VERY LONG-TERM RESULTS OF ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE THERAPY IN NON-HIGH RISK ACUTE PROMYELOCYTIC LEUKEMIA: LATEST UPDATE OF THE ITALIAN-GERMAN APL0406 RANDOMIZED TRIAL
Author(s): ,
Laura Cicconi
Affiliations:
Biomedicine and Prevention, University Tor Vergata,Rome,Italy
,
Uwe Platzbecker
Affiliations:
Universitatsklinikum Carl Gustav Carus der Technischen Universitat Dresden,Dresden,Germany
,
Giuseppe Avvisati
Affiliations:
University Campus Biomedico,Rome,Italy
,
Francesca Paoloni
Affiliations:
Gruppo Italiano Malattie Ematologiche dell’Adulto Central Office,Rome,Italy
,
Christian Thiede
Affiliations:
Universitatsklinikum Carl Gustav Carus der Technischen Universitat Dresden,Dresden,Germany
,
Marco Vignetti
Affiliations:
Gruppo Italiano Malattie Ematologiche dell’Adulto Central Office,Rome,Italy
,
Paola Fazi
Affiliations:
Gruppo Italiano Malattie Ematologiche dell’Adulto Central Office,Rome,Italy
,
Felicetto Ferrara
Affiliations:
Cardarelli Hospital,Naples,Italy
,
Mariadomenica Divona
Affiliations:
Policlinico Tor Vergata,Rome,Italy
,
Francesco Albano
Affiliations:
University of Bari,Bari,Italy
,
Fabio Efficace
Affiliations:
Gruppo Italiano Malattie Ematologiche dell’Adulto Central Office,Rome,Italy
,
Marco Sborgia
Affiliations:
U.O. di Ematologia Clinica,Pescara,Italy
,
Eros Di Bona
Affiliations:
San Bortolo Hospital,Vicenza,Italy
,
Massimo Breccia
Affiliations:
University La Sapienza,Rome,Italy
,
Erika Borlenghi
Affiliations:
U.O. di Ematologia, Spedali Civili,Brescia,Italy
,
Roberto Cairoli
Affiliations:
Ospedale Niguarda, Ca’ Granda,Milan,Italy
,
Alessandro Rambaldi
Affiliations:
Azienda Opsedaliera Papa Giovanni XXIII,Bergamo,Italy
,
Lorella Melillo
Affiliations:
Casa Sollievo della Sofferenza Hospital, IRCCS,San Giovanni Rotondo,Italy
,
Giorgio La Nasa
Affiliations:
Centro Trapianti Midollo Osseo, Ospedale R. Binaghi,Cagliari,Italy
,
Walter Fiedler
Affiliations:
University Hospital Hamburg-Eppendorf,Hamburg,Germany
,
Peter Brossart
Affiliations:
Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie,Bonn,Italy
,
Bernd Hertenstein
Affiliations:
Klinikum Bremen Mitte,Bremen,Germany
,
Helmut R Salih
Affiliations:
University Hospital Tubingen,Tubingen,Germany
,
Ombretta Annibali
Affiliations:
University Campus Biomedico,Rome,Italy
,
Mohammed Wattad
Affiliations:
Kliniken Essen-Sued,Essen,Germany
,
Michael Lubbert
Affiliations:
University Medical Center,Freiburg,Germany
,
Christian H Brandts
Affiliations:
Goethe University ,Frankfurt,Germany
,
Mathias Haenel
Affiliations:
Klinikum Chemnitz gGmbH,Chemnitz,Germany
,
Christoph Rollig
Affiliations:
Universitatsklinikum Carl Gustav Carus der Technischen Universitat Dresden,Dresden,Germany
,
Norbert Schmitz
Affiliations:
Asklepios Klinik St Georg Hamburg,Hamburg,Germany
,
Hartmut Link
Affiliations:
Klinik fur Innere Medizin I, Westpfalz-Klinikum,Keiserslauten,Germany
,
Chiara Frairia
Affiliations:
Hematology-Citta della Salute e della Scienza,Torino,Italy
,
Claudio Fozza
Affiliations:
University of Sassari, Sassari,Sassari,Italy
,
Alfonso Maria D'Arco
Affiliations:
U.O. Medicina Interna e Onco-Ematologica P.O. “Umberto I,Nocera Inferiore,Italy
,
Nicola Di Renzo
Affiliations:
Ospedale Vito Fazzi,Lecce,Italy
,
Agostino Cortellezzi
Affiliations:
Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda Ospedale Maggiore Policlinico and University of Milan,Milan,Italy
,
Francesco Fabbiano
Affiliations:
Ospedali Riuniti Villa Sofia-Cervello,Palermo,Italy
,
Konstanze Dohner
Affiliations:
University Hospital Ulm,Ulm,Germany
,
Arnold Ganser
Affiliations:
Hannover Medical School,Hannover,Germany
,
Hartmut Dohner
Affiliations:
University Hospital Ulm,Ulm,Germany
,
Sergio Amadori
Affiliations:
Gruppo Italiano Malattie Ematologiche dell’Adulto Central Office,Rome,Italy
,
Franco Mandelli
Affiliations:
Gruppo Italiano Malattie Ematologiche dell’Adulto Central Office,Rome,Italy
,
Gerhard Ehninger
Affiliations:
Universitatsklinikum Carl Gustav Carus der Technischen Universitat Dresden,Dresden,Germany
,
Richard F Schlenk
Affiliations:
Department of Medicine, Hematology, Oncology and Rheumatology, Heidelberg University,Heidelberg,Germany
Francesco Lo-Coco
Affiliations:
Biomedicine and Prevention, University Tor Vergata,Rome,Italy
(Abstract release date: 05/17/18) EHA Library. Cicconi L. 06/15/18; 214593; S115
Laura Cicconi
Laura Cicconi
Contributions
Abstract

Abstract: S115

Type: Oral Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 11:30 - 11:45

Location: Room A4

Background
All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination therapy has been recently established as the new standard of care for non-high risk acute promyelocytic leukemia (APL). The Italian-German randomized trial APL0406 has first shown that this chemotherapy-free approach is at least not inferior to the ATRA and chemotherapy-based regimen. In addition to significantly improving EFS, OS and CIR rates, ATRA-ATO resulted in considerably reduced hematologic toxicity as compared to ATRA-chemotherapy, while ATO-specific side effects were frequent but manageable. 

Aims
We hereby provide a very long-term outcome update (median f.up 66.4 months) on the 276 patients enrolled in APL0406 trial. 

Methods
The APL0406 study was a prospective, randomized, multicenter, phase III non-inferiority trial designed by the Italian cooperative group GIMEMA and joined by German groups AMLSG and SAL. Enrolment started in Oct 2007 and was completed in Jan 2013. The present analysis has been performed in February 2018 and data were analyzed following an intent-to-treat principle. The primary objective of the study was EFS. The study enrolled patients aged 18-70 years with newly diagnosed, genetically proven low-intermediate risk APL. Survival distributions were estimated using the Kaplan-Meier method, while cumulative incidence of relapse (CIR) was calculated using the proper nonparametric method. Differences in terms of OS, EFS, and disease-free survival (DFS) were evaluated using the log-rank test. The Gray test was applied to compare cumulative incidence curves. All tests were two-sided.

Results
With a median follow-up of 66.4 months (range: 0.9-116.7), the EFS rate at 72 months for the 263 evaluable patients in the intention-to-treat analysis was 96.6% (95%CI: 93.4-99.9) in the ATRA-ATO group and 77.4% (95%CI: 70.2-85.4) in the ATRA-chemotherapy group (p<0.0001). The total number of events was 28 in the ATRA–chemotherapy (17 relapses, 4 induction deaths, 2 molecular resistant cases and 5 deaths in CR) as compared to the 23 published in the previous report (Platzbecker et al., JCO 2016). By contrast, no further events were recorded in the ATRA-ATO group in the present update in addition to the previously reported ones (2 relapses and 2 deaths in CR). Two cases of therapy-related myeloid neoplasms occured in the ATRA-chemotherapy group, while no cases of secondary malignancies were reported in the ATRA-ATO cohort. DFS rate in the ATRA-ATO group was 96.6% (95%CI: 93.4-99.9) and 79.8% (95%CI: 72.7-87.6) in the ATRA-chemotherapy group (p<0.0001) and CIR was 1.7 (95% CI: 0.0-4.0) and 15.5% (95% CI: 9.0-22.0) in the ATRA-ATO and in the ATRA-chemotherapy groups, respectively (p=0.00015). Finally, the OS rate at 72 months was 98.3% (95% CI: 96.0-100.0) and 89.8% (95% CI, 84.3-95.7) in the respective groups (P=0.0040). Survival outcomes are reported in Figure 1. 

Conclusion
This updated analysis of the APL0406 study establishes also in the very long-term the advantage of ATRA-ATO over ATRA-CHT with respect to both efficacy and safety.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Promyelocytic Leukemia, ALL-trans retinoic acid (ATRA), Arsenic trioxide

Abstract: S115

Type: Oral Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 11:30 - 11:45

Location: Room A4

Background
All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination therapy has been recently established as the new standard of care for non-high risk acute promyelocytic leukemia (APL). The Italian-German randomized trial APL0406 has first shown that this chemotherapy-free approach is at least not inferior to the ATRA and chemotherapy-based regimen. In addition to significantly improving EFS, OS and CIR rates, ATRA-ATO resulted in considerably reduced hematologic toxicity as compared to ATRA-chemotherapy, while ATO-specific side effects were frequent but manageable. 

Aims
We hereby provide a very long-term outcome update (median f.up 66.4 months) on the 276 patients enrolled in APL0406 trial. 

Methods
The APL0406 study was a prospective, randomized, multicenter, phase III non-inferiority trial designed by the Italian cooperative group GIMEMA and joined by German groups AMLSG and SAL. Enrolment started in Oct 2007 and was completed in Jan 2013. The present analysis has been performed in February 2018 and data were analyzed following an intent-to-treat principle. The primary objective of the study was EFS. The study enrolled patients aged 18-70 years with newly diagnosed, genetically proven low-intermediate risk APL. Survival distributions were estimated using the Kaplan-Meier method, while cumulative incidence of relapse (CIR) was calculated using the proper nonparametric method. Differences in terms of OS, EFS, and disease-free survival (DFS) were evaluated using the log-rank test. The Gray test was applied to compare cumulative incidence curves. All tests were two-sided.

Results
With a median follow-up of 66.4 months (range: 0.9-116.7), the EFS rate at 72 months for the 263 evaluable patients in the intention-to-treat analysis was 96.6% (95%CI: 93.4-99.9) in the ATRA-ATO group and 77.4% (95%CI: 70.2-85.4) in the ATRA-chemotherapy group (p<0.0001). The total number of events was 28 in the ATRA–chemotherapy (17 relapses, 4 induction deaths, 2 molecular resistant cases and 5 deaths in CR) as compared to the 23 published in the previous report (Platzbecker et al., JCO 2016). By contrast, no further events were recorded in the ATRA-ATO group in the present update in addition to the previously reported ones (2 relapses and 2 deaths in CR). Two cases of therapy-related myeloid neoplasms occured in the ATRA-chemotherapy group, while no cases of secondary malignancies were reported in the ATRA-ATO cohort. DFS rate in the ATRA-ATO group was 96.6% (95%CI: 93.4-99.9) and 79.8% (95%CI: 72.7-87.6) in the ATRA-chemotherapy group (p<0.0001) and CIR was 1.7 (95% CI: 0.0-4.0) and 15.5% (95% CI: 9.0-22.0) in the ATRA-ATO and in the ATRA-chemotherapy groups, respectively (p=0.00015). Finally, the OS rate at 72 months was 98.3% (95% CI: 96.0-100.0) and 89.8% (95% CI, 84.3-95.7) in the respective groups (P=0.0040). Survival outcomes are reported in Figure 1. 

Conclusion
This updated analysis of the APL0406 study establishes also in the very long-term the advantage of ATRA-ATO over ATRA-CHT with respect to both efficacy and safety.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Promyelocytic Leukemia, ALL-trans retinoic acid (ATRA), Arsenic trioxide

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