Severe Rhabdomyolysis and Acute Renal Failure Secondary to Use of All–Trans-Retinoic Acid in a Patient with Acute Promyelocytic Leukemia.
Authors: Qian Shenxian , Xie Yaping , Huang Xilian , Gao DaQuan , Liu LiRong , Chen Kuang 
Published: October 2019

Abstract
Abstract 4138
To report a case of All–Trans-Retinoic Acid(ATRA)-induced rhabdomyolysis and acute renal failure in a patient with Acute Promyelocytic Leukemia(APL). A 44-year-old man with underlying APL. Results of the laboratory investigation were as follows: WBC 1.400/dl, hemoglobin 5.7 g/dl and platelets 15000/dl; prothrombin time 15.8 sec, activated partial thromboplastin time 23.4 sec, fibrinogen 75mg/dL (200-590 mg/dL), 3P(+), D-dimer>0.8 mg/dl(<0.025 mg/dl); stool occult blood test (+++), urine occult blood test (+++); normal liver and kidney function tests. Bone marrow aspirate displayed a morphologic and cytogenetic diagnosis of APL (FAB M3) in a hypercellular marrow. Cytogenetic studies confirmed the presence of the characteristic 15;17 translocation in 12 of 20 metaphases, and the characteristic fusion of PML and RARA was detected by PCR. The patient was taking of ATRA (45 mg/m2 / day). The ongoing coagulopathy was treated with appropriate plasma-derived products, and intravenous unfractionated heparin until the coagulation disorder resolved. No complications were observed and coagulation parameters were improved until 17 day from the start of therapy. But on day 18, the patient became febrile and complained of severe pain at the waist, sacrococcygeal and xiphoid. dark orange urine for 3 days, On day 19, he developed nausea, vomiting and oliguria without headache, dyspnea and visual disturbance. Several ecchymosis were noted on his extremities and trunk. Laboratory investigations revealed the following serum levels: CK1043 U/L, WBC 4400/dl, hemoglobin 4.1 g/dl and platelets 12000/dl; prothrombin time 22.8 sec, activated partial thromboplastin time 44.4 sec, fibrinogen 205 mg/dL(200-590 mg/dL), 3P(+), D-dimer>0.8 mg/dl(<0.025 mg/dl); Urine occult blood test (+++); CK-MB 284 U/L (1-25U/L), LDH 7984 U/L (50-240 U/L), Cr 458μmol/L), BUN 18.4mmoL/L(1.70-8.30mmol/L). No obious abnormality is found in the ultrasonography of urinary system, electrocardiogram, and abdominal plain film. A working diagnosis of ATRA-related rhabdomyolysis, DIC and ARF was made. Treatment with ATRA was temporarily discontinued and the patient was given forced alkaline diuresis. Arsenic trioxide and daily treatment with intravenous dexamethasone (10 mg/day) was started. Supportive care including plasma, intravenous unfractionated heparin, platelet transfusions, intravascular volume repletion, intravenous diuretics and sodium bicarbonate was given to improving coagulation and renal parameters.. Nine days later the patient's creatine kinase had dropped to 156 U/L and for 1 month until his renal function recovered .A bone marrow aspirate and biopsy obtained on day 40 confirmed a morphologic and cytogenetic complete remission. There have been a few reports of elevated CK with ATRA. The mechanism of ATRA association with elevated CK levels and its potential to cause rhabdomyolysis and ARF remains speculative, but it is likely multifactorial, with environmental factors and abnormalities in leukocytes, surface integrins and their receptors, and cytokines playing a role. Rhabdomyolysis as a complication of the treatment of APL with ATRA is rare. To our knowledge, there has been only eleven reports involving the musculoskeletal system during treatment with ATRA. And none of them developed DIC and ARF like our patient. All reported cases with ATRA-induced myositis involved lower extremities, frequently being bilateral (7/11 patients). The median time to onset of muscular symptoms from beginning of induction with ATRA was 18 days (9-24 days) in the current literature. Our patient had no recent musculoskeletal injuries, myalgias, surgical procedures, excessive exercise, or intramuscular injections, presented on day 18 with muscle pain, oliguria, elevated CK(exceed 5 times the normal values) and Cr level with abnormal coagulation parameters. The clinical setting of muscle disease and the speedy improvement after ATRA discontinuation and a short course of corticosteroids, led us to the interpretation of rhabdomyolysis because of ATRA therapy.

Conclusion,:
although ATRA-induced rhabdomyolysis in the induction treatment of APL is a very rare complication, rhabdomyolysis - related ARF carries the risk of high morbidity and mortality. The authors recommended CK monitoring in all patients undergoing ATRA therapy, and withdrawal of ATRA when CK levels exceed 5 times the normal values.

Disclosures:
No relevant conflicts of interest to declare.