Is there a best TKI for chronic phase CML?

Abstract

The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) over the past 20 years has dramatically improved the outcomes for patients with every stage of Philadelphia chromosome-positive (Phϩ) chronic myeloid leukemia (CML). Clinicians now have access to 5 oral, generally well-tolerated, and highly effective TKIs. How should these agents be used for an individual patient to ensure the best possible duration and quality-of-life, to avoid treatment-related complications, and potentially to achieve a cure at an affordable cost? Because CML patients may need to continue TKI therapy indefinitely, the long-term safety of each treatment option must be considered. Evidence-based care requires an understanding of the optimal use of these drugs, their specific early and late toxicities, the prognostic significance of achieving treatment milestones, and the critical importance of molecular monitoring. Efficacy is important, but treatment choice does not depend only on efficacy. Choosing among various treatment options is informed by understanding the distinct benefits and risks of each agent, along with careful consideration of patient-specific factors, such as risk status, age, and comorbidities. Learning Objectives• To compare the efficacy and safety of frontline BCR/ABL1 tyrosine kinase inhibitors in newly diagnosed chronic phase CML • To recognize the utility of risk assessment and molecular monitoring to individualize treatment • To understand the importance of early molecular response assessment with respect to long-term outcomesA 58-year-old man presented with asymptomatic leukocytosis. His past medical history included hypertension, adequately controlled with metoprolol, and diabetes for which he took metformin. His physical exam was notable only for an enlarged spleen palpable 5 cm below the left costal margin. His white blood cell count was 128 000/L with a predominance of neutrophilic cells, 2% blasts, 3% eosinophils, and 2% basophils. His hemoglobin was 13 g/dL and platelet count 640 000/L. Qualitative RT-PCR for BCR/ABL1 on blood was positive for the p210 transcript. Is there a best TKI for this patient with newly diagnosed chronic myeloid leukemia (CML) in chronic phase? The development of tyrosine kinase inhibitors (TKIs) over the past 20 years has dramatically altered the management as well as the outcomes for patients with every stage of Philadelphia chromosome-positive (Phϩ), BCR-ABL1ϩ, CML. Over a relatively short period of time, treatment recommendations have evolved from allogeneic hematopoietic cell transplantation (alloHCT) early in the disease course or recombinant interferon-alfa (rIFN␣), to the availability of 5 oral, generally well-tolerated and highly effective TKIs. Three (imatinib, dasatinib, and nilotinib) are approved for front-line use. Two others (bosutinib and ponatinib) are approved for intolerance or failure of prior TKI therapy. How should these agents be used for an individual patient to ensure the best possible duration and quality-oflife, to avoid treatment-related complications,...

Sequential use of second‐generation tyrosine kinase inhibitors following imatinib therapy in pediatric chronic myeloid leukemia: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group

“…In the present study, EUTOS scores were not significantly different between cases that switched to 2G‐TKIs and those who continued with imatinib. However, for adult patients with a high Sokal score, starting treatment with either nilotinib or dasatinib has been recommended . 2G‐TKIs as first‐line treatment might bring therapeutic benefit to pediatric CP‐CML patients with some risk factors that have not yet been established.…”

“…Side effects from TKI therapy are rarely severe, and perhaps for that reason, their importance tends to be minimized by clinicians. However, low‐grade toxicities from a therapy that patients may need to continue indefinitely can impact adherence and thus overall outcome . In an International Randomized Study of Interferon versus STI571 (IRIS) study, adverse symptoms within 5 years of imatinib treatment were identified, which include fluid retention (61.8%), muscle cramps (50.0%), musculoskeletal pain (47.8%), and diarrhea (57.3%) .…”

“…The choice of sequence for the use of nilotinib and dasatinib as second‐line TKIs is governed mostly by their side effect profiles in adults. Dasatinib would not be the first choice for a patient with prior lung disease or gastrointestinal bleeding, and nilotinib would not be the first choice for a patient with poorly controlled diabetes mellitus, hepatic disease, or cardiovascular risk factors . Taking into account all of the adverse effects, for the use of 2G‐TKIs, including recently available TKIs, it is clear that an important goal of pediatric CML management should be the avoidance of lifelong treatment with TKIs .…”

“…However, for adult patients with a high Sokal score, starting treatment with either nilotinib or dasatinib has been recommended. 25 2G-TKIs as first-line treatment might bring therapeutic benefit to pediatric CP-CML patients with some risk factors that have not yet been established. Thus, it would be useful to develop risk score systems for pediatric patients to predict their therapeutic response.…”

Case of relentless chronic phase of chronic myeloid leukaemia

“…However, in both cases, there were no significant differences in survival compared to imatinib at 5 years follow-up 8. Bosutinib is currently being evaluated under the BELA trial (bosutinib vs imatinib) with promising results at 2 years 9. EPIC trial (ponatinib vs imatinib) was stopped prematurely due to unacceptable rates of arterial thrombotic events 9…”