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Editorials
Precision tyrosine kinase inhibitor dosing in chronic myeloid leukemia?
Giuseppe Saglio,1 Carmen Fava1 and Robert Peter Gale2
1Department of Clinical and Biological Sciences of the University of Turin, Mauriziano Hospital, Italy and 2Haematology Research Center, Division of Experimental Medicine, Department of Medicine, Imperial College London, UK
E-mail: GIUSEPPE SAGLIO - giuseppe.saglio@unito.it doi:10.3324/haematol.2018.214445
Therapy for chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has made this a
1,2
potentially curable disease. However, many chal-
lenges remain, including: i) defining the best TKI, dose and schedule; ii) how to reduce the frequency and sever- ity of adverse events (AEs); iii) how to increase the num- ber of subjects who can achieve therapy-free remission (TFR), and others. In this issue of Haematologica, using data from the German CML-Study IV,2 Michel et al.3 tack- le two of these challenges: the best TKI dose and reducing AEs. They report that subjects randomized to receive high-dose imatinib, 800 mg/day (d), achieving a stable major molecular response (MMR, 0.1% of BCRABL1IS) can have their imatinib dose reduced to 400 mg/d with- out losing their response, with the additional benefits of reducing AEs and cost, and likely increasing compliance.
Several prior clinical trials tested whether high-dose imatinib, 800 mg/d, was more effective than the approved dose, 400 mg/d.4-6 The primary end point of most of these trials was the proportion of study subjects achieving a MMR at 1 year, a landmark associated with a very low risk of leukemia progression and death from CML-related causes.7 A secondary end point was the time
to MMR achievement. The conclusion of most studies was that high-dose imatinib resulted in faster MMRs but later led to a similar proportion of MMRs after 1 or 2 years.4-6 However, high-dose imatinib was associated with increased rates of ≥ grade 3 AEs, worse compliance, and higher costs.4-6 Consequently, many study subjects assigned to high-dose imatinib reverted to 400 mg/d. Recently, a landmark analysis of data from the CML- Study IV reported that study subjects receiving an opti- mized high-dose of imatinib (median dose, 600 mg/d) achieved deeper and faster molecular responses (MMR, MR4 and MR4.5) compared with those receiving 400 mg/d, with no increase in ≥ grade-3 AEs.8 Importantly, the conventional and optimized strategies of giving imatinib resulted in similar event-free survival (EFS), progression- free survival (PFS), and overall survival (OS).2
There are several caveats to accepting these conclusions including biases associated with landmark analyses and discordances between molecular responses (surrogate end points) and clinically important end points such as EFS, PFS and OS.9,10 Such discordances are common to many, if not most, clinical trials and underscore the limitations of surrogate end points.11 This is not surprising in chronic
FIgure 1. Possible future therapeutic strategy for CML. TKI: tyrosine kinase inhibitors; MMR: major molecular response; MR: molecular response.
haematologica | 2019; 104(5)