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Myelodysplastic Syndromes
A phase II study of guadecitabine in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure
Ferrata Storti Foundation
Haematologica 2019 Volume 104(8):1565-1571
Marie Sébert,1,2 Aline Renneville,3 Cécile Bally,2 Pierre Peterlin,1,4
Odile Beyne-Rauzy,1,5 Laurence Legros,1,6 Marie-Pierre Gourin,1,7 LaurenceSanhes,1,8 EricWattel,1,9 EmmanuelGyan,1,10 SophiePark,1,11 Aspasia Stamatoullas,1,12 Anne Banos,1,13 Kamel Laribi,1,14 Simone Jueliger,15 Luke Bevan,15 Fatiha Chermat,1 Rosa Sapena,1 Olivier Nibourel,3
Cendrine Chaffaut,16 Sylvie Chevret,16 Claude Preudhomme,3 Lionel Adès,1,2 and Pierre Fenaux,1,2 on behalf of the Groupe Francophone des Myélodysplasies (GFM)
1Groupe Francophone des Myélodysplasies, Paris, France; 2Hématologie Clinique, Hôpital Saint Louis, Paris, France; 3Laboratoire d’Hématologie, CHU de Lille, France; 4CHU de Nantes, France; 5IUCT ONCOPOLE Toulouse, France; 6CHU de Nice, France; 7CHRU de Limoges, France; 8CHU de Perpignan, France; 9CHU Lyon Sud, Lyon, France; 10CHRU de Tours, France; 11CHU de Grenoble, France; 12Centre Henri Becquerel, Rouen, France; 13CH de la Côte Basque, France; 14CHU Côte de Nacre, Caen, France; 15Astex Pharmaceuticals Inc., Cambridge, UK; 16Service de Biostatistiques, Hôpital Saint-Louis, APHP, Paris, France
ABSTRACT
High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high- risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two com- plete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response (P=0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high (P=0.03) primary versus secondary azacitidine failure (P=0.01) and a high rate of demethylation in blood during the first cycle of treatment (P=0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered at clinicaltrials.gov identifier: 02197676)
Introduction
The first generation hypomethylating agents (HMA) azacitidine (AZA) or decitabine are considered to be the reference treatment for high-risk myelodysplas- tic syndromes (MDS) and low blast count acute myeloid leukemia (AML) (<30% marrow blasts) in elderly patients who are not candidates for allogeneic stem cell transplantation (allo-SCT). However, responses are seen in only 50-60% of patients,
Correspondence:
PIERRE FENAUX
pierre.fenaux@aphp.fr
Received: October 5, 2018. Accepted: February 7, 2019. Pre-published: February 7, 2019.
doi:10.3324/haematol.2018.207118
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