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Starting with a lower daily dose of dasatinib in patients with chronic myeloid leukemia in chronic phase: Less is more, or is it?

Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) that is used in the treatment of patients with chronic myeloid leukemia (CML), both in the upfront and salvage settings. After the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients (DASISION) trial, dasatinib was approved in the frontline treatment of patients with CML in chronic phase (CML-CP). The daily dose of dasatinib for first-line therapy in patients with CML-CP is 100 mg, and dasatinib therapy can be associated with some adverse events (AEs), for which dose reduction as well as temporary and/or permanent cessation of the drug may be needed. Starting with a lower daily dose of dasatinib was shown to be effective, at least in some groups of elderly patients with acceptable toxicity, and lowering the dose of this TKI during treatment resulted in favorable outcomes without sacrificing efficacy. Putting these together, Naqvi et al designed a prospective study in which a total of 75 patients with newly diagnosed CML-CP received dasatinib at a dose of 50 mg once daily. After a median follow-up of 9 months, major and deep molecular responses at defined time points were comparable to those observed in the DASISION trial. Only 9 patients had a dose interruption, and just 1 patient developed a pleural effusion (PE) requiring a dose reduction. Although the authors clearly demonstrated that this therapeutic maneuver was active and well tolerated, there are some points that need further clarification. As shown previously, dasatinib therapy can be associated with natural killer/T-cell lymphocytosis, and patients with lymphocytosis generally demonstrated better outcomes than those without high lymphocyte counts while receiving standard-dose dasatinib. Therefore, what was the percentage of patients developing lymphocytosis while receiving dasatinib at a dose of 50 mg daily? And did the authors notice any difference in terms of efficacy between patients with and without lymphocytosis? PE is a relatively common AE observed in patients receiving a standard daily dasatinib dose, and it has clearly been demonstrated that the percentage of patients developing PE increases as the duration of TKI therapy is extended. It was also shown that even at lower daily doses of second-line dasatinib therapy, patients may experience PE, and PE usually occurs in patients with comorbidities that might predispose the individual toward the generation of PE. Although the reason for the low percentage of PE cases observed in the cohort of the study by Naqvi et al might be the lower daily dasatinib dose, it also may be due to the relatively short duration of follow-up. In addition, may be the patients enrolled in this study did not have any comorbidities that may have played a part in the development of PE, although no such exclusion criteria were stated within the methodology part of the article. Among the patient cohort, the majority of cases (65%) were in the low Sokal risk group, whereas only 6 patients (8%) had a high Sokal risk score as commented on in the editorial accompanying the study by Naqvi et al. Were there any differences regarding efficacy between the different Sokal risk groups receiving 50 mg per day of dasatinib? TKIs are the mainstay of treatment of CML, but TKI therapy is not without toxicities. Lowering the daily dose of TKI therapy might result in a reduction in AE rates, but this should be done without losing the efficacy of the treatment. Naqvi et al demonstrated that a 50 mg daily dose of dasatinib induced similar responses compared with a dose of 100 mg daily, with a very favorable toxicity profile noted in patients with newly diagnosed CML-CP. However, a larger number of patients and a longer duration of follow-up still are needed to draw firm conclusions. And as stated by the authors, a randomized study comparing daily doses of dasatinib of 50 mg and 100 mg most likely would find answers to some questions remain unanswered.