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Findings:A 28-year-old female with relapsing promyelocytic leukemia was placed on trans retinoic acid (90 mg PO q day) following admission to the hospital for worsening neutropenia, and thrombocytopenia. Nine days after admission she developed fever, chills, headache and subconjunctival hemorrhage. Papular hemorrhagic lesions were found on both arms. Blood gas analysis was remarkable for a P02 of 36. A chest radiograph showed a patchy right upper lobe infiltrate. The patient was placed on ceftazidine and vancomycin for broad spectrum antibacterial coverage and acyclovir for possible disseminated herpes zoster. Repeat chest radiographs demonstrated worsening right upper lobe infiltrate, and new areas of infiltrate in the left lower lobe. Erythromycin was added to her antibiotic coverage. The patient's respiratory condition continued to worsen. She was placed on decadron and all antibiotics were discontinued. Serial chest radiographs demonstrated resolution of the pulmonary infiltrates and supplemental oxygen requirement began to decrease. Her skin rash resolved and she was discharged from the hospital seven days after initiation of steroid therapy.
Diagnosis:Complications of retinoic acid therapy
Discussion: All-trans retinoic acid is used to induce remission in patients with acute promyelocytic leukemia.(1,2,3) It stimulates the differentiation of leukemic cells into mature myeloid cells.(2,3) This causes the patients peripheral neutrophil count to rise transiently. Most patients tolerate this well, however, complications have been described. Frankel et al identified a syndrome of complications consisting of fever, respiratory distress, lower extremity edema, pleural and pericardial effusions and pulmonary infiltrates.(4,5) The symptoms developed 2-21 days following initiation therapy in 9 of 35 patients treated with trans retinoic acid. All nine developed findings on chest radiographs including parenchymal infiltrates and pleural effusions. Three deaths occurred and post mortem evaluations revealed pulmonary interstitial infiltration with mature myeloid cells. The cause of these infiltrates is unknown but is presumed secondary to increased capillary permeability, similar to that seen with administration of cytokines (IL-2).(6) Four patients were treated with high dose corticosteroids (dexamethasone 10 mg IV q 12 hours), three of these experienced symptomatic relief and full recovery.
References:
1. Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L: Use of
all-trans retinoic acid in treatment of acute
promyelocytic leukemia. Blood. 1988;72:567-72.
2. Castigne S, Chomienne C, Daniel MT, Ballerini P, Berger R,
Fenaux P: All-trans retinoic acid as a differentiation
therapy for acute promyelocytic leukemia. Clinical
results. Blood 1990;76:1704-9.
3. Warrell RP, Frankel SR, Miller WH, Scheinberg DA, Itri LM,
Hittelman WN, Differentiation therapy of acute
promyelocytic leukemia with retinoic acid. N. Engl. J.
Med 1991;324:1385-93.
4. Frankel SR, Weiss M, Warrell RP: A "retinoic acid
syndrome" in acute promyelocytic leukemia: Reversal by
corticosteroids. Blood 1991; 78:380a.
5. Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP.
The "retenoic Acid Syndrome" in acute promyelocytic
leukemia. Annals of Int. med 1992; 117:292-296.
6. Margolin KA, Raynor AA, Hawkins MJ, Atkins MB, Potcher JP,
Fisher RI: Interleukin 2 and lymphokine activated killer
cell therapy in solid tumors: analysis of Toxicity. J.
Clinical Oncology 1989; 7:486-98.
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