosis (n=1) and pericardial effusion (n=1). Conclusions: This real-world analysis provides the first clinical evidence supporting the efficacy and safety of olverembatinib in transplant-eligible BC-CML. Olverembatinib significantly enhances pre-transplant molecular responses, compared to 1/2G-TKIs, associating with improved survival and reduced NRM in BC-CML patients receiving allo-HSCT. With a manageable safety profile, olverembatinib represents a promising bridging strategy prior to allo-HSCT, potentially redefining frontline management of BC-CML.