Defining Higher-Risk Chronic Myeloid Leukemia: Risk Scores, Genomic Landscape, and Prognostication

Abstract

Purpose of Review The chronic myeloid leukemia (CML) treatment success story is incomplete as some patients still fail therapy, leading to end-stage disease and death. Here we discuss recent research into CML incidence, the role of comorbidities on survival and detecting patients at risk of failing therapy. Recent Findings The incidence of CML has fallen markedly in high social-demographic index (SDI) regions of the world but there is disturbing evidence that this is not the case in low and low-middle SDI countries. Now that CML patients more frequently die from their co-morbid conditions than from CML the Adult Comorbidity Evaluation-27 score can assist in risk assessment at diagnosis. Non-adherence to therapy contributes greatly to treatment failure. A good doctor-patient relationship and social support promote good adherence, but patient age, gender, and financial burden have negative effects, suggesting avenues for intervention. Mutations in cancer-associated genes adversely affect outcome and their detection at diagnosis may guide therapeutic choice and offer non-BCR::ABL1 targeted therapies. A differential gene expression signature to assist risk detection is a highly sought-after diagnostic tool being actively researched on several fronts. Summary Detecting patients at risk of failing therapy is being assisted by recent technological advances enabling highly sensitive genomic and expression analysis of insensitive cells. However, patient lifestyle, adherence to therapy, and comorbidities are critical risk factors that need to be addressed by interventions such as social and financial support.

The Success of Treatment Free Remission in Chronic Myeloid Leukaemia in Clinical Practice: A Single-Centre Retrospective Experience from South Africa

“…One patient attempted TFR because of pregnancy and the risk posed to the foetus by TKI therapy (Dasatinib) in pregnancy, despite having a mutation (Y253H-resistant to Imatinib and Nilotinib). A mutation is considered a contraindication to attempting TFR in CML [21][22][23][24][25], as the risk for clonal selection and disease progression is high [53]. Tis patient had achieved a DMR at the time of discontinuing TKI, but failed TFR trial, and lost CCyR of TKI after 6 months of discontinuing TKI.…”

Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukemia

“…The latest European Leukemia Network (ELN) treatment guidelines and the National Comprehensive Cancer Network (NCCN) CML Clinical Practice Guidelines consider clinical responses to include "best", "failure", and "warning" 1 , 9 . TKI resistance is defined as "failure" in the evaluation of CML treatment response, referring to the definition of ELN failure in 2020 recommendations, with BCR-ABL IS > 10% if confirmed within 1-3 months, BCR-ABL IS > 10% at 6 months of TKI treatment, BCR -ABL IS > 1% at 12 months of treatment, or BCR-ABL IS >1% at any time after 12 months of treatment, with resistance mutations, the emergence of high-risk additional chromosome abnormalities (ACA) 10 , 11 . The same definitions are recommended for second-line treatment 1 .…”

“…Compound mutations (variants containing ≥ 2 mutations within the same BCR-ABL1 allele that presumably arise sequentially or simultaneously) exhibit different spectra of resistance from single mutations 10 . For example, while ponatinib is effective in treating a CML with a single T315I mutation, most compound mutations containing T315I are resistant to ponatinib 25 , 26 .…”

25 years of experience in the treatment of chronic myeloid leukemia with tyrosine kinase inhibitors: results, opportunities, questions

“…), определяемые при диагностике: у пациентов группы высокого риска в условиях реальной практики в 1-й линии терапии часто отдают предпочтение ИТК2 перед иматинибом. Для пациентов более низких групп риска результативность иматиниба и ИТК2 различается незначительно [10,[68][69][70].…”