Olverembatinib is a novel third-generation TKI with potent activity against both wild-type and T315I-mutated BCR::ABL1. While its efficacy has been demonstrated in chronic myeloid leukemia (CML), its role in Ph+ALL remains underexplored. This open-label, multicenter Phase II study (NCT06578546) evaluates the efficacy and safety of a combination regimen comprising Olverembatinib (BCR-ABL1 inhibitor), venetoclax (a BCL-2 inhibitor), and azacitidine (a hypomethylating agent) in newly diagnosed adult Ph+ALL patients. The study aimed to enhance CMR rates while minimizing treatment-related toxicity. Patients received this triplet therapy in induction and consolidation phases with appropriate supportive care. The primary endpoint was CMR in typical ALL or MRD-negative complete remission (CR) in all evaluable patients by the end of cycle 1 or 2.

Seventeen patients (median age 48 years) were enrolled, with 52.9% male. Transcript variants included p190 (58.8%) and p210 (41.2%); 29.4% had IKZF1plus poor-risk features. All patients achieved CR after cycle 1 (100%), with a median neutrophil recovery time of 18 days. MRD-negative CR was observed in 88.2% (15/17) after cycle 1 and 86.7% (13/15) after cycle 2. Among CML-like ALL patients, MRD-negative CR rates were 80.0% (8/10) and 75.0% (6/8) after cycles 1 and 2, respectively. In typical ALL patients, CMR was achieved in 57.1% (4/7) after both cycles. 

The safety profile was manageable, with Grade ≥3 AEs including febrile neutropenia (23.5%), pneumonia (17.6%), and thrombocytopenia (11.8%). No tumor lysis syndrome or treatment-related deaths occurred. Twelve-month OS and RFS were 76.5% and 64.7%, respectively. Over half of the patients (52.9%) proceeded to allo-HSCT.

KOL insights

“Study findings indicate that allogeneic hematopoietic stem cell transplantation has shown efficacy in treating patients with high-risk subtypes of ALL. The key message for clinicians is the critical significance of early referral. Patients must be referred for transplant as soon as they achieve CR because the data shows how delays affect OS.” – Expert Opinion

“In pediatric acute lymphoblastic leukemia (ALL), modern risk-directed treatments have achieved 5-year overall survival rates surpassing 90%. Efforts now concentrate on enhancing outcomes and reducing intensive therapy-related toxicity through expanded utilization of immunotherapy, identification of targetable genetic anomalies, and refinement of risk assessment accuracy.” – Expert Opinion

Conclusion

TKIs are typically not used as standalone treatments for ALL, they are most effective when combined with other therapies, such as combination chemotherapy regimens. Commonly used TKIs in the treatment of Ph+ ALL include GLEEVEC (imatinib), SPRYCEL (dasatinib), ICLUSIG (ponatinib), BOSULIF (bosutinib), and TASIGNA (nilotinib).

In contrast, newer non-chemotherapy approaches—such as third-generation TKIs or immunotherapy—offer improved tolerability and quality of life, often eliminating the need for transplantation altogether. Notably, these modern therapies are suitable for a broader patient population. Currently, clinical trials are incorporating third-generation TKIs and immunotherapy, leading to a significant shift in the treatment landscape. These approaches are producing remarkable responses, including strong and deep MRD negativity. As a result, the role of transplantation in these trials has become limited. This chemotherapy-free regimen of olverembatinib, venetoclax, and azacitidine showed promising efficacy with rapid, deep molecular responses and a manageable safety profile in newly diagnosed Ph+ALL. The high rates of MRD-negative CR and CMR, along with good tolerability, support its potential as a frontline, outpatient treatment option for both induction and consolidation phases, offering a compelling alternative to conventional intensive chemotherapy. Currently, Olverembatinib is in Phase III of the development process.