Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial

Abstract

This prospective phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for >8 weeks and a transfusion need of ⩾4 units over 8 weeks were included. Aza 75 mg m−2 d−1, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ⩾one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza+Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n=3) and DNMT3A (n=4) were only observed in non-responders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations.

A randomized phase II trial of azacitidine +/- epoetin- in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents

“…Overall survival at 3 years in the present trial was 72.1% and 66.8% in the AZA arm and in the AZA plus EPO arm, respectively. It was similar, but with longer follow-up, than previously reported in a phase II trial with decitabine 21 and with azacitidine in the Nordic trial, 11 where median OS survival was not reached after 14.6 and 30 months, respectively. Recent USA retrospective data reported a median OS of 16 months after HMA failure in lower-risk MDS.…”

“…lower than the 45% and 44% RBC-TI rates previously reported by other groups in unselected lower-risk MDS. 6,8,12 Explanations for those differences possibly include the fact that our patients had been selected for their resistance to ESA (which was not a prerequisite in most prior studies), and had a minimal RBC transfusion dependency of 4 units in the 8 weeks prior to the study (the median number of RBC units in the 8 weeks prior to study entry was 6 [4][5][6][7][8][9][10][11][12][13][14]). By comparison, in the Lyons et al trial 8 only 47% of patients were RBC transfusion dependent, and a lower RBC transfusion requirement (less than 2 units/8 weeks) was predictive of RBC-TI achievement with AZA (Online Supplementary Table S4).…”

“…Sylvain Thépot, 1* Raouf Ben Abdelali, 2* Sylvie Chevret, 3 Aline Renneville, 2 Odile Beyne-Rauzy, 4 Thomas Prébet, 5 Sophie Park, 6 Aspasia Stamatoullas, 7 Agnes Guerci-Bresler, 8 Stéphane Cheze, 9 Gérard Tertian, 10 Bachra Choufi, 11 Laurence Legros, 12 Jean Noel Bastié, 13 Jacques Delaunay, 14 Marie Pierre Chaury, 15 Laurence Sanhes, 16 Eric Wattel, 17 Francois Dreyfus, 6 Norbert Vey, …”

“…5,6 In lower-risk MDS, AZA using 5 or 7 day regimens has been reported to yield RBC transfusion independence (RBC-TI) in 30-40% of LR-MDS, 8 although lower response rates to AZA were recently reported in Europe in compassionate use programs 9,10 and in a prospective trial. 11 In a recent report of preliminary results of a 3-day only administration of either AZA or decitabine in 83 evaluable LR-MDS patients, overall response was 61%, but RBC-TI was only 24% in the 38 transfusion dependent patients. 12 In those studies, the resistance of anemia to ESA was not always documented, and the use of AZA has not been prospectively tested in LR-MDS patients selected for their resistance to ESA, an important subset of LR-MDS in daily practice.…”

Treatment of low-risk myelodysplastic syndromes

“…With a median followup of 13 months, median OS has not been reached, and the response rate was 61%. 46 Despite these interesting results, other studies indicate a limited efficacy of HMTs in lower-risk MDS, 47 but apparently activity is more pronounced for SF3B1-mutated cases. 48 An international randomized phase 3 clinical trial with oral azacitidine (cc-486) is ongoing for lower-risk MDS patients who are red blood cell (RBC) transfusion dependent, and concomitant thrombocytopenia (www.clinicaltrials.gov; #NCT01566695).…”