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Refractory pancytopenia upon initiation of asciminib in tyrosine kinase inhibitor-resistant chronic myeloid leukemia.

ABSTRACT: Asciminib, a "Specifically Targeting the ABL Myristoyl Pocket" inhibitor, is a new drug in the treatment of tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML). Hemocytopenias associated with asciminib are common adverse events documented by clinical trials. We report a case of precipitous-onset pancytopenia with the initiation of asciminib treatment in a patient with TKI-resistant CML. This case had a confounding array of laboratory findings that evidenced a drug-induced hemophagocytic component. We hope that our case stimulates further reporting of similar cases to enhance the understanding of the pathophysiology underlying asciminib-induced hemocytopenias.

SUBMITTER: Tessier S

PROVIDER: S-EPMC10401557 | biostudies-literature | 2023 Apr-Jun

REPOSITORIES: biostudies-literature

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Refractory pancytopenia upon initiation of asciminib in tyrosine kinase inhibitor-resistant chronic myeloid leukemia.

Tessier Steven S Aiad Mina M Longo Santo S Wilson Melissa M Faroun Yacoub Y

International journal of critical illness and injury science 20230401 2

Asciminib, a "Specifically Targeting the ABL Myristoyl Pocket" inhibitor, is a new drug in the treatment of tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML). Hemocytopenias associated with asciminib are common adverse events documented by clinical trials. We report a case of precipitous-onset pancytopenia with the initiation of asciminib treatment in a patient with TKI-resistant CML. This case had a confounding array of laboratory findings that evidenced a drug-induced he ...[more]

PMID: 37547190

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Project description:BackgroundAsciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown.MethodsIn this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months.ResultsPatients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.ConclusionsAsciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).

Project description:BackgroundPonatinib and asciminib are approved for third-line therapy in chronic-phase chronic myeloid leukemia (CP-CML) and are the only drugs approved for patients with the T315I mutation in the United States. In Europe, only ponatinib is approved for patients with the T315I mutation.MethodsClinical trials evaluating ponatinib or asciminib in patients with relapsed and refractory (R/R) CP-CML who failed one or more second-generation TKIs or had the T315I mutation were identified in a systematic review of medical literature databases. A matching-adjusted indirect comparison (MAIC) analysis with individual patient-level data with ponatinib was used to balance baseline characteristics between ponatinib and asciminib groups. After matching, the response rate was calculated using the MAIC weight for each patient and the difference in response rate was calculated using a two-independent proportion Z-test. Cumulative rates of BCR::ABL1 IS ≤1% and major molecular response (MMR) in patients without baseline response were compared. Patients were further stratified by T315I mutation status.ResultsThe MAIC included four trials (ponatinib: NCT02467270, NCT01207440; asciminib: NCT02081378, NCT03106779). In patients without baseline response of BCR::ABL1 IS ≤1%, the adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 9.33% (95% confidence interval [CI]: 0.79%-17.86%; adjusted MMR rate difference: 6.84% [95% CI: -0.95%-14.62%]) by 12 months in favor of ponatinib. In patients with the T315I mutation, adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 43.54% (95% CI: 22.20%-64.87%; adjusted MMR rate difference: 47.37% [95% CI: 28.72%-66.02%]) by 12 months.ConclusionAfter key baseline characteristics adjustment, cumulative BCR::ABL1 IS ≤1% and MMR rates were statistically higher with ponatinib than asciminib in patients without a baseline response in most of the comparisons by 12 months. Favorable efficacy outcomes observed in ponatinib vs. asciminib were consistently stronger in the T315I mutation subgroup.

Project description:BackgroundThe objective of this study was to assess patient-reported outcomes (PROs), including health-related quality of life (HRQoL) and anxiety and depression symptoms, and to identify associated variables in patients with tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) in chronic-phase (CP) or accelerated-phase (AP) who were receiving olverembatinib.MethodsPatients in multicenter studies were invited to complete the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 Questionnaire, the Self-Rating Anxiety Scale, and the Self-Rating Depression Scale at baseline and regularly during olverembatinib therapy. The time trends in PROs were estimated with a linear model using a generalized estimating equation based on an independent working correlation matrix. A generalized estimating equation model was used to assess the variables associated with PROs.ResultsIn total, 146 patients with CML-CP or CML-AP were included in this study. Scores on seven items from the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 Questionnaire, including global health, physical functioning, emotional functioning, fatigue, dyspnea, diarrhea, and financial difficulties, improved significantly over time during olverembatinib therapy. In multivariate analysis, age younger than 40 years was significantly associated with greater improvement in social functioning (p = .033), and CML-CP (vs. CML-AP) was associated with greater improvements in dyspnea (p = .031) and diarrhea (p = .031) over time. Scores on the Self-Rating Anxiety Scale and the Self-Rating Depression Scale decreased significantly over time during olverembatinib treatment (p < .001).ConclusionsThe authors concluded that HRQoL significantly improved over time during olverembatinib therapy in heavily treated patients with TKI-resistant CML, especially among those who were younger and those who had CML-CP. Anxiety symptoms also significantly decreased over time.

Project description:Previously, it has been stated that the BCR-ABL fusion-protein is sufficient to induce Chronic Myeloid Leukemia (CML), but additional genomic-changes are required for disease progression. Hence, we profiled control and tyrosine kinase inhibitors (TKI) alone or in combination with other drug-treated CML-samples in different phases, categorized as drug-sensitive and drug-resistant on the basis of BCR-ABL transcripts, the marker of major molecular-response. Molecular-profiling was done using the molecular-inversion probe-based-array, Human Transcriptomics-Array2.0, and Axiom-Biobank genotyping-arrays. At the transcript-level, clusters of control, TKI-resistant and TKI-sensitive cases were correlated with BCR-ABL transcript-levels. Both at the gene- and exon-levels, up-regulation of MPO, TPX2, and TYMS and down-regulation of STAT6, FOS, TGFBR2, and ITK lead up-regulation of the cell-cycle, DNA-replication, DNA-repair pathways and down-regulation of the immune-system, chemokine- and interleukin-signaling, TCR, TGF beta and MAPK signaling pathways. A comparison between TKI-sensitive and TKI-resistant cases revealed up-regulation of LAPTM4B, HLTF, PIEZO2, CFH, CD109, ANGPT1 in CML-resistant cases, leading to up-regulation of autophagy-, protein-ubiquitination-, stem-cell-, complement-, TGFβ- and homeostasis-pathways with specific involvement of the Tie2 and Basigin signaling-pathway. Dysregulated pathways were accompanied with low CNVs in CP-new and CP-UT-TKI-sensitive-cases with undetectable BCR-ABL-copies. High CNVs (previously reported gain of 9q34) were observed in BCR-ABL-independent and -dependent TKI, non-sensitive-CP-UT/AP-UT/B-UT and B-new samples. Further, genotyping CML-CP-UT cases with BCR-ABL 0-to-77.02%-copies, the identified, rsID239798 and rsID9475077, were associated with FAM83B, a candidate for therapeutic resistance. The presence of BCR-ABL, additional genetic-events, dysregulated-signaling-pathways and rsIDs associated with FAM83B in TKI-resistant-cases can be used to develop a signature-profile that may help in monitoring therapy.

Dataset Information

Refractory pancytopenia upon initiation of asciminib in tyrosine kinase inhibitor-resistant chronic myeloid leukemia.

Publications

Refractory pancytopenia upon initiation of asciminib in tyrosine kinase inhibitor-resistant chronic myeloid leukemia.

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