Management of De Novo CML and Imatinib-Induced Acute Rhabdomyolysis With the Second-Generation TKI, Dasatinib

The aim of this report is to describe a newly diagnosed chronic myeloid leukemia (CML) patient who had imatinib mesylate (IM)-induced rhabdomyolysis and tolerated the second-generation tyrosine kinase inhibitor (TKI) dasatinib that controlled CML disease progression without precipitating the already present muscle damage. A 42-year-old man was admitted to the local hospital with left lumbar region pain. He had polycystic kidney disease, and leukocytosis in the routine tests had been observed. The patient admitted to our hematology outpatient unit for the evaluation of leukocytosis. After the investigations, he had been diagnosed as de novo chronic phase CML. In June 2014, he had been given IM 400 mg once a day. He was not taking any other drug. Pain began in both lower extremities 15 days after the start of medication. The patient’s baseline creatinine level was 1.5 mg/dL before the admission. The laboratory tests were as follows: creatinine 1.4 mg/dL, serum calcium and phosphorus levels in normal range, and creatine kinase (CK) levels 1533 U/L. Therefore, the patient was diagnosed as having rhabdomyolysis. The urine was clear in appearance, yellow colored, with a pH of 5, density 1010, protein glucose bilirubin ketone nitrite negative, and urobilinogen normal, with a few erythrocytes and leukocytes. Other causes of rhabdomyolysis (trauma or direct injury, excessive muscle activity, hereditary muscle enzyme defects, drugs and toxins, muscle hypoxia, metabolic and endocrine disorders, infections, temperature alterations, myocardial infarction, and stroke) were ruled out, and rhabdomyolysis was considered to have been caused by IM. We performed the Naranjo algorithm, and the score was 9 points. Therefore, IM treatment was stopped and secondgeneration TKI (dasatinib) was given instead. We preferred dasatinib because there are trials that confirmed the efficiency of dasatinib in patients with imatinib intolerance. Nilotinib could have also been used; however, its molecular mimicry cast doubts that it might cause the same intolerance and/or adverse events in terms of rhabdomyolysis. Two weeks after IM withdrawal, the pain in the patient’s extremities decreased, and CK levels were 195 U/L. His real-time polymerase chain reaction (PCR) analysis revealed that the disease was controlled with dasatinib treatment, and CK levels remained in normal ranges (Figure 1). He is still on follow-up with dasatinib in our clinic, without any sign of rhabdomyolysis. CML is a slowly progressive clonal malignant disease characterized by myeloid neoplastic expansion with heterogeneous clinical manifestations. CML could be functionally cured by the TKI drugs. IM is the first TKI to be used widely for CML treatment. Diarrhea, edema, myalgia, and skin reactions are common side effects of IM. In one previous study, myalgia occurred in 39% versus 22% of newly diagnosed chronic-phase CML patients who were treated with imatinib and dasatinib, respectively. Rarely, IM-induced rhabdomyolysis cases have been reported. Myalgia is a common side effect of IM. However, rhabdomyolysis with CK elevations is quite rare. In such a patient with CML, IM should be discontinued, and second-generation TKIs (such as dasatinib) should be administered. Because rhabdomyolysis recurs with the reintroduction of IM, the patient should be followed up while under secondgeneration TKIs. Dasatinib treatment could be used as an alternative TKI, so that CML remains under control during the rhabdomyolysis phase, and dasatinib does not precipitate the muscle damage with imatinib already present. It would have been better if we had investigated the plasma levels of imatinib in our patient; however, we failed to perform the plasma analyses. The interrelationships between IM and CK elevations are not well known. Some researchers suggest that IM-induced electrolyte imbalance is the reason for CK elevations. However, although our patient had polycystic kidney disease and creatinine levels of 1.4 mg/dL, he had no electrolyte imbalance. Monitoring the CML disease and TKI drug off-target risks are vital in clinical practice. Expected hematological, cytogenetic, and molecular responses to those drugs during the monitoring of CML vary based on some parameters. These parameters are the disease phase, mutational status, resistance profile, molecular BCR-ABL dynamics, compliance, patient drug adherence, and drug adverse effects. If there is myalgia with muscle weakness after the initiation of IM, rhabdomyolysis should be considered. No reports of rhabdomyolysis occurred during the clinical trial conducted for imatinib approval; however, postmarketing surveillance has captured some case reports of rhabdomyolysis. We have compared such cases in Table 1. In these cases, CK; complete blood count, including differential and platelet count; blood urea nitrogen; creatinine; routine electrolytes, including potassium, calcium, 579425 AOPXXX10.1177/1060028015579425Annals of PharmacotherapyMalkan et al research-article2015