Chronic myeloid leukemia without major molecular response after 2 years of treatment with tyrosine kinase inhibitor

Abstract

Achieving major molecular response (MMR) with BCR::ABL1 tyrosine kinase inhibitors (TKIs) is associated with lower chances of progression to advanced phase disease and higher chances of treatment‐free remission (TFR) in patients with chronic myeloid leukemia (CML). Failure to achieve this molecular milestone after 1 year has been highlighted as “suboptimal” or “warning” sign of treatment failure in CML guidelines and recommendations and implied to predict a poor long‐term outcome. In this analysis, we report the long‐term outcome of 131 patients who did not achieve MMR within the first 2 years of TKI therapy. Patients who achieved a major cytogenetic response (MCyR; roughly equivalent to BCR::ABL1 transcript levels on the International Scale [IS] <10%) had good long‐term overall survival (OS) (10‐year OS of 88%) and CML‐related overall survival (CML‐OS) (10‐year CML‐OS of 95%). The achievement of MCyR within the first 2 years of treatment predicted a better OS (HR = 0.43, p = .03). The value of MMR was even less pronounced among patients aged 60 years or older at diagnosis, in whom mortality was primarily due to comorbidities unrelated to CML (10‐year OS of 55% vs. 10‐year CML‐OS of 100%). In conclusion, achievement of MCyR within 2 years is a reasonable milestone in CML, and these patients can still have good outcomes even when MMR is not achieved.

Real-world experience with ponatinib therapy in chronic phase chronic myeloid leukemia: impact of depth of response on survival and prior exposure to nilotinib on arterial occlusive events

“…The more di cult question to tackle is whether or not it is always necessary to use a more potent, more expensive, and, often, more dangerous TKI, in order to improve upon a CCyR, or even a CHR, which is often achieved by a rst-or second-generation TKI, and might be adequate enough to secure long-term survival. 7 Finally, we are fully cognizant of the limitations of the current retrospective study including its relatively small sample size, heterogeneity in patients and treatment strategies, the lack of accurate information on cardiovascular risk factors, and variable monitoring time points.…”

“…3 Despite the above-discussed advances in attaining deeper responses and now TFRs, neither "cure" nor MMR/DMR is necessarily a prerequisite for long-term survival in CML-CP, which might be possible by simply achieving TKI-induced CCyR. 7 The latter observation is practically relevant considering the consensus rst-line drug of choice being imatinib, which might not necessarily be the most effective in rapidly inducing MMR/DMR, 8-10 and yet arguably the safest and least expensive, among the currently FDA-approved TKIs for CML, 11 the others being dasatinib, nilotinib, bosutinib, ponatinib, and asciminib. 9,[12][13][14][15][16][17][18][19][20][21] However, a substantial minority of patients with CML-CP are either intolerant or fail to achieve the desired response milestone with imatinib and, therefore, require treatment with an alternative TKI.…”

Current CML guidelines overemphasize second generation TKIs: revisiting the paradigm

“…However, it is unclear whether deeper molecular and cytogenic responses translate to improved patient-centered outcomes, and recent evidence suggests the contrary. Bidikian et al reported long-term outcomes of 131 patients who did not achieve MMR after 2 years of treatment with TKIs, finding that 10-year CML-related OS was 95% if MCyR was achieved and 80% if MCyR was not achieved [4]. MMR is a poor measure of treatment failure, as patients who fail to achieve MMR can still achieve good outcomes.…”

Is it time to reconsider molecular response milestones in chronic myeloid leukemia?

“…In the current issue of the American Journal of Hematology, Bidikian et al report long-term survival data on 131 patients with CML who failed to achieve MMR within 2 years of treatment with TKIs. 1 Ten-year OS and CML-related OS were 76% and 88%, respectively, in their cohort, with achievement of a major or complete cytogenetic response (MCyR, CCyR) within 2 years of therapy being predictive of higher survival (10-year CML-related OS of 95%). Their results are in stark contrast with very early reports from the dawn of the TKI era, which show dismal outcomes from failing to meet the milestone.…”

“…Failure to achieve MMR has been widely accepted as a warning sign of treatment failure and grounds for therapeutic changes, despite a lack of data clearly showing that acting upon this outcome (i.e., switching or escalating therapy for failing to meet MMR) improves clinically relevant endpoints like overall survival (OS). In the current issue of the American Journal of Hematology , Bidikian et al report long‐term survival data on 131 patients with CML who failed to achieve MMR within 2 years of treatment with TKIs 1 . Ten‐year OS and CML‐related OS were 76% and 88%, respectively, in their cohort, with achievement of a major or complete cytogenetic response (MCyR, CCyR) within 2 years of therapy being predictive of higher survival (10‐year CML‐related OS of 95%).…”