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Treatment-free remission in chronic myeloid leukemia: floating between expectation and evidence

Leukemia volume 31, pages 1015–1016 (2017)Cite this article

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The main goal of the treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) is becoming the achievement of a stable molecular remission after treatment discontinuation (treatment-free remission, TFR).1, 2, 3 Two registration studies comparing imatinib 400 mg once daily with second-generation TKIs (nilotinib and dasatinib) in the first-line treatment of newly diagnosed patients with chronic phase, Philadelphia chromosome positive (Ph+), BCR-ABL1+ CML showed that the molecular response to second-generation TKIs was faster and deeper.4, 5, 6, 7 Similar data were reported from other subsequent single-arm studies testing nilotinib in first line as well as in second-line.8, 9, 10 These findings have generated the expectation that a larger use of second-generation TKIs should bring more patients into the deep molecular response that is required for treatment discontinuation, then into a condition of TFR.2, 3, 6, 7 Since second-generation TKIs are more potent than imatinib, the expectation is well founded. The pros and cons of the choice of the first-line TKI have been discussed extensively.2, 3 There are studies addressing the question of the cost of the drugs,11 but there are no studies addressing comparatively the questions of efficacy and toxicity, with one exception in second-line, but without data on TFR.8

Based on the 5-year report of the ENESTnd trial (Table 1), it may be calculated that for every 100 newly diagnosed patients 24.1 patients could have achieved TFR with nilotinib versus 13.9 with imatinib, a difference of 10.2. Based on the 5-year report of the DASISION trial (Table 1), it may be calculated that 18.9 patients could have achieved TFR with dasatinib versus 14.9 with imatinib, a difference of 4. On the other hand, 8.2 patients with nilotinib and 8.0 patients with dasatinib suffered from cardiovascular adverse events (CVAEs) of any grade and of a pleural effusion grade 3 or 4, versus 2.1 and 2.0 with imatinib, a difference of about 6 in both trials. In the ENESTnd trial, the expected number of patients who would have benefited (who would have achieved TFR) is higher than the number of patients who developed a complication, but it is difficult to weigh and to compare the value of the benefit (TFR) with the value of the complications. It should not be overlooked that those complications occurred in optimal responders who have a life expectancy very close to normal, and a fairly good quality of life.1 A CVAE, by itself, increases the risk of developing other CVAEs, and of dying of a cardiovascular cause.12 Moreover, 5% of dasatinib-treated patients developed pulmonary hypertension, whose clinical outcome is still unclear.8, 12 In the ENESTcmr trial8 comparing a late switch to nilotinib with the continuation of imatinib, the figures were not much different from ENESTnd; by 2 years after the switch to nilotinib, 13.4 more patients ever achieved a condition of ‘confirmed undetectable BCR-ABL1’, and 6 more patients suffered from peripheral artery obstructive disease and of ischemic heart disease (with one death caused by myocardial infarction), a difference of 7.4.

Table 1 Calculation of the number of patients who could have achieved a condition of TFR in the ENESTnd and the DASISION trials
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  1. GIMEMA CML Working Party and University of Bologna, Bologna, Italy

    M Baccarani

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MB has received consultant and speaker fees for Novartis, Pfizer and Ariad/Incyte.

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Baccarani, M. Treatment-free remission in chronic myeloid leukemia: floating between expectation and evidence. Leukemia 31, 1015–1016 (2017). https://doi.org/10.1038/leu.2017.20

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