Olverembatinib(HQP1351)-Based Therapy in Adults with Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Advanced Chronic Myeloid Leukemia: Results of the Real-Life Study

Background Relapsed or refractory (R/R) Philadelphia chromosome positive acute lymphoid leukemia (ALL) and advanced chronic myeloid leukemia (CML) including accelerated phase (AP) and blast phase (BP) usually result in treatment failure due to therapeutic resistance, intolerance, T315I mutations, or compound mutations, with a poor prognosis. Olverembatinib (HQP1351) is a novel third generation BCR-ABL tyrosine kinase inhibitor (3G-TKI), exhibiting a high potency of inhibition on wild and almost all mutated BCR-ABL1 kinases, including the T315I mutation and exhibiting preliminary favorable efficacy and safety profile in clinical trials.

Methods In this open label, single-arm, single-center study, patients with advanced Ph+ leukemia (including CML-BP, CML-AP and R/R Ph+ ALL) were enrolled. Patients with severe cardiovascular diseases, arterial occlusion, hypertension, and pulmonary arterial hypertension were excluded. Eligible patient received olverembatinib monotherapy, combined chemotherapy, or combined immunotherapy. The primary endpoints was overall response rate (ORR) at 28 days, including complete remission (CR) and complete remission with incomplete hematological recovery (CRi), in patients with advanced Ph+ leukemia.

Results Between Dec 8, 2021, to Jun 1, 2023, a total of 56 patients (Ph+ALL (n=40), CML-BP (n=13) and CML-AP(n=3)) assessed were included and received olverembatinib-based therapy. 34(60.7%) patients were men and 22 (39.3%) were women. The median age was 38 years old (IQR 29-48) and the median duration of follow-up was 8.3 months (IQR 4.6-11.9). BCR::ABL1 transcript was of p210 type in 29 (51.8%), p190 in 27 (48.2%). 13 (23.2%) and 11 (19.6%) patients had received 2 and ≥ 3 prior TKIs, respectively. 17 (30.4%) patients were pretreated with third-generation TKI (ponatinib). Genetic testing revealed mutations in 48 (85.7%) patients including compound mutation in 11 (19.6%%) patients, of whom 8 (72.3%) patients had the T315I mutation. 11 (19.6%) patients had central nervous system leukemia (CNSL) and 1 (1.8%) had extramedullary disease. Of 56 evaluable patients, 48 (85.7%) patients reached CR/CRi. After achieving CR/CRi, 13/48 (27.1%) patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), 3/48 (6.3%) patients received donor lymphocyte infusion (DLI), and 3/48 (6.3%) patients received chimeric antigen receptor T-cell immunotherapy (CAR-T therapy). During further follow-up, 24 (42.9%) patients achieved BCR::ABL1< 0.1% and 29 (49.2%) achieved BCR::ABL1 < 1%. In additional, probabilities of DFS, EFS and OS at 12 months were 80.3% (95%CI 61.0%-90.7%), 80.2% (95%CI 61.0%-90.7%), 93.3% (95%CI 75.8%-98.3%) in R/R Ph+ALL and 55.4% (95%CI 18.4%-81.4%), 38.6% (95%CI 9.8%-67.6%), 80.0% (95%CI 37.4%-95.1%) in advanced CML, respectively (Fig. 1). Common treatment-related adverse events (TRAEs) included skin hyperpigmentation, proteinuria, Elevated liver enzyme and hypertriglyceridemia (Table 1). Most nonhematologic TRAEs were grade 1/2. Only one patient died from pulmonary embolism. As of the data cutoff date, 37 (66.1%) patients continued on treatment and 19(33.9%) discontinued because of disease progression, intolerance, loss to follow-up or death.

Conclusion Olverembatinib-based therapy showed strong efficacy and tolerable toxicity in advanced Ph+ leukemia.