Sivelestat relieves respiratory distress refractory to dexamethasone in all-trans retinoic acid syndrome: a report of two cases

Abstract

Treatment with all-trans retinoic acid (ATRA) improves the prognosis of patients with acute promyelocytic leukemia (APL), but ATRA syndrome may occur as a possible fatal side effect, especially in cases refractory to medication or involving pulmonary hemorrhage. We describe two patients with APL who suffered from intracranial hemorrhage. The first patient was a 16-yr-old girl who was treated with ATRA and then developed respiratory distress refractory to treatment with dexamethasone combined with anthracycline-cytarabine cytoreduction therapy. Treatment with Sivelestat, a small molecule inhibitor of neutrophil elastase, achieved rapid improvement in oxygenation and chest radiograph findings, and the patient has been in complete remission for 24 months. The second patient was a 10-yr-old boy in whom pulmonary hemorrhage developed following administration of ATRA, dexamethasone and cytoreduction therapy. Aspiration and administration of Sivelestat improved oxygenation and he remained stable. Hematological improvement was also achieved, but the patient died of brain dysfunction because of cerebral edema accompanied by intracranial bleeding. The two cases suggest that Sivelestat may be effective as an additional agent in the treatment of refractory ATRA syndrome, and, therefore, prospective randomized studies of treatment protocols are warranted.

Fig. 1

(A) A cranial CT-scan showing a high intensity lesion of 7 cm in diameter in the left subcortical region. (B–D) Serial chest radiographs showing progression and resolution of pulmonary infiltrates. (B) Five days after ATRA treatment, a chest radiograph showed bilateral diffuse ground-glass opacity, which was prominent in the right-middle to lower lung fields, and an enlarged cardiac silhouette. (C) Despite withdrawal of ATRA and administration of dexamethasone, daunorubicin and cytarabine, another radiograph on hospital day 6 revealed extensive consolidation. (D) After administration of Silvelestat, the consolidation had almost disappeared on the following morning.

Fig. 2

(A) A radiograph of the chest taken during recovery from general anesthesia, showing hazy perihilar and right upper zone opacities. (B) ATRA, dexamethasone, daunorubicin and cytarabine were administered on hospital day 7, and the patient then became drowsy. A computed tomography scan of the head disclosed multiple high intensity lesions of varying sizes in the brain parenchyma. (C) On hospital day 9, another radiograph showed new consolidations in the bilateral lower lung fields. (D) After administration of Silvelestat and suctioning of a bloody specimen using a bronchoscope, the consolidation diminished in thickness and oxygenation remained stable without suctioning.