Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results

Mauro, Michael J.; Hughes, Timothy P.; Kim, Dong-Wook; Réa, Delphine; Cortes, Jorge; Hochhaus, Andreas; Sasaki, Koji; Breccia, Massimo; Talpaz, Moshe; Ottmann, Oliver G.; Minami, Hironobu; Goh, Yeow Tee; DeAngelo, Daniel J.; Heinrich, Michael C.; Soria, V Gómez-García de; Coutre, Philipp le; Mahon, François‐Xavier; Janssen, Jeroen; Deininger, Michael W.; Shanmuganathan, Naranie; Geyer, Mark B.; Cacciatore, Silvia; Polydoros, Fotis; Agrawal, Nithya; Hoch, Matthias; Lang, Fabian

doi:10.1038/s41375-023-01860-w

Cited by 18 publications

(19 citation statements)

References 48 publications

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“…Although the third generation ABL1 TKI, ponatinib, is highly potent and effective even in the presence of the gatekeeper T315I mutation, it is susceptible to other BCR-ABL mutations (T315M and T315V) and compound mutations (Y253H/T315I or E255V/T315I) (36-38). The allosteric inhibitor, asciminib, that binds to the myristoylation pocket of BCR-ABL has demonstrated signi cant clinical e cacy in CML patients with two or more prior TKIs with a major molecular response rate of 61.6% after ~ 4-year median exposure to asciminib monotherapy (39). While this potent TKI can avoid resistance arising from common ABL1 mutations, it loses e cacy in the presence of mutations at certain ATP-competitive kinase domain residues (e.g.…”

Section: Discussionmentioning

confidence: 99%

Lipopolymer Mediated siRNA Delivery Targeting Aberrant Oncogenes for Effective Therapy of Myeloid Leukemia

Uludag,

Ansari,

et al. 2023

Preprint

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In contrast to exploiting proteins as targets like most conventional drugs and tyrosine kinase inhibitors (TKI), that are rendered futile in the face of emerging drug resistance, RNA Interference (RNAi) exerts its therapeutic action towards disease-driving aberrant genes. To realize the potential of RNAi, the major challenge is to efficiently deliver the therapeutic mediator of RNAi, small interfering RNA (siRNA) molecules. In this study, we explored the feasibility of using aliphatic lipid-grafted polymers (lipopolymers) for the delivery of siRNAs against the FLT3 oncogene in acute myeloid leukemia (AML) and BCR-ABL oncogene in chronic myeloid leukemia (CML). The lipopolymer delivered siRNA potently suppressed the proliferation AML and CML cells via silencing of the targeted oncogenes. In mouse subcutaneous xenograft models, intravenously administered lipopolymer/siRNA complexes displayed significant inhibitory effect on tumor growth. Combining siFLT3 complexes with gilteritinib allowed for reduction of effective drug dosage, longer duration of remission, and enhanced survival after relapse. Anti-leukemic activity of siBCR-ABL complexes was similar in wild-type and TKI-resistant cells, and therapeutic efficacy was confirmed in vivo through prolonged survival of the NCG hosts systemically implanted with TKI-resistant cells. These results demonstrate the preclinical efficacy of lipopolymer facilitated siRNA delivery, providing a novel therapeutic platform for myeloid leukemias.

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Section: Discussionmentioning

confidence: 99%

Lipopolymer Mediated siRNA Delivery Targeting Aberrant Oncogenes for Effective Therapy of Myeloid Leukemia

Uludag,

Ansari,

et al. 2023

Preprint

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“…This phase I, first-in-human, dose-finding study was described previously [25,26]. The current analysis focused on 48 patients with CML-CP with a confirmed T315I mutation who received a starting dose of asciminib monotherapy 200 mg BID in the dose-escalation or -expansion phases of this study arm.…”

Section: Methodsmentioning

confidence: 99%

“…Coding and grading of AEs, assessment of molecular response, and BCR::ABL1 mutational analysis were described previously [25].…”

Section: Study Assessmentsmentioning

confidence: 99%

“…Assessment of molecular response rates by time point was defined previously [25]. The analyses herein are based on data collected by the January 6, 2021, cutoff, when all patients had completed their week 60 follow-up visit or discontinued earlier and represent cumulative rates unless otherwise specified.…”

Section: Statistical Analysesmentioning

confidence: 99%

“…Asciminib is the first approved BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket, inhibiting BCR::ABL1 kinase activity by locking it in an inactive conformation via allosteric binding [12,[22][23][24][25]. Asciminib has high specificity and selectivity for the ABL kinase family with limited off-target activity [12,23].…”

Section: Introductionmentioning

confidence: 99%

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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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Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring

Jabbour,

Kantarjian

2024

American J Hematol

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Disease overviewChronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an annual incidence of two cases/100 000. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults.DiagnosisCML is characterized by a balanced genetic translocation, t(9;22) (q34;q11.2), involving a fusion of the Abelson murine leukemia (ABL1) gene from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein.Frontline therapyFour tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration (FDA) for first‐line treatment of newly diagnosed CML in the chronic phase (CML‐CP). Clinical trials with second and third‐generation TKIs in frontline CML‐CP therapy reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of their potent efficacy and the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy. All four TKIs are equivalent if the aim of therapy is to improve survival. In younger patients with high‐risk disease and in whom the aim of therapy is to induce a treatment‐free remission status, second‐generation TKIs may be favored.Salvage therapyFor CML post‐failure on frontline therapy, second‐line options include second and third‐generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities and financial status, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML‐CP and failure (due to resistance) of at least two TKIs and for all patients in advanced‐phase disease. Older patients who have a cytogenetic relapse post‐failure on all TKIs can maintain long‐term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non‐TKI anti‐CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, and others).

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Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results

Cited by 18 publications

References 48 publications

Lipopolymer Mediated siRNA Delivery Targeting Aberrant Oncogenes for Effective Therapy of Myeloid Leukemia

Lipopolymer Mediated siRNA Delivery Targeting Aberrant Oncogenes for Effective Therapy of Myeloid Leukemia

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

Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring

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