All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (As2O3) Combination Therapy Induces High Rates of Durable Molecular Remission in Newly Diagnosed Acute Promyelocytic Leukemia (APL).
Authors: Tsimberidou Apostolia-Maria , Kantarjian Hagop , O’Brien Susan , Garcia-Manero Guillermo , Koller Charles , Jones Daniel , Pierce Sherry , Brandt Mark , Keating Michael , Estey Estey 
Published: October 2019

Background: Although ATRA and anthracyclines provide durable remissions in patients with untreated APL, we have reported that ATRA plus As2O3 may do the same while avoiding “chemotherapy.” However, follow-up of patients treated with ATRA plus As2O3 has been relatively limited, prompting this report.

Methods: From 2/02 to 4/07, 67 patients with untreated APL were given ATRA 45 mg/m2 daily followed by As2O3 0.15 mg/kg IV 1-hr infusion daily starting on D10. Patients with leukocyte counts (WBC) > 10×109/L (low-risk) also received gemtuzumab ozogamicin (GO) 9 mg/m2 on D1 and/or idarubicin 12 mg/m2 on D1-4. Patients in complete remission (CR) received As2O3 0.15 mg/kg IV on D1-5 weekly for 4 weeks on and 4 weeks off and ATRA 45 mg/m2 daily for 2 weeks on and 2 weeks off (for 28 weeks). Polymerase chain reaction (PCR) testing for PML-RARα (sensitivity level, 10−4) was performed every 3 months from CR for at least 2 yrs. Patients with molecular relapse, defined by two sequential positive PCR tests for PML-RARα within 2 wks, received GO 9 mg/m2 once monthly for 3 months in addition to ATRA and As2O3 as in post-remission therapy. If the PCR results subsequently became negative, low-risk patients received no chemotherapy and high-risk patients received a single dose of GO.

Results: The median patient age was 46 yrs (range, 14–81), and 30% were >60 yrs. Thirty-six percent of patients had WBC ≥10×109/L, 54% had coagulopathy, and 27% had Zubrod performance status (PS) > 1. The overall response rate was 91% (CR 90%, CRp 1%). The median time to response was 29 days (range, 19–70). Response rates were higher in patients with PS 0–1 (98% vs. 72%, p=.001), no coagulopathy (100% vs. 83%, p=.02), and LDH <1.5 × upper limit of normal (ULN)(97% vs. 83%, p=.046). The median follow-up in surviving patients is 25 months. Six patients died during induction; 1 died with central nervous system relapse; and 3 died in remission from other metastatic cancers (malignant melanoma, 1; breast, 1; and prostate, 1). The 2-yr survival rate was 84%. Survival rates were higher in patients with PS<1 (p=.0004), no coagulopathy (p=.01), and LDH <1.5×ULN (p=.02). The 2-yr failure-free survival (FFS) rate in responding patients was 92% (Sanz risk: low and intermediate 100%; high, 78%). Four patients relapsed (at 9, 9, 13, and 16 months); molecular relapse preceded hematologic relapse by 21, 23, 38, and 128 days, respectively. None of the remaining patients had evidence of molecular relapse. WBC ≥10×109/L (p=.006), LDH ≥1.5×ULN (p=.02), and high Sanz risk (p=.02) predicted relapse. Molecular remission rates are shown in Table.

Time from CR (months) No. of pts in CR tested PCR negative Negative, % 0 52 2 4 3 45 44 98 6 40 40 100 9 37 35 95 12 33 31 94 15 11 11 100 18 22 22 100 24 20 20 100 30 9 9 100 36 8 8 100 48 3 3 100

Grade 3–4 nonhematologic toxicities were infections (n=18), neurologic (n=5), cardiac arrhythmias (n=4), APL differentiation syndrome (n=4), headache (n=3), renal failure (n=3); mucositis (n=1), rash (n=1), and transaminitis (n=1).

Conclusions: ATRA plus As2O3 results in high rates of CR, molecular remission, FFS, and survival. PCR testing for PML-RARα accurately predicted relapse and should be performed in high-risk patients during the first year after CR.