Musculoskeletal Pain - TKI Withdrawal Syndrome?

Rousselot et al1 recently reported on the According to Stop Imatinib (A-STIM) study evaluating the persistence of major molecular response (MMR) in patients with chronic-phase chronic myeloid leukemia (CP CML) who had discontinued imatinib after prolonged deep molecular remission. They found that 61% of the patients were still in MMR and were treatment free after 36 months, whereas those who lost MMR and restarted tyrosine kinase inhibitor (TKI) therapy all regained MMR. They concluded that loss of MMR is a safe criterion for restarting therapy after TKI discontinuation. However, possible adverse effects derived from this therapeutic strategy were not mentioned in the report.

Although it is well known that imatinib can induce adverse events in, for example, the musculoskeletal system,2,3 it has been assumed that such adverse events are generally reversible on cessation of therapy. In Europe, a multinational trial of TKI discontinuation, Europe Stop Tyrosine Kinase Inhibitors (EURO-SKI, NCT01596114, approved by the regional ethical board in Lund, Sweden) is ongoing. In this trial, patients with CML treated for at least 3 years with a TKI, having achieved and maintained MR4 (BCR/ABL1 < 0.01%) for at least 1 year, are offered TKI discontinuation and follow-up. In EURO-SKI we have, somewhat unexpectedly, observed a substantial rate of patients reporting musculoskeletal pain that begins or worsens within weeks after stopping imatinib therapy. More specifically, in a cohort consisting of the first 50 patients in Sweden who were included in EURO-SKI and were observed for at least 6 months (range, 6 to 15 months) after stopping imatinib, 15 patients (30%) reported musculoskeletal pain evolving gradually from 1 to 6 weeks after TKI discontinuation (Table 1). The pain was localized to various parts of the body, including the shoulder and hip regions, extremities, and/or hands/feet; sometimes the pain manifested as muscle tenderness, whereas at other times it resembled polymyalgia rheumatica.

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http://jco.ascopubs.org/content/32/25/2821.full#