Progression-free survival (PFS) in patients with chronic myeloid leukemia (CML) with a major molecular response (MMR) may be best predicted 2.5 years after diagnosis, according to a study published in Leukemia.1 Effectively defining the goals of therapy, however, remains elusive.

Current recommendations from the European LeukemiaNet (ELN) include reaching a complete cytogenetic response (CCyR) with a tyrosine kinase inhibitor (TKI), a well-established metric of drug efficacy.2 The recommendations also define the optimal time point for reaching MMR as 12 months after CML diagnosis, though ELN does not regard failure to reach MMR as treatment failure.2-6

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It remains unclear, therefore, whether clinicians should consider alternate CML therapy for patients not reaching MMR after 12 months.

To determine when it is necessary to switch therapies, investigators analyzed data from the CML study IV ( Identifier: NCT00055874) to estimate, using a mathematical model, the time necessary for defining treatment failure in patients with CML receiving imatinib who do not have an MMR, defined as a BCR-ABL/ABL value below 0.1%.

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The authors included data from 1228 patients with a valid molecular analysis on MR4 level. CML study IV is a randomized phase 3 trial evaluating the efficacy and safety of imatinib mesylate with or without interferon alfa or cytarabine compared with interferon alfa followed by hematopoietic cell transplantation in patients with newly diagnosed CML in chronic phase.

Investigators randomly assigned patients 2:1 to a learning or a validation cohort. The learning sample included 819 patients, including 805 who were alive and without progression at 6 months. Of these patients, 534 (66%) had no remission, 182 (23%) had an MR2, and 89 (11%) had an MMR.

A Cox model was used to define the time to progression at monthly landmarks between 1 and 5 years after diagnosis. Compared with patients who had not reached MMR, the minimum risk for progression among patients who had an MMR was identified between the landmarks 2.33 and 2.75 (hazard ratio [HR], 0.28; 95% CI, 0.16-0.51). Investigators also observed the minimum HR for progression (0.34; 95% CI, 0.20-0.56) for patients who achieved MR2 at 1.25 years.

“These data show that an optimum time frame exists in order to predict PFS based on the achievement of MMR,” the authors wrote. “This should be important for the optimization of treatment in CML concerning prolongation of survival.”

Given the results of the learning sample — and because 3-month visits are standard practice in clinical trials — the researchers used the landmark of 2.5 years for further analysis in the validation set. Compared with those without remission, the HR for PFS among the 409 patients in MMR was 0.20 (95% CI, 0.13-0.69; P = .007), validating the MMR landmark of 2.5 years as a significant predictor of PFS.