ASXL1 and BIM germ line variants predict response and identify CML patients with the greatest risk of imatinib failure

Abstract

Key Points• Germ line variants in ASXL1 and BIM are strong biomarkers of response to imatinib in chronic phase CML.• A combined Sokal risk and ASXL1 and BIM variant model identified a subgroup of patients with the greatest risk of treatment failure.Scoring systems used at diagnosis of chronic myeloid leukemia (CML), such as Sokal risk, provide important response prediction for patients treated with imatinib. However, the sensitivity and specificity of scoring systems could be enhanced for improved identification of patients with the highest risk. We aimed to identify genomic predictive biomarkers of imatinib response at diagnosis to aid selection of first-line therapy. P 5 .041), progression to AP/BC (12% vs 1%; P 5 .034), FFS (P , .001), and MRs (P , .001).The ultra-high-risk patients may be candidates for more potent or combination first-line therapy. These data suggest that germ line genetic variation contributes to the heterogeneity of response to imatinib and may contribute to a prognostic risk score that allows early optimization of therapy.

Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

“…Major route ACAs may also help identify patients at greater risk of progression [53]. Some biological factors have also been proposed in single studies (e.g., germline variants in ASXL1 and BIM genes [176,177]; CIP2A protein levels at diagnosis [178]). So far, however, no validated prediction algorithm has ever been derived that may soundly predict who will develop BP.…”

<p>Myeloid Blast Crisis of Chronic Myeloid Leukemia Followed by Lineage Switch to B-Lymphoblastic Leukemia: A Case Report</p>

“…However, the Ph chromosome also occurs as a specific primary chromosomal change in acute myeloid leukemia. The mechanisms underlying CML-BC are complex, involving changes to many aspects of the molecular pathology, including the interaction of oncogenes, anti-oncogenes, and other abnormal genes 2,5,16 in addition to the BCR-ABL1 gene. Further research is needed to assess the frequency, treatment, and prognosis of CML-BC patients with lineage switch.…”

“…4 Patients with CML are treated with tyrosine kinase inhibitor (TKI) therapy according to the blast phenotype. 5,6 Here, we report a rare case in which the blast lineage switched from myeloid to B-lymphoid.…”

Impact of Genetic Polymorphisms and Biomarkers on the Effectiveness and Toxicity of Treatment of Chronic Myeloid Leukemia and Acute Myeloid Leukemia

“…A study identified a cohort of imatinib-treated patients with the highest risk of treatment failure, disease progression, and low likelihood of MR by combining the SOKAL risk score and heritable genetic biomarkers, including BIM. However, the utility of this risk score should be determined in prospective clinical trials [ 76 , 77 ].…”