In an earlier study we used a
In an earlier study, we used a questionnaire to assess musculoskeletal pain in patients with CML who had achieved DMR (MR4.0) and discontinued TKI treatment, including IM, nilotinib, and dasatinib . Nine out of the 27 patients surveyed developed musculoskeletal pain after discontinuing TKIs. In the present study, we investigated whether there was an association between physical size and musculoskeletal pain in patients following the discontinuation of IM treatment.
Materials and methods This study was approved by the Institutional Review Board of Tokyo Medical University (No. 3052) and involved additional analysis of data acquired from IM discontinuation patients who had completed a questionnaire in a previous study . In the questionnaire, participants were asked whether they vegf inhibitor had developed musculoskeletal pain during TKI therapy and after TKI cessation. The participants with musculoskeletal pain were asked to describe the location, severity, and duration of symptoms, the time taken to experience symptoms following the discontinuation of TKIs, and the type of treatment (Table 1). Symptom severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE; version 4.0). We evaluated several factors including sex, age, Sokal category, history of interferon-α, duration of TKI therapy, time to achieve DMR, duration of DMR, electrolyte abnormalities (Na+, K+, Ca2+), along with creatine phosphokinase (CPK) and C-reactive protein (CRP) concentrations. TKIs were restarted in patients who experienced a loss of major molecular response (MR3.0). We also evaluated characteristic differences in body height, body weight (BW), body mass index (BMI) and body surface area (BSA) between patients with and without musculoskeletal pain following the discontinuation of IM. These data were analyzed by the Mann-Whitney U test, Fisher\'s exact test and the Log-rank test using Graph PAD Prism 6 (GraphPad Software, San Diego, CA).
Results Twenty-four patients were included in this study (16 men, eight women; median age 62 years [range: 37–84 years]). Twenty patients had low, and four had intermediate, Sokal categories. None of the patients had been treated with TKIs other than IM. The median duration of IM therapy was 91.5 months (range: 51–138 months) and the median daily dose was 400mg (range: 200–400mg). The time to achieve DMR and the duration of DMR were 36 months (range: 11–84 months) and 50.5 months (range: 31–97 months), respectively. Differences in clinical factors and body characteristics when compared between patients with and without musculoskeletal pain after ceasing IM are shown in Table 2. Body height did not differ between the two groups, however those with symptoms had a significantly lower BW and BMI than those without symptoms (p=0.013, p=0.028, respectively). Furthermore, BSA tended to be lower in those with symptoms; however, this difference was not statistically significant (p=0.072). Clinical factors including sex, age, Sokal category, history of interferon-α, daily IM dose, duration of IM therapy, time to achieve DMR, and the duration of DMR were not significantly different. Finally, the persistence of MR3.0 tended to be higher in those with symptoms (p=0.077).
Discussion The main goal of CML therapeutic strategies is the safe discontinuation of TKIs; however withdrawal syndrome is a noteworthy phenomenon after TKI cessation. Although approximately 30% of patients who cease IM reportedly proceed to develop musculoskeletal pain or pruritus [2–5], inheritance of acquired characteristics is not yet known which factors can predict musculoskeletal pain after the discontinuation of TKIs. In current study, we focused upon patient physical size parameters such as BW, BMI and BSA. The International Randomized Study of Interferon Versus STI571 (IRIS) study also identified weak correlations between steady-state trough levels of IM and both BW and BSA . Breccia et al. further showed that patients with higher BMIs (25–40kg/m2) took significantly longer to achieve complete cytogenetic response and major molecular response than those with lower BMIs (<25kg/m2) . In a prospective Japanese multicenter phase Ⅱ study, patients receiving 300mg of IM as tolerable daily doses had a lower BW and BSA than those who could tolerate daily doses of 400mg although mean trough levels did not differ between these groups . Kim et al. further showed that the pharmacokinetic profile of IM in Korean patients was similar in caucasians  and these reports suggested that physical size is related to the pharmacokinetics of IM and associated with treatment effects or adverse reactions.