Outcomes of Olverembatinib Based Regimen in Patients with Philadelphia Chromosome-Positive Advanced Leukemias: A Real-World, Single-Center Experience

Background Philadelphia chromosome-positive (Ph+) advanced leukemias including chronic myeloid leukemia blast phase and acute lymphoblastic leukemia have poor outcomes. Olverembatinib, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells(CML) and tumor models, is currently approved for treating resistant CML patients with T315I mutation by the National Medical Products Administration in China, and in phase Ib clinical trials in the US for ponatinib resistant and/or intolerant CML patients. Olverembatinib also inhibited p-KIT, p-AKT, p-ERK1/2, and p-STAT3 to a higher extent than ponatinib, and suppresses pre-B ALL cells through inhibition of the SRC kinase and PI3K/AKT pathways and may be a potential therapeutic agent for the management of pre-B ALL. However, the efficacy of Olverembatinib based regimen in Philadelphia chromosome- positive advanced leukemias is still unknown.

Methods We conducted a retrospective study on patients with Philadelphia Chromosome- Positive Advanced Leukemias including Ph+ CML (n=11) and Ph+ ALL (n=5) who received a Olverembatinib-based regimens in our center.

Results The trial included 11 patients with Ph+ CML and 5 patients with Ph+ ALL who had relapsed after transplantation. Among the 11 CML patients, there were 2 CML-AP, 6 chronic myeloid leukemia-myeloid blast phase (MBP), 2 chronic myeloid leukemia-lymphoblastic bast phase(LBP), 1 chronic myeloid leukemia- myeloid and lymphoblastic mixed blast phase. Median age was 34 years and the median follow-up time was 4 months. Also, two (18.2%) CML-AP patients were treated witholverembatinib alone. Six (54.5%) CML-BP patients were treated with olverembatinib in combination with demethylating agents. And two patients with LBP received VDP and stem cell transplantation (SCT)-based regimens combined with olverembatinib. Treatment for patients with chronic myeloid leukemia- myeloid and lymphoblastic mixed blast phase is consistent with patients with MBP. The overall response rate of 8 evaluable patients was 100%. CR/CRi rate was 100%, and CCyR/PCyR rates 62.5% vs 37.5%, respectively. In addition, 6 patients achieved major molecular responses (MMR). the remaining three patients were not yet due for evaluation. Of 5 patients with ph+ ALL that relapsed after transplantation, 1patient was treated with blinatumomab and olverembatinib, 2 patients were treated with intensive chemotherapy and olverembatinib followed by donor lymphocyte infusion(DLI), The treatment for the remaining 2 patients was Anti-CD19 chimeric antigen receptor T cell (CAR-T) technology followed by olverembatinib, and this 5 Ph+ ALL patients achieved complete molecular remission(CMR). In addition, treatment-related adverse reactions included cytopenias, skin pigmentation, proteinuria and high triglycerides, all grades less than 2. No deaths have occurred.

Conclusion Olverembatinib-based regimens show encouraging activity and safety in very heavily pre-treated, advanced Ph+ leukemias.

No relevant conflicts of interest to declare.