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Update to Chapter 89: Chronic Myelogenous Leukemia and Related Disorders

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In a recent study called the EURO-SKI trial, 760 patients throughout Europe who were on a tyrosine kinase inhibitor (TKI) for at least 3 years were followed. Patients were on either their first TKI (710 of 760 on imatinib mesylate; 35 on nilotinib; 14 on dasatinib; 1 unknown) or a second TKI (7 on imatinib; 47 on nilotinib; 57 on dasatinib) as a result of intolerance to imatinib (not resistance). Patients had a median age of diagnosis of 52 years (range, 11.2–85.5). The median age at which TKI was stopped was 60.3 years (range, 19.5–89.9). The median duration of TKI therapy was 7.6 years (range, 3.0–14.2). Patients who had a deep molecular remission with BCR-ABL1 of <0.01% (MR4) for at least 1 year, confirmed on 3 consecutive polymerase chain reaction (PCR) measurements, had their TKI stopped. The median duration of TKI therapy in this patient population was 7.6 years (range, 3.0–14.2), and the median duration of MR4 before the TKI was stopped was 4.7 years (range, 1.0–13.3). The patients off their TKI were followed by real-time quantitative polymerase chain reaction (RT-qPCR) every 4 weeks for 6 months and every 6 weeks for 6 months. In the second and third year of study, RT-qPCR was done every 3 months.

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The cumulative rate of molecular relapse after stopping the TKI was 37% at 6 months, 43% at 12 months, 47% at 24 months, and 50% at 36 months. In all, 347 patients lost their molecular remission and 11 of those regressed to the loss of a complete cytogenetic response, but none progressed to accelerated phase or blast crisis. At the time of reporting, 80% of patients restarted on their TKI had regained an MR4 state. No patients died from CML during the study. A TKI withdrawal syndrome of largely transient musculoskeletal pain was noted in 235 patients (30.9%) who had their TKI stopped.

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TKI treatment duration and duration of MR4 state were the only significant variables correlated with sustained MR4 state off the TKI. Analysis showed that each additional year of TKI treatment or MR4 state increased the probability of staying in MR4 state at 6 months by 16%. Duration of TKI therapy and duration of MR4 state were very highly correlated. This made it difficult to determine which of the two variables was the more important predictor of a prolonged MR4 state after discontinuation of the TKI. There was a significant increase in the fraction of patients who were in MR4 remission off therapy at 6 months if they had been treated for at least 6 years prior to discontinuation of their TKI (65.5%) compared with those who had been treated for less than 6 years (42.6%).

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The study is ongoing to determine more precisely whether prediction of a prolonged molecular remission off therapy can be determined by the duration of the MR4 state. The principal benefits would be to the patient who could avoid the side effects of continued treatment and to the healthcare system by a very large reduction in drug costs.

References +
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Richter  J, Mahon  F-X. 2016. Cessation of Tyrosine Kinase Therapy in Chronic Myeloid Leukemia: The EURO-SKI Trial. 21St Congress of the European Hematology Association. Abstract S145.
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Sauβele  S, Richter  J, Hochhaus  A, Mahon  F-X. 2016. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia
[PubMed: 27133824]