I have just done a little research on TKI 'withdrawal syndrome' and came across this interesting article- see link and copy below (my italics in bold). I absolutely agree with Darley that 'normal wear and tear' is a meaningless (although common and unhelpful) comment usually uttered by GP's although sometimes from specialists too- probably when confronted with conditions/symptoms that they either cannot explain or have no intention of treating (or both).
Sandy
http://jco.ascopubs.org/content/32/25/2821.full
Musculoskeletal Pain in Patients With Chronic Myeloid Leukemia After Discontinuation of Imatinib: A Tyrosine Kinase Inhibitor 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.
The 15 patients consisted of nine women and six men with a median age at TKI discontinuation of 62 years (range, 49 to 74 years). The median duration of CML disease and imatinib therapy was 10 years (range, 4 to 16 years) and 9 years (range, 4 to 10 years), respectively. In eight patients the symptoms were graded as 2 on the Common Terminology Criteria for Adverse Events scale (version 4.0), and in seven patients as grade 1. Four had a previous medical history that included musculoskeletal system symptoms.
Only minor laboratory abnormalities were noted in association with the musculoskeletal symptoms. The C-reactive protein serum level was marginally increased in two of 10 patients, who had levels of 3.5 mg/L and 7 mg/L, respectively, but was normal in the other eight patients. Serum protein electrophoresis showed marginal inflammatory activity in three of eight investigated patients, but was normal in the others. Creatinine kinase and lactate dehydrogenase were normal in all patients analyzed, 14 and seven patients, respectively.
Although these adverse events were mild in seven individuals, only leading to use of nonprescription drugs (paracetamol or nonsteroidal anti-inflammatory drugs), eight patients were more severely afflicted, with manifestations that interfered with everyday activities. In five of these patients, corticosteroids were given (10 to 20 mg prednisolone per day), with tapering within weeks. All five patients demonstrated clear improvement within days, but in one patient, prednisolone could not be tapered without the reappearance of symptoms.
The rate of molecular relapse within the first 6 months after imatinib discontinuation did not differ between patients presenting with musculoskeletal adverse effects and those without (data not shown). Among these 15 patients, seven lost MMR and restarted imatinib, at which point six patients had persistent musculoskeletal symptoms. In all six patients, the symptoms completely resolved within 1 to 3 months after imatinib reinitiation. Among the remaining eight patients, still in MMR without TKI therapy, the musculoskeletal symptoms have fully resolved in two, partially resolved in four, but prevail in two (Table 1). In none of the patients was there any concomitant medication that was suspected of having a possible association with the musculoskeletal adverse effects. It is known that long-term imatinib treatment can cause disturbances in electrolyte balance (ie, hypophosphatemia) and bone metabolism.4 Whether the symptoms described here represent rebound phenomena from these adverse effects, or have another background, warrants further investigation. It should be remembered that imatinib, in addition to blocking BCR/ABL1 activity, also inhibits c-Kit and platelet-derived growth factor receptor, that is, receptor signaling that may possibly be linked to the observed adverse effects.5
Manifestations similar to those described here have also been observed in patients at other centers participating in EURO-SKI (in Germany, Holland, Finland, and Norway; J.S. Saussele, J. Janssen, P. Koskenvesa, personal communication, December 2013).
It would thus be of great interest to learn from Rousselot et al1 whether a similar so-called withdrawal syndrome was also noted in their trial. If supported and confirmed, our observations should raise awareness among investigators and clinicians as to the appearance of adverse events after the cessation of long-term TKI therapy, prompt the rapid reporting of such symptoms, and incite investigations into underlying mechanisms."
