Olverembatinib for the treatment of chronic myeloid leukemia in chronic phase

Introduction

Chronic myeloid leukemia (CML) accounts for about 15% of all adult leukemia cases with an incidence of approximately 4,800 to 5,200 new cases in the United States (1). Before the advent of the BCR::ABL1 tyrosine kinase inhibitors (TKIs), the treatment landscape for CML was characterized by limited therapeutic options and a grim prognosis. Conventional therapies included interferon-alpha, hydroxyurea, and busulfan. Hematopoietic stem cell transplantation was considered curative but was associated with a high risk of morbidity and mortality, and was therefore reserved for younger patients with good performance status and an appropriate donor (2). Over the last two decades, the outcome of CML has significantly improved with the introduction the BCR::ABL1 TKIs, with a 10-year overall survival (OS) of approximately 90% (3).

Patients undergoing TKI therapy are now expected to achieve a near-normal life expectancy, given that they can financially support the treatment, adhere to the prescribed TKI, and are switched to subsequent therapy if they develop resistance [BCR::ABL1 transcripts on the International Scale (IS) above 1% after more than 12 months of treatment] (4-7). Four different TKIs are FDA-approved for the frontline treatment of CML in chronic phase (CML-CP): imatinib (first-generation TKI), dasatinib, nilotinib, and bosutinib (second-generation TKIs) (8-11). These TKIs can also be used as later-line therapies in case of intolerance or resistance. Deciding on the best TKI in this setting will depend on prior TKIs used, presence of ABL1 kinase domain mutations, patient comorbidities, and cost of therapy (12).

Ponatinib and asciminib as third-line therapy and for T315I-mutated disease

Approximately 2% to 20% of patients treated with imatinib develop a T315I mutation, depending on the phase of the disease (13,14). Among patients treated with frontline second-generation TKIs, around 5% eventually acquire a T315I mutation (15-17). The emergence of T315I mutation is associated with resistance to first- and second-generation TKIs (18).

Ponatinib is a third-generation BCR::ABL1 TKI approved by the FDA for patients with T315I mutation or patients who failed 2 prior TKIs based on the results from the PACE trial showing improvement in the rates of major cytogenetic response (MCyR) (19). However, using ponatinib at the dose of 45 mg/day was associated with a high incidence of adverse events (AEs), particularly arterial occlusive events (15–20%). The OPTIC trial suggested that a starting dose of ponatinib 45 mg/day had a more favorable risk/benefit ratio compared to 15 mg/day (26.3% improvement in response rate and 6.4% increase in the risk of arterial-occlusive events). Additionally, it suggested that the higher dose of 45 mg/day is most useful in patients with T315I mutation (20). Results from the PACE and OPTIC trials showed that with ponatinib therapy, the 2-year OS rates were 85% and 91%, respectively, in patients with CML-CP resistant to prior second-generation TKIs. With longer-term follow-up, the 5-year OS rate was 73% (19-21).

Asciminib is the first inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP) which was approved by the FDA for patients with CML-CP previously treated with ≥2 TKIs and for those with T315I-mutated disease. The approval was based on the results of the ASCEMBL trial showing higher rates of major molecular response (MMR) at 6 months with asciminib compared to bosutinib (26% versus 13%) (22). With longer follow-up, no survival difference was noted between asciminib and bosutinib, with 2-year OS rates of 97% and 99%, respectively (23).

Olverembatinib: a novel BCR::ABL1 inhibitor for CML

Despite the availability of multiples TKIs, a subset of patients fail to respond to these therapies or develop treatment-related AEs preventing the administration of the drug, despite dose optimization (12). Olverembatinib (HQP1351) is a novel third-generation BCR::ABL1 inhibitor that tightly binds to ATP-binding sites. Preclinical studies showed in vitro inhibitory activity of olverembatinib against wild-type and mutant BCR::ABL1 and enhanced cell cycle arrest and apoptosis in CML cells (24).

Olverembatinib was shown to be safe and effective in patients with TKI-resistant CML-CP and CML in accelerated phase (CML-AP), particularly those harboring the T315I mutation. In a phase I/II trial conducted in China, 127 patients with CML-CP were treated with olverembatinib at doses ranging from 1 to 60 mg every other day (QOD), in 28-day cycles. Their median age was 43 years (range, 20–70 years) (25). Seventy-one patients (56%) had received 2 prior TKIs and 35 (28%) had received at least 3 prior TKIs. Ninety-three patients (73%) had a T315I mutation detected by Sanger sequencing, either alone (n=77; 61%) or concomitantly with additional ABL1 kinase mutations (n=16; 12%). Thrombocytopenia was the most frequent hematologic AE (73%; Grade 3–4, 49%), followed by anemia (52%; Grade 3–4, 21%) and leukopenia (29%; Grade 3–4, 17%). The most common non-hematologic treatment-related AE was skin hyperpigmentation (85%; Grade 3–4, none), hypertriglyceridemia (57%; Grade 3–4, 9%), proteinuria (51%; Grade 3–4, 4%), hyperbilirubinemia (44%; Grade 3–4, 2%), hypocalcemia (35%; Grade 3–4, none), elevated liver transaminases (39%; Grade 3–4, 2%), and increased creatine phosphokinase (34%; Grade 3–4, 8%). Median time to onset of these treatment-related AEs was 70 days (range, 1–1,315 days). Treatment-related cardiovascular events (CVEs) occurred in 35% of the patients (Grade 3–4, 12%), mainly hypertension (15%; Grade 3–4, 6%). Acute coronary syndrome, myocardial infarction, angina pectoris, and arteriosclerosis coronary artery disease, occurred in 1 patient each (1%), cerebrovascular accident occurred in 2 patients (2%), and retinal vein occlusion occurred in 3 patients (2%). After a median follow-up of 37 months (range, 7–58 months) from starting the effective dose of 30 mg QOD, all patients achieved a complete hematologic response (CHR). The 3-year cumulative incidence rates of MCyR, CCyR, MMR, MR4.0, and MR4.5 were 79%, 69%, 56%, 44% and 39%, respectively (Table 1). A total of 5 patients progressed to CML-AP (n=4) or CML blastic phase (n=1). The estimated 3-year progression-free survival (PFS) and OS rates were 92% and 94%, respectively (25). In a 5-year follow-up, all evaluable patients with CML-CP achieved CHR (100%), 80% achieved MCyR, 71% achieved CCyR, and 55% achieved MMR (26,27). Among those harboring the T315I mutation, the rate of CHR was 100%, MCyR was 84%, CCyR was 78%, and MMR was 73%. The 4-year cumulative incidence rates of MCyR, CCyR, and MMR were 80%, 75%, and 56%, respectively. The 4-year PFS rate was 86% (26,27).

Another recent study evaluated olverembatinib in a cohort of patients treated outside of China. A total of 76 patients were enrolled [57 with CML-CP and 19 with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL)] with a median age of 55 years (range, 21–80 years) (28). Patients were heavily pretreated with 11 (15%), 23 (30%), and 39 patients (51%) having received 2, 3, or ≥4 prior TKIs, respectively. In the overall population, 40 patients (53%) had prior ponatinib, of whom 27 (68%) were resistant and 10 (25%) were intolerant to the drug. Twenty-one patients (28%) were previously treated with asciminib, of whom 15 (71%) were resistant and 4 (19%) were intolerant. Twenty-four patients (32%) had T315I mutation detected at baseline. Twelve patients with CML-CP and seven with Ph-positive ALL discontinued therapy due to AEs (n=4), disease progression (n=7), or other reasons (n=8). Patients with CML-CP received olverembatinib QOD at the dose of 30, 40, or 50 mg in continuous 28-day cycles. Among patients with CML-CP evaluable for response, 25 of 44 (57%) achieved CCyR and 21 of 49 (43%) achieved MMR (Table 2). The rate of MMR improved from 66% at 6 months to 88% at 12 months of therapy. Olverembatinib demonstrated robust activity in heavily pretreated patients. The rates of CCyR and MMR were 57% and 42%, respectively, in patients failing ≥4 prior TKIs. The rates of CCyR (60% versus 55%) and MMR (44% versus 42%) were similar in patients with or without the T315I mutation. Olverembatinib was efficacious in patients failing prior third-generation TKIs. Among patients who had ponatinib resistance, 8 of 15 (53%) achieved CCyR and 6 of 16 (38%) achieved MMR. Similarly, 3 out of 7 patients (43%) with resistance to asciminib achieved CCyR and 3 out of 8 (38%) achieved MMR after treatment with olverembatinib. Two of eight patients (25%) previously treated with both ponatinib and asciminib achieved MMR. The 24-month PFS and OS rates were 75% and 98%, respectively (28).

After a median of 11 months (range, 0.03–53 months) of olverembatinib therapy, 53 (32%) patients with a median age of 43 years (range, 20–74 years) developed CVEs that were possibly related to olverembatinib, of which 12% were of Grade 3–4. These included hypertension, pericardial effusion, arrhythmias, retinal-vein occlusion, angina pectoris, myocardial infarction, and/or brain stroke. Olverembatinib treatment was temporarily held, and patients received disease-specific therapies which resulted in improvement or resolution of symptoms in most patients. Treatment was then resumed at reduced dosing with the exception of two patients in whom olverembatinib was permanently discontinued due to myocardial infarction in one patient and fatal pericardial effusion in another (29). If an increased incidence of cardiovascular AEs is confirmed in additional olverembatinib trials and with longer follow-up, then physicians might consider cardiovascular preventive measures. These encompass stringent control of blood pressure, regular monitoring of cholesterol and diabetes levels, the use of prophylactic low-dose aspirin and/or statins, and emphasizing the importance of physical activity, akin to the strategies applied to patients receiving ponatinib (30).

In summary, treatment with olverembatinib was highly effective and overall well-tolerated in patients with heavily pretreated CML-CP, including patients failing ponatinib and/or asciminib, and those with T315I mutation. Future studies in CML-CP are aiming to (I) compare olverembatinib with second-generation TKIs in the third-line setting, and (II) evaluate olverembatinib among newly diagnosed patients in the frontline setting.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Blood for the series “Chronic Myeloid Leukemia”. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-5/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-5/coif). The series “Chronic Myeloid Leukemia” was commissioned by the editorial office without any funding or sponsorship. F.G.H. serves on the advisory board for Sobi and served as the unpaid Guest Editor of the series. E.J. received research grants from Abbvie, Adaptive Biotechnologies, Amgen, Pfizer, and Takeda; and consultancy fees from Abbvie, Adaptive Biotechnologies, Amgen, BMS, Genentech, Incyte, Novartis, Pfizer, and Takeda. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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