CML-466 Asciminib Provides Durable Molecular Responses in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With the T315I Mutation: Updated Efficacy and Safety Data From a Phase I Trial

Hughes, Timothy P.; Cortes, Jorge E.; Réa, Delphine; Mauro, Michael J.; Hochhaus, Andreas; Kim, Dong-Wook; Sasaki, Kenji; Lang, Fabian; Heinrich, Michael C.; Breccia, Massimo; Deininger, Michael W.; Goh, Yeow-Tee; Janssen, Jeroen J. W.M; Talpaz, Moshe; Coutre, Philipp le; Kapoor, Shruti; Cacciatore, Silvia; Polydoros, Fotis; Agrawal, Nithya; Mahon, François‐Xavier

doi:10.1016/s2152-2650(22)01388-x

Cited by 3 publications

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“…Use of the highest tested dose of asciminib, 200 mg BID, was justified by overall major molecular response (MMR; BCR::ABL1 IS ≤0.1%) rates predicted by pharmacokinetic/ pharmacodynamic analysis in patients with T315I-mutated CML-CP and may improve the probability of response by maximizing the predicted proportion of patients with asciminib exposure above the preclinical 90% maximal effective concentration [28]. Results from this trial supported full approval of asciminib 200 mg BID for patients with T315I-mutated CML-CP in the US with subsequent approvals worldwide [29][30][31].…”

Section: Introductionmentioning

confidence: 81%

Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results

Cortes,

Sasaki,

Kim

et al. 2024

Leukemia

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Asciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1T315I, which is resistant to most approved adenosine triphosphate–competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years’ median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib’s effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.

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Section: Introductionmentioning

confidence: 81%

Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results

Cortes,

Sasaki,

Kim

et al. 2024

Leukemia

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“…Клиническая безопасность и эффективность применения асциминиба у ранее получавших лечение больных ХМЛ в ХФ или ФА с наличием мутации T315I или без нее были продемонстрированы в нескольких клинических исследованиях. К настоящему времени опубликованы результаты исследования I фазы по применению асциминиба в режиме монотерапии [28], промежуточные результаты терапии в расширенной когорте больных с мутацией T315I [35], получавших асциминиб по 200 мг 2 раза в сутки, а также промежуточные результаты применения асциминиба в комбинации с одним из трех препаратов: иматинибом, нилотинибом, дазатинибом. Кроме того, продолжается исследование III фазы по сравнению эффективности асциминиба с бозутинибом у пациентов с ХМЛ в ХФ, ранее получавших не менее 2 ИТК (ASCEMBL) [36].…”

Section: результаты клинических исследований по применению асциминибаunclassified

“…Когорта больных с мутацией T315I была расширена: включено 48 пациентов с ХМЛ в ХФ и мутацией T315I для терапии асциминибом в дозе 200 мг 2 раза в сутки [35]. Медиана продолжительности терапии составила 2 года.…”

Section: результаты терапии асциминибом у больных с хф хмл в клиничес...unclassified

“…У 20 (54,1 %) и 23 (62,2 %) из 37 пациентов с изначальным уровнем BCR::ABL1 > 1 % достигнут МО2 (BCR::ABL1 ≤ 1 %, эквивалент ПЦО) к 48 и 96 нед. соответственно [35].…”

Section: результаты терапии асциминибом у больных с хф хмл в клиничес...unclassified

“…У больных с мутацией T315I, получавших асциминиб в дозе 200 мг 2 раза в сутки, наиболее часто (> 3 %) отмечались следующие НЯ III-IV степени: повышение уровня липазы (18,8 %), тромбоцитопения (14,6 %), рвота, повышение уровня аланинаминотрансферазы, боль в животе, артериальная гипертензия, анемия, нейтропения (по 6,3 %) [35]. Артериальные окклюзионные события имели место у 4 (8,3 %) больных в этой группе, ни одно из них не привело к корректировке дозы/прерыванию/прекращению лечения.…”

Section: результаты терапии асциминибом у больных с хф хмл в клиничес...unclassified

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Результаты Применения Асциминиба, Первого Аллостерического Ингибитора BCR::ABL1-тирозинкиназы, У Больных Хроническим Миелолейкозом Со Множественной Резистентностью К Предшествующей Терапии

Туркина,

Кузьмина

2024

Clinical Oncohematology

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Currently, there is a crucial need for new treatment approaches to overcome the resistance and intolerance of several tyrosine kinase inhibitor (TKI) therapy lines in chronic myeloid leukemia (CML) patients. Asciminib, the first in its class BCR::ABL1-tyrosine kinase inhibitor specifically targeting ABL myristoyl pocket (STAMP), demonstrated efficacy and safety in CML patients with prior TKI therapy failure, including the cases with pan-resistant T315I mutation in the chimeric BCR::ABL1 gene. The present review focuses on the asciminib mechanism of action, the results of both preclinical and clinical phase I and III studies. Due to the favorable cardiovascular toxicity profile of asciminib, the scope of its application can be extended to patients with cardiovascular co-morbidities. Asciminib is registered in the Russian Federation in January 2023, so treatment algorithms for CML patients with ineffectiveness or intolerance of prior therapy should be updated in line with this new option.

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Asciminib in the Treatment of Philadelphia Chromosome-Positive Chronic Myeloid Leukemia: Focus on Patient Selection and Outcomes

Hijiya,

Mauro

2023

CMAR

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Tyrosine kinase inhibitors (TKIs) have significantly changed the treatment of chronic myeloid leukemia (CML) and improved outcomes for patients with CML in chronic phase (CML-CP) and accelerated phase (AP). Now armed with numerous effective therapeutic options, clinicians must consider various patient- and disease-specific factors when selecting the most appropriate TKI across lines of therapy. While most patients with CML expected to have a near-normal life expectancy due to the success of TKIs, emphasis has expanded beyond response and survival to include factors like quality of life, tolerability, and long-term toxicity management. Importantly, a subset of patients can achieve sustained deep molecular response and can attain treatment-free remission. Despite these successes, unmet needs remain related to CML treatment, including the persistent challenge of treatment resistance and intolerance, broadening treatment options for patients with resistance mutations or serious comorbidities, and focus on specific populations such as children and young adults. In particular, the only previously available treatments for patients with CML-CP with the T315I mutation were ponatinib, olverembatinib (exclusively approved for use in China at the time of this writing), omacetaxine, and hematopoietic stem cell transplantation. Asciminib has entered the CML treatment landscape as a new option for adult patients with CML-CP who have received ≥2 prior TKIs or those with the T315I mutation. Asciminib’s unique mechanism of action, Specifically Targeting the ABL Myristoyl Pocket, sets it apart from traditional adenosine triphosphate-competitive TKIs. While asciminib may overcome unmet needs for patients with CML-CP and continues to be studied in other novel settings, guidance on how to integrate asciminib in treatment algorithms is needed. This review focuses on clinical data and how asciminib can overcome current unmet needs, discusses how to individualize patient selection, and highlights future directions to investigate asciminib in earlier lines of therapy and in children and adolescents.

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CML-466 Asciminib Provides Durable Molecular Responses in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With the T315I Mutation: Updated Efficacy and Safety Data From a Phase I Trial

Cited by 3 publications

References 0 publications

Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results

Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results

Asciminib in the Treatment of Philadelphia Chromosome-Positive Chronic Myeloid Leukemia: Focus on Patient Selection and Outcomes

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