Retinoic acid and arsenic trioxide for acute promyelocytic leukemia

TY - JOUR

T1 - Retinoic acid and arsenic trioxide for acute promyelocytic leukemia

AU - Lo-Coco, Francesco

AU - Avvisati, Giuseppe

AU - Vignetti, Marco

AU - Thiede, Christian

AU - Orlando, Sonia Maria

AU - Iacobelli, Simona

AU - Ferrara, Felicetto

AU - Fazi, Paola

AU - Cicconi, Laura

AU - Di Bona, Eros

AU - Specchia, Giorgina

AU - Sica, Simona

AU - Divona, Mariadomenica

AU - Levis, Alessandro

AU - Fiedler, Walter

AU - Cerqui, Elisa

AU - Breccia, Massimo

AU - Fioritoni, Giuseppe

AU - Salih, Helmut R

AU - Cazzola, Mario

AU - Melillo, Lorella

AU - Carella, Angelo M

AU - Brandts, Christian H

AU - Morra, Enrica

AU - von Lilienfeld-Toal, Marie

AU - Hertenstein, Bernd

AU - Wattad, Mohammed

AU - Lübbert, Michael

AU - Hänel, Matthias

AU - Schmitz, Norbert

AU - Link, Hartmut

AU - Kropp, Maria Grazia

AU - Rambaldi, Alessandro

AU - La Nasa, Giorgio

AU - Luppi, Mario

AU - Ciceri, Fabio

AU - Finizio, Olimpia

AU - Venditti, Adriano

AU - Fabbiano, Francesco

AU - Döhner, Konstanze

AU - Sauer, Michaela

AU - Ganser, Arnold

AU - Amadori, Sergio

AU - Mandelli, Franco

AU - Döhner, Hartmut

AU - Ehninger, Gerhard

AU - Schlenk, Richard F

AU - Platzbecker, Uwe

AU - Gruppo Italiano Malattie Ematologiche dell'Adulto

PY - 2013/7/11

Y1 - 2013/7/11

N2 - BACKGROUND: All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.METHODS: We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.RESULTS: Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.CONCLUSIONS: ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

AB - BACKGROUND: All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.METHODS: We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.RESULTS: Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.CONCLUSIONS: ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

KW - Adult

KW - Aged

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Arsenicals

KW - Consolidation Chemotherapy

KW - Disease-Free Survival

KW - Female

KW - Humans

KW - Induction Chemotherapy

KW - Leukemia, Promyelocytic, Acute

KW - Maintenance Chemotherapy

KW - Male

KW - Middle Aged

KW - Neutropenia

KW - Oxides

KW - Thrombocytopenia

KW - Tretinoin

KW - Young Adult

U2 - 10.1056/NEJMoa1300874

DO - 10.1056/NEJMoa1300874

M3 - SCORING: Journal article

C2 - 23841729

VL - 369

SP - 111

EP - 121

JO - NEW ENGL J MED

JF - NEW ENGL J MED

SN - 0028-4793

IS - 2

ER -