Haematologica 2002; 87:(02)ECR08
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ATRA-induced myositis in induction therapy of acute promyelocytic leukemia
Carmen Martínez-Chamorro, Elena Martínez*, Juan José Gil-Fernández, Aránzazu Alonso, Antonio Escudero, José Mª Fernández-Rañada
Hematology and Radiology* Departments, Clínica Rúber, C/ Juan Bravo 49, 28006 Madrid, Spain.

Correspondence: Carmen Martínez-Chamorro, C/ General Oraá, 3-1º, 28006 Madrid, Spain. Telephone number: 34.1/4111917, Fax: 34.1/4111853. E-Mail: m-chamorro@navegalia.com
We report a case of isolated myositis induced by all-trans retinoic acid (ATRA) in the induction treatment of acute promyelocytic leukemia (APL) and analyze previously reported cases. Despite its rareness, features that may allow its recognition are lower extremities involvement, commonly bilateral, onset during 2nd-4th week of therapy, frequent association with Sweet's syndrome and rapid response to corticosteroids.
A 28-year-old woman with an unremarkable past medical history was diagnosed as having typical hypergranular acute promyelocytic leukemia (APL) (M3 by FAB classification) with disseminated intravascular coagulation and typical 15; 17 translocation in June 2001. Induction treatment with all-trans retinoic acid (ATRA) (45 mg/m2/p.o./daily) and idarubicin (12 mg/m2/i.v./daily/days 2, 4, 6 and 8) was started. Plasma, platelet and fibrinogen transfusions were supported until resolution of APL-associated coagulopathy. On day 11 she presented febrile neutropenia with progressive severe oral mucositis. She was empirically treated with sequential meropenem, amikacin, acyclovir and amphotericin B, with fever and symptom resolution from day 16. No pathogenic organisms were isolated on repeated blood and urine cultures. On day 23 she complained of severe bilateral symmetric pain on the lateral upper portion of her lower legs. Physical examination only revealed slight tenderness and firmness in the affected muscles. She did not develop fever, cutaneous lesions, arthralgias nor other symptoms. Repeated creatine kinase, lactate dehydrogenase and aldolase values were normal. Magnetic resonance (MR) imaging demonstrated bilateral focal areas of increased T2 signal intensity within extensor muscle compartments, mainly in tibialis anterior muscles and less prominent within peroneal muscles. Thickening of adjacent fascia with associated subcutaneous edema was also noted (Figure 1). A working diagnosis of ATRA-induced myositis was made. An infective origin was ruled out. ATRA was discontinued and dexamethasone (8 mg/12 hr/i.v.) was introduced on day 24, with prompt relief of the pain. Dexamethasone was discontinued on day 26 and ATRA restarted on day 29 with good tolerance. A bone marrow aspirate obtained on day 31 showed a morphologic and cytogenetic complete remission.
ATRA has became standard induction therapy for APL. Muscular involvement associated with ATRA therapy in APL has only been described in three reports including five patients: in four cases associated with Sweet's syndrome or acute febrile neutrophilic dermatosis1-3 and in the other patient with isolated myositis without cutaneous lesions,3 as the case we report. Table 1 summarizes the patients' main characteristics. Interestingly, our patient did not develop fever, in contrast to the other reported cases. Median time of onset of muscular symptoms from beginning of induction with ATRA was 18 days (range 9-23). All reported ATRA-induced myositis involved lower extremities, frequently being bilateral (4 / 6 patients). MR showed signs consistent with myositis and fascitis. As typically occurs in Sweet's syndrome, all patients rapidly responded to a short course of corticosteroids and discontinuation of ATRA therapy without recurrence of symptoms; in one case4 ATRA was not even discontinued. In summary, although ATRA-induced musculoskeletal involvement in the induction treatment of APL is rare, it has distinctive clinical features and MR findings that should allow its recognition in order to initiate prompt steroid therapy. It should be suspected in case of lower extremities myalgias and MR signs of myositis, associated or not with Sweet's syndrome, in patients with APL during induction treatment with ATRA. It shares some characteristics with ATRA-induced Sweet's syndrome4-9 and both frequently coexist.1-3 In fact, they might be part of the same inflammatory spectrum.

References

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