Introduction
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia, which is characterized by a cytogenetic abnormality of t (15;17). This abnormality results in a fusion gene of PML/RARα, which inhibits the differentiation and apoptosis of leukemic cells [
]. Arsenic trioxide (ATO) is a component of arsenic sublimate, a traditional Chinese medicine. In 1971, researchers at the Harbin Medical University in China found that ATO is effective in treating APL [
]. In September 2000, the US Food and Drug Administration approved ATO for APL treatment based on the promising results of several clinical trials [
3]. Combined with all-
trans-retinotic acid (ATRA), ATO has become one of the first-line induction therapies of APL [
]. The most common side effect of ATO is hepatotoxicity, gastrointestinal symptoms, water-sodium retention, and nervous system damage [
]. Rhabdomyolysis has only been reported in fatal ATO poisoning [
]; moreover, it is rarely associated with APL treatments with low dosage. Here, we report a rare side effect of rhabdomyolysis, in a 68-year-old female with APL treated with ATO.
Case report
A 68-year-old female was admitted to our hospital for fatigue and dizziness in October 2014. The patient has a history of hypertension. Her peripheral blood count was as follows: white blood cell (WBC) count, 1.0×109/L; red blood cell count, 3.37×1012/L; hemoglobin (Hb), 108 g/L; and platelet count, 47×109/L. Her renal and hepatic functions were normal. She was diagnosed with APL based on the combined analysis of morphology, immunophenotype, cytogenetics, and molecular biology. Promyelocytic leukemia cells were found in her bone marrow smear with a proportion of 85%, and cytogenetic analysis revealed a karyotype with t(15;17) and trisomy 8. Molecular analysis was positive for PML/RARα.
The patient received combined ATRA and ATO as the initial induction therapy. She received 18 mg/m2 ATRA in 3 divided daily doses and 0.18 mg/kg ATO intravenously over 1 h daily. Six days later, she developed severe chest tightness, shortness of breath, progressive muscle weakness of extremities and trunk, and myodynia. Urine output decreased to less than 400 ml per day. Laboratory tests showed that serum creatinine increased from a normal value to 295 mmol/L within 2 days, lactate dehydrogenase (LDH) increased from 110 U/L to 5885 U/L, aspartate transaminase (AST) increased to 456 U/L, cardiac troponin T (cTnT) increased from 0.07 U/L to 13.7 U/L, myoglobin (Mb) increased from 65 to 937.5 U/L, urine analysis was positive with trace hemoglobin, and creatine kinase (CK) levels increased to 1507 IU/L. Serum potassium, phosphorous, and calcium were within normal ranges (Table 1).
Rhabdomyolysis and acute renal dysfunction were diagnosed based on clinical presentation and laboratory tests. ATRA and ATO were discontinued immediately and the patient received continuous renal replacement therapy (CRRT). After 4 days of hemodialysis, her creatinine value decreased to 145 mmol/L and her symptoms and physical condition improved. She was discharged and followed-up in the outpatient department. After 2 weeks, all of her biochemical parameters normalized. She received low doses of ATRA (18 mg/m2 ATRA in 2 divided doses daily) again and no longer developed rhabdomyolysis. One month later, the patient reached complete remission of APL, as evidenced by peripheral blood and bone marrow examinations. She received 2 cycles of mitoxantrone (8 mg, 1–3 days) as consolidation chemotherapy and continuous single ATRA. She was still alive and the response of APL remained in CR until the last follow-up.
Discussion
Rhabdomyolysis is characterized by elevated creatine kinase, urine myoglobin, and acute renal insufficiency. Typical symptoms include myodynia, weakness, tenderness, and swelling of injured muscles [
]. Rhabdomyolysis is most commonly caused by trauma in the general population and by prescription or over-the-counter medications in the patient population [
]. Drugs that are related to myotoxicity and rhabdomyolysis include HMG-CoA reductase inhibitors, antiepileptics, and some antimicrobials. Some of the newer tyrosine kinase inhibitors used in cancer treatment [
], such as Sunitinib and Erlotinib, are associated with increased CK levels and/or rhabdomyolysis.
The major toxicity associated with ATO is APL differentiation syndrome, which is observed in approximately a third of patients. Other toxicities include hepatotoxicity, nephrotoxicity, neurotoxicity, metabolic disturbance, fluid retention, skin discoloration, xerodermia, and conjunctivitis [
]. To the best of our knowledge, this is the first report that described ATO-induced rhabdomyolysis during APL treatment.
The patient was diagnosed with rhabdomyolysis 6 days after initiation of treatment. She was only on two medications: ATRA and ATO. Both are associated with retinoic acid syndrome [
,
]. However, elevated CK does not occur in retinoic acid syndrome. ATRA is rarely reported in rhabdomyolysis, whereas ATO is associated with rhabdomyolysis in fatal ATO poisoning. The patient received ATRA again when the rhabdomyolysis was in remission and did not experience recurrence of rhabdomyolysis. Therefore, we speculated that ATO caused rhabdomyolysis.
Given that acute renal insufficiency occurred rapidly in this patient, the withdrawal of the suspicious causative agent immediately was crucial. The complete remission of rhabdomyolysis, which is indicated by normalized renal and hepatic parameters, was observed within 2 weeks of ATO cessation. The recovery time for organ impairment in this patient was consistent with those of other drug-induced rhabdomyolysis cases [
].
Conclusions
We reported a rare and severe adverse effect of ATO. The early identification of the condition is crucial to withdraw the causative agents. We conclude that ATO-induced rhabdomyolysis is a potential cause of serious metabolic derangement and multi-organ impairment.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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