ATRA induces CCL expression in APL patients in vitro and in vivo. (A) Primary leukemia cells derived from 5 different APL patients at diagnosis were cultured with ATRA (10−6 M) for 0, 8, and 48 hours CCL mRNA expression was determined at the indicated time points by quantitative PCR. Expression relative to GAPDH is plotted. (B) CCL2 protein levels were determined in supernatant of the leukemic cells at the indicated time points using ELISA. (C) Protein levels of CCLs were determined in plasma of 3 APL patients before and during induction therapy with ATRA (45 mg/m2 per day), idarubicin (Ida, 12 mg/m2 per day on days 2, 4, 6, and 8), and prednisone (PRED, 0.5 mg/kg per day) using ELISA. Patient A (left panel) and patient B (middle panel) had no signs of DS. Patient C (right panel) developed a DS within 24 hours after initiation of induction therapy. (D) Clinical course of APL patient C who developed DS. The patient presented with a high WBC count (8.2 × 109/L). One day after onset of induction therapy, DS manifested with mild respiratory distress, pleural effusion, and diffuse pulmonary infiltrates on chest X-ray. ATRA was discontinued and dexamethasone (10 mg/12 hours) was administered. A peak WBC count of 17.1 × 109/L (black line) was reached 3 days after start of therapy. Although ATRA therapy was discontinued, the patient developed generalized edema, weight gain (gray line), and headache. Respiratory distress aggravated on days 4 to 5, resulting in an increasing need for oxygen supply. High resolution computed tomography on day 6 showed evident signs of interstitial and alveolar pulmonary edema. After DS completely resolved, ATRA was resumed on day 8 at a 20% dose and gradually increased to a 100% dose at day 12. Dexamethasone was continued until day 11.
