Abstract
Abstract
Current strategies for the treatment of patients with acute promyelocytic leukemia provide event-free survival of 75 – 85%. Most multicenter studies have used large doses of anthracyclines and multiple cycles of treatment. Based on the extremely high efficacy of arsenic trioxide (ATO) as single agent re-induction therapy, we conducted a Phase II study which minimized anthracycline exposure and treatment duration in newly diagnosed APL patients. The study design was modified from a previous trial which successfully used a single cycle of consolidation chemotherapy (Am. J. Heme.2005;79:119–27). All patients received ATRA for 60 days with daunorubicin (DRN, 60 mg/m2/dose IV) on days 4, 6, 8 unless urgent cytoreduction was required. Consolidation, begun between days 60 and 67, consisted of cytarabine 0.667 gm/m2/day IV continuous infusion days 1 – 3, DRN 60 mg/m2/dose IV days 1 – 3, and ATO 0.15 mg/kg IV for 30 doses, administered five days per week beginning on day 8 of consolidation on an outpatient basis. A second module of ATO was planned for patients with a positive qualitative rt-PCR for PML-RARα (sensitivity 1/10000) following recovery from consolidation. Patients whose initial WBC was < 10,000 per microliter proceeded to ATRA maintenance given for 15 days every three months for 8 cycles. Patients with WBC counts greater than 10,000 per microliter also received 6-mercaptopurine and methotrexate as part of the maintenance regimen. Forty-five patients received induction therapy. Median age was 50; relapse risk categories (Sanz et al. Blood. 2000;96:1247–1253): Low, 36%; Intermediate, 29%; High, 32%. Four patients expired during induction. Of the 41 remaining patients, 4 patients withdrew consent prior to consolidation due to difficulty traveling to the treatment center. 27/31 patients tested following induction achieved molecular remission at that time point (qualitative rt-PCR). 37 patients received consolidation therapy. No patients expired during consolidation, and no patients required a second module of ATO therapy. Only two events have been recorded in patients who underwent consolidation treatment: one patient with Hemoglobin SC disease expired during maintenance therapy due to intrahepatic sickle crisis, possibly related to methotrexate administration, while one patient developed central nervous system relapse. The table compares overall, event free- and disease-free survival of this series to three recent series, including the ATO-containing arm of C9810. Although median follow-up of the current series is shorter, to date the results are comparable to these three studies which employed more extensive therapy. No cases of secondary MDS or AML have been reported to date. Echocardiographic monitoring pre- and post-induction therapy in 24 patients revealed a decrement in ejection fraction post-induction of ≥ 10% in nine patients, including > 20% in three patients to EF values of 20 – 30%, with biopsyproven anthracycline-induced cardiomyopathy documented by biopsy in two patients, indicating possible cardiac sensitization by ATRA to anthracycline. These data suggest that the inclusion of ATO in primary APL management may allow further minimization of conventional cytotoxic chemotherapy without compromising cure rates, and demonstrate the critical need to determine the minimum curative therapy for APL patients.
Series Total anthracycline dose administered (mg/m2 DRN equivalent)a Age (median) Sanz Relapse risk: High (percent) Follow- up (years, median) Overall survival Disease- Free Survival Event- Free Survival a Daunorubicin= 1. Mitoxantrone = 2.5. Idarubicin = 5. b nr indicates not reported c Selected based on Sanz risk score 90.5 92.9 83.6 Current 360 50 32 1.8 86 87 77 C9710 ATO arm 500 nrb 24 2.4 82 84 nr PETHEMA LPA99 525 – 625c 37 25 5.4 APL2000 Ara-C arm 495 43 46 5.2 90.5 nr 85.6