Updated Results of Pivotal Phase 2 Trials of Olverembatinib (HQP1351) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant Chronic- and Accelerated-Phase Chronic Myeloid Leukemia (CML-CP and CML-AP) with T315I Mutation

Qian, Jiang; Li, Zongru; Hou, Yue; Hu, Yu; Liu, Xiaoli; Xu, Na; Song, Yongping; Li, Meng; Hong, Zhenya; Liu, Bingcheng; Li, Yan; Chen, Suning; Xue, Mengxing; Zhu, Huanling; Li, He; Du, Xin; Lou, Jinning; Zhang, Xiaohan; Liang, Yang; Dai, Yu-Jun; Chen, Zi; Niu, Qian; Men, Lichuang; Yang, Dajun; Zhai, Yifan; Huang, Xiao‐Jun

doi:10.1182/blood-2022-170698

Cited by 8 publications

(6 citation statements)

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“…The study enrolled patients with CP-CML who had been previously treated with at least 2 TKIs or had a T315I mutation. Patients were randomized (ratio 1:1:1) to 3 starting doses of ponatinib (45,30, or 15 mg daily). 26 Once in CCyR, patients were continued on ponatinib 15 mg daily.…”

Section: Phase 2 Clinical Trial Opticmentioning

confidence: 99%

Ponatinib‐review of historical development, current status, and future research

Kantarjian,

Chifotides,

Haddad

et al. 2024

American J Hematol

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Ponatinib is a third‐generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with high potency against Philadelphia chromosome (Ph)‐positive leukemias, including T315I‐mutated disease, which is resistant to first‐ and second‐generation TKIs. Ponatinib was approved for T315I‐mutated chronic myeloid leukemia (CML), CML resistant/intolerant to ≥2 prior TKIs, advanced phase CML and Ph‐positive acute lymphoblastic leukemia (ALL) where no other TKIs are indicated, and T315I‐mutated CML and Ph‐positive ALL. The response‐based dosing of ponatinib in chronic phase CML (CP‐CML) improved treatment tolerance and reduced the risk of toxicities, including cardiovascular risks. Ponatinib‐based therapy also resulted in significantly better outcomes in frontline Ph‐positive ALL compared with prior TKIs and is becoming a new standard of care in this setting. As the clinical development of third‐generation TKIs and their rational combinations progresses, we envision further transformative changes in the treatment of CML and Ph‐positive ALL.

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Section: Phase 2 Clinical Trial Opticmentioning

confidence: 99%

Ponatinib‐review of historical development, current status, and future research

Kantarjian,

Chifotides,

Haddad

et al. 2024

American J Hematol

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“…Clinical studies with olverembatinib showed that the maximum tolerated dose was 50 mg QD and that the drug consistently achieved ≥70% complete cytogenic response (CCyR, ≤1% BCR::ABL1 IS ) and ≥50% MMR with minimal adverse effects in patients with the T315I mutation as well as those with resistance to other TKIs such as PON [ 117 , 118 , 119 , 120 ]. Results from a recent phase I clinical trial (NCT04260022) on 76 CML-CP and Ph + ALL patients outside of China treated with olverembatinib also demonstrated promising results comparable to those acquired from Chinese patients ( Table 1 ).…”

Section: Tki Treatment Strategies In the Clinicmentioning

confidence: 99%

Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia

Wu,

Liu,

Fruhstorfer

et al. 2024

IJMS

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Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article.

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“…In another update of 64 patients with CML-CP ( n = 41) or CML-AP ( n = 23) and T315I mutation, the results were encouraging. In CML-CP the CCyR rate was 71%, the MMR rate 58%, the estimated 3-year PFS rate was 86% and OS rate 95% [ 122 ]. In CML-AP, the CCyR rate was 52%, the MMR rate 48%, the estimated 3-year PFS rate was 57% and OS rate 70%.…”

Section: Third-generation Tkismentioning

confidence: 99%

Management of chronic myeloid leukemia in 2023 – common ground and common sense

et al. 2023

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With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient’s comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results.

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Updated Results of Pivotal Phase 2 Trials of Olverembatinib (HQP1351) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant Chronic- and Accelerated-Phase Chronic Myeloid Leukemia (CML-CP and CML-AP) with T315I Mutation

Cited by 8 publications

References 0 publications

Ponatinib‐review of historical development, current status, and future research

Ponatinib‐review of historical development, current status, and future research

Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia

Management of chronic myeloid leukemia in 2023 – common ground and common sense

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