Predictive factors of all-trans-retinoic acid related complications during induction therapy for acute promyelocytic leukemia

Abstract

Background: The combination of all-trans-retinoic acid (ATRA) and chemotherapy has made acute promyelocytic leukemia (APL) a highly curable leukemia. However, several complications are reported with this treatment the most serious and life threatening being Retinoic Acid Syndrome (RAS). We aimed at identifying factors that could predict complications caused by ATRA during induction treatment of APL.

Patients: Forty-two patients with confirmed APL (by t(15;17) and/or PML/RARA) treated at our institution (University hospital of Tunis) between January 1998 and June 2006 using two consecutive protocols: European APL93 trial (24 patients) until February 2004 and Spanish PETHEMA LPA99 trial (18 patients) more recently. Induction regimen consisted of ATRA 45 mg/m²/d until CR combined to DNR 60 mg/m²/d×3+Cytarabine 200 mg/m²/d×7 (APL93) and Idarubicin 12 mg/m² d2, 4, 6, 8 (LPA99). Prednisone (0·5 mg/kg d1–d15) was added if WBC >10×10⁹/L to prevent RAS in LPA 99.

Results: Median age was 36 yr (7–64 yr), M/F=16/26 (0·61), median WBC was 2·4×10⁹/L (range 0·6–100×10⁹/L). WBC >10×10⁹/L was noted in 14 patients (33%). Additional cytogenetic abnormalities were seen in 12/42 (28%). Median body mass index (BMI=weight/height²:N 20–25) was 24 kg/m² (range 16–40 kg/m²), BMI >30 was noted in nine patients (8F and 1M). Thirty-three patients achieved CR (78·57%):18/24 (75%) in APL93 versus 15/18 (83%) in LPA99. Nine patients (21·42%) had early death. Causes of early death were: RAS (6) and CNS hemorrhage (3). Complications due to ATRA were: RAS (10), Scrotal ulcerations (3), Sweet syndrome (2), Perineal ulcerations (1), and Pseudotumor cerebri (1). Prognostic factors for complications of ATRA (Fisher exact test) were: BMI >35 (p=0·055), induction treatment without cytarabine (LPA99 trial) (p=0·047), whereas age (p=0·74), gender (p=0·51), initial WBC (p=0·47), and additional cytogenetic abnormalities (p=0·83) were not predictive. Retinoic Acid Syndrome was more reported in patients with initial WBC >10×10⁹/L (p=0·08).

Conclusion: We found high BMI (>35) in female and treatment without Cytarabine to increase the risk of developing complications with ATRA.

Keywords:

• APL
• ATRA
• INDUCTION
• COMPLICATIONS