Promising results for olverembatinib in combination with venetoclax for Ph+ ALL

In a phase 2 study in participants with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph⁺ ALL), the third-generation tyrosine kinase inhibitor olverembatinib combined with venetoclax and reduced-intensity chemotherapy showed excellent efficacy results without a worrisome toxicity profile.

Preclinical evidence indicates that BTK inhibition with olverembatinib in addition to venetoclax may be synergistic in acute leukaemia [1]. In a single-arm phase 2 study (NCT05594784), the third-generation BCR-ABL1 tyrosine kinase inhibitor olverembatinib was added to venetoclax and reduced-intensity chemotherapy with vincristine and prednisone as an investigational treatment regimen in 45 participants with newly diagnosed Ph⁺ ALL. The primary endpoint was the complete molecular response (CMR) rate after 3 x 28-day cycles of therapy [2]. Dr Xiaoyuan Gong (Chinese Academy of Medical Sciences, China) presented the results.

Complete remission (CR; n=43) or CR with incomplete count recovery (CRi; n=2) was reached by all participants. Therefore, all participants were allowed to follow cycles 2 and 3, as per the study protocol. “After 3 cycles of therapy, the CMR rate was 62.2%,” said Dr Gong. In addition, the CMR rates at week 4 and 8 were 53.3% and 60.0%, respectively. Indeed, olverembatinib resulted in quick improvements in haematologic variables during the first therapy cycle (see Figure). Depending on the CMR status of the participant and the availability of stem cell donors, subsequent therapy options were provided. Independent of the subsequent treatment option applied, CMR was achieved in 88.9% of the participants at any time over the course of treatment.

Figure: Rapid improvements in haematologic variables during cycle 1 [2]



PLT, platelets.

Regarding the safety of olverembatinib combination therapy, grade 3 febrile neutropenia was observed in 22.2% of the participants. The most common adverse events were of grade 1 or 2 and mainly restricted to fatigue and sensory neuropathy. Coronary artery stenosis led to a study discontinuation for 1 participant and 1 participant died due to an infection after autologous stem cell transplant.

Overall, olverembatinib plus venetoclax and reduced chemotherapy appeared safe and effective in previously untreated participants with Ph⁺ ALL.

1. Fang DD, et al. Transl Oncol. 2022;15(1):101244.
2. Gong X, et al. Olverembatinib combined with venetoclax and reduced-intensity chemotherapy for patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: early results from a phase II study. Abstract 827, 65^th ASH Annual Meeting, 9–12 December 2023, San Diego, CA, USA.

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Posted on 7 February 2024