Publication

Abstract : All-trans-retinoic acid (ATRA), a vitamin A derivative is used in the treatment of acute promyelocytic leukemia (APL) and has resulted in significantly improved outcome in these patients. ATRA is used in supraphysiological doses in the management of APL and is associated with few adverse effects. The major side effects include retinoic acid syndrome which consists of fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusion. The cutaneous side effects are dry skin, cheilosis, cutaneous ulcerations and Sweet's syndrome. Cutaneous ulcerations particularly scrotal ulcerations have been reported though rare [1], [2], [3], [4], usually developing at the time of neutrophil recovery. Ulcers involving gastrointestinal tract have been very rarely reported with only two case reports of patients with gastric and duodenal ulcer [5], [6]. Another patient who developed pan-enteritis following ingestion of isotretinoin for nodular acne has been reported [7]. Ulcer involving terminal ileum following ATRA in APL has never been reported till date. We describe a case of ileal ulceration resulting in severe gastrointestinal hemorrhage, in a patient with APL during the induction therapy with ATRA. A 38-year-old woman was admitted with fever and ecchymotic patches for 15 days. There was no bleeding from any other site. Laboratory studies showed increased white blood cell (WBC) count of 133,000/μl, hemoglobin level 9.4 g/dl, and platelet count 16,000/μl. Prothrombin time (PT) was 19 s (normal 12 s), activated partial thromboplastin time (aPTT) was 35 s (normal 30 s), fibrinogen 185 mg/dl. Peripheral smear showed 76% promyelocytes and 16% myeloblasts. Bone marrow aspiration showed 90% promyelocytes strongly positive for myeloperoxidase. The immunophenotype of the promyelocytes was CD13+, CD33+, CD65+, HLADR−, and CD34−. Cytogenetic analysis revealed the presence of t(15;17) translocation. Qualitative polymerase chain reaction (PCR) for the promyelocytic leukemia retinoic acid receptor alpha (PML/RARA) was positive. The patient received all-transretinoic acid (ATRA, 45 mg/m2 daily in two divided doses) and daunorubicin (60 mg/m2 daily for 3 days) along with supportive treatment with platelets and fresh frozen plasma transfusion and intravenous antibiotics for fever (cefaperazone plus sulbactam and amikacin). Patient became afebrile on 8th day. Her coagulation parameters (PT and aPTT) normalized on day 11 and she did not require platelet transfusion after day 12 of induction. On day 19 post induction therapy patient developed severe bleeding per rectum (about 700–800 ml). Investigations at this time revealed total WBC count 3900/μl, absolute neutrophil count 3100/μl, hemoglobin 8.9 g/dl, platelet count of 430,000/μl with normal PT and aPTT. She remained hemodynamically stable and was transfused packed red blood cells. Colonoscopy revealed a large ulcer 2 cm × 1.5 cm in terminal ileum with blood oozing from it. Adrenaline was injected into the ulcer base to achieve hemostasis and ATRA was withheld. Patient continued to have malena for 4 days which then subsided. Biopsy from ulcer showed mild neutrophilic infiltration of lamina propria and did not reveal any evidence of viral inclusion, bacterial, tubercular and fungal infection or malignant cells. Viral serology tests for CMV IgM and HSV 1 and 2 IgM were negative. Stool examination did not reveal ova or cysts and was negative for Clostridial difficle toxin. ATRA was restarted after one week. Repeat colonoscopy after 14 days showed near complete healing of ulcer. Complete hematological remission was obtained on day 34 and patient tolerated further cycles of ATRA without recurrence of gastrointestinal symptoms. The ulceration of terminal ileum coincided with neutrophil recovery. The cause of ATRA induced ulceration is not well known. The lesion may be due to the release of various cytokines e.g. tumor necrosis factor alpha, interleukins (IL1, IL6, and IL8) or to superoxide production leading to tissue damage [8]. Gastric and duodenal ulcers have been reported previously [5], [6] due to hyperhistaminemia caused by differentiation of promyelocytes to basophils, but our patient neither had basophilia nor developed hypotension. Gastrointestinal bleeding in a case of APL may be due to disseminated intravascular coagulation, thrombocytopenia, chemotherapy therapy induced mucositis or due to infections e.g. bacterial (salmonella, shigella, clostridium entero-colitis), viral (CMV or herpitic entero-colitis) or protozoal. Only once these causes have been ruled out, one can implicate ATRA as the cause of gastrointestional ulcer and hemorrhage. ATRA is a very important drug and has improved our management of APL, however we need to be aware of this rare gastrointestinal side effect which may complicate therapy.