All‐trans retinoic acid induced cardiac and skeletal myositis in induction therapy of acute promyelocytic leukaemia

All-trans retinoic acid (ATRA)-induced myositis in the induction treatment of acute promyelocitic leukaemia (APL) is a very rare complication and has been reported in only six patients to date (Miranda et al, 1994; Christ et al, 1996; Der Vliet et al, 2000; Martinez-Chamorro et al, 2002). Cardiac involvement has never been described in the context of muscular damage. We report a case of acute myositis with bilateral limb and myocardial involvement. A 45-year-old man was admitted to our department for a typical hyper granular APL. He presented t(15;17) translocation and rar/alpha rearrangement. Intestinal haemorrhage and APL-associated coagulopathy were present. Induction treatment with the AIDA schedule (ATRA 45 mg/m2 o.s., days 1–30 and idarubicin 12 mg/m2/i.v./d, days 2, 4, 6 and 8) was started. Supportive therapy with prednisone, tranexamic acid, platelets and plasma transfusion was used until the coagulation disorder resolved. The patient was also treated with antibiotic prophylaxis, antiviral and antimycotic therapy. No complications were observed until 23 d from the start of therapy, when his white blood cell (WBC) count was 1·1 × 109/l and platelet count was 22 × 109/l . The next day, the patient became febrile and complained of severe bilateral symmetric pain at the front of his thighs. Physical examination showed soft swellings that were hot to the touch. Ultrasonography of bilateral femoral quadricepses revealed a hyperecogenic bilateral area secondary to oedema. Laboratory findings showed an increased WBC count (4·0 × 109/l) with 80% neutrophils, increased muscular enzymes, with creatine kinase (CK) of 432 U/l (normal range (nr) 30–170 U/l), myoglobin 190 ng/ml (nr 17–105 ng/ml). Cardiac enzymes were also significantly elevated, but with no related symptoms. Troponine was 4·9 ng/ml (nr < 0·06 ng/ml) and CK-MB was 19 U/l (nr 2–16 U/l); an electrocardiogram (ECG) showed findings consistent with a postero-lateral ischemia (ST segment elevation in D1 and AVL and ST depression in precordial leads V1,V2); echocardiographic examination showed hypokinesia in postero-lateral walls and the presence of a tiny pericardial effusion. A diagnosis of ATRA-induced skeletal and cardiac myositis was made. ATRA was discontinued on day 26, prednisone (50 mg/d) was continued. In the successive days, the fever and painful muscle involvement disappeared. Muscular and cardiac enzymes normalized after 8 d. The successive cardiac course was uneventful and the ECG became normal after the temporary appearance of negative postero-lateral T waves. No further wall movement abnormalities or pericardial effusion were observed. The WBC count fell to 0·25 × 109/l on day 28, and haematological parameters were normal 4 d later. A bone marrow aspirate, obtained on day 32, showed a morphological and molecular remission. The patient then continued therapy with the consolidation schedules keeping the same dosage of ATRA, with no further complications. This is, to our knowledge, the first case of ATRA-induced cardiac muscular alteration. The absence of coronary risk factors, or of any chest disturbance, the clinical setting of muscle disease and the speedy improvement after ATRA discontinuation, led us to the interpretation of the cardiac findings as myocarditis because of ATRA therapy. The temporary WBC elevation appearing together with the myositis suggests ATRA-induced granulocytic maturation of promyelocitic leukaemic cells and was, in our opinion, the cause of the skeletal and cardiac muscular damage in our patient. This was also demonstrated by the absence of any muscular alterations during consolidation therapy, despite a further course of ATRA. In conclusion this is, to our knowledge, the first case of ATRA-induced cardiac and skeletal myositis and we think that this rare alteration should be included in the ATRA syndrome (Tallman et al, 2000).