Persistently Increased Creatine Kinase Levels in Patients with Chronic Myeloid Leukemia Treated with Imatinib Correlate with Major Cytogenetic Remission.

Introduction: Myalgias and muscle cramps occur in 11% and 33% of patients (pts) on imatinib, but are usually not dose-limiting. Rhabdomyolysis has been reported once. We analysed serial creatine kinase (CK) levels and their correlation with clinical symptoms and response to imatinib in 113 (pts) treated with imatinib at the University of Leipzig.

Patients and methods: 113 pts (55 m/58 f; median age 55 y) treated with imatinib for at least 6 months (mon) were included (follow up range 6–42 mon). Disease phase was chronic phase (CP) (n=83), accelerated phase (AP) (n=22), and myeloid blastic phase (M-BP) (n=8). 77 (68%) pts received IFN-alpha prior to imatinib for a median duration of 24 mon (range 2–120). Pts with known cardiac or skeletal muscle disease were excluded. CK, SGOT, and SGPT were measured according to IFCC recommendations. Initial values were compared to a control group of 102 healthy persons. Normal values for CK, and transaminases were < 2.9, and 0.17–0.85 μkat/L respectively. CK isoenzymes (CK-BB, CK-MB and CK-MM) were separated by electrophoresis. The Common Toxicity Criteria of the NCI were used to grade toxicities.

Results: Response to imatinib was major cytogenetic remission (MCR) (<35% Ph+ metaphases) in 72 (64%) and only hematologic remission (complete or partial) in 41 (36%) pts. Cramps and/or myalgias occurred in 29% of pts, and were > grade I in 39%. Initial median CK levels in CML pts were lower than that in the control group (0.8 vs. 1.19 μkat/L, p=0.008), and tended to be higher in pts with CP compared to AP (0.9 vs. 0.53 μkat/L, p=0.04). Within 6 mon of therapy, 91 pts (80.5%) had a > 50% increase of CK values compared to baseline. Median CK levels in symptomatic pts were higher than in asymptomatic pts (2.05 vs. 1.57 μkat/L, p=0.015). CK electrophoresis revealed elevated CK-MM in 83% (including one pt with Makro-CK-I) and elevated CK-MB in 17%. Median CK levels at 6 mon were lower in pts with previous IFN therapy than in pts treated with imatinib up-front (1.55 vs. 2.38 μkat/L, p=0.01). Age, sex, disease phase and disease duration prior to imatinib had no effect. Interestingly, CK > ULN at 6 mon was correlated with MCR (p= 0.048). Consistent with this, the median CK level at 6 months was 3.35 μkat/L in pts with MCR and 1.1 μkat/L in pts without MCR. Only 8 pts (11%) achieving MCR experienced no CK elevation. On the other hand, no cytogenetic remission was noticed in 69% of pts without CK elevation. SGOT, and SGPT elevations frequently accompanied the CK increase, but the differences compared to baseline levels did not reach statistical significance. IFN-alpha induced elevation of SGOT and SGPT did not correlate with their subsequent values under imatinib.

Conclusions: (1) Imatinib causes persistent CK elevation of >50% above baseline in the majority of responding pts. (2) Elevated CK correlates with myalgia and cramps (3) Elevated levels of SGOT and SGPT should not automatically be ascribed to hepatotoxicity (4) Elevated CK levels correlate with MCR, possibly reflecting higher drug levels. Longer follow-up is needed to determine if imatinib-induced myotoxicity may cause permanent muscle damage and if pts should be advised to take special precautions, such as the avoidance of strenuous physical activity.