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Guadecitabine in selected MDS and AML after azacitidine failure
Results
Patients’ baseline characteristics
Between August 2014 and January 2016, we enrolled 56 patients in 13 French centers; one patient died from infec- tion before receiving guadecitabine (Table 1 and Figure 1). Of the 56 patients (intent-to-treat population), 66% were males, with a median age of 75 years (range, 70-79). At inclusion, according to WHO classification, 11 (20%) patients had RAEB-1, 31 (55%) had RAEB-2, and 11 (20%) had AML. Thirty-four (61%) patients had very high-risk IPSS-R and 43 (77%) patients were red blood cell transfu- sion-dependent (TD), while ECOG status was >1 in five (9%) patients. The median number of prior AZA cycles was 13 (range 6-23). Forty-one (73%) patients had relapsed after a response to AZA, while 15 (27%) had pri- mary resistance. The median IQR time interval between the HMA failure and study initiation was 50 days (33; 76) (range, 0-251 days).
Forty-nine (87.5%) of the 56 patients had at least one somatic mutation, with a median number of two muta- tions (range 0-7), the most common being ASXL1 (n=14, 25%), RUNX1 (n=12, 21%), TP53 (n=11, 20%), U2AF1
(n=11, 20%), and DNMT3A (n=11, 20%) (Figure 2A). Median variant allele frequency (VAF) of those mutations was 29.5% (Online Supplementary Figure S2). Baseline methylation levels of LINE-1 were similar in blood and bone marrow samples with an average of 73% and 71%, respectively.
Treatment outcomes
Fifty-five patients received at least one cycle of guadecitabine. The median number of treatment cycles received was three (range, 0-27), eight patients having received only one cycle. Most patients received the planned dose in all treatment cycles, but 18 patients had a dose reduction.
Eight of 56 (14.3%) patients responded, including two CR, one PR, three hematologic improvements, and two marrow CR (Table 2). Seven patients had responded by three cycles and one additional patient by six cycles, but we observed no later response (after 9 cycles) in this study. The median duration of response was 11.5 months (95%CI: 9; not available) (Figure 3B), and response was longer than 12 months in four patients (13, 19, 21, 31 months, respectively).
Median overall survival was 7.1 months [95%CI: (5.6;11.8)] with a one-year survival of 33% (95%CI: 22.9;48.4) (Figure 4A). Responders to guadecitabine had a median OS of 17.9 months, and three patients had >2-year OS (24, 34, and 42 months, respectively). Forty-nine patients had died, because of progressing disease in 28 (57.1%), infection in 13 (26.5%), bleeding in two, heart
Figure 1. Flow chart of the study.
Table 1. Patients’ baseline characteristics.
Age (years)
Sex
Male
Female
ECOG performance status 0
1
2 5(9%)
N=56 (%)
75 [70-79]
37 (66%)
19 (34%)
20 (36%)
31 (55%)
WHO
MDS-MLD CMML MDS-EB-1 MDS-EB-2 AML
IPSS Int-1
Int-2 High NA
IPSS-R
Low/Int High Very High NA
AZA first response
Primary resistance (≥ 6 cycles) Relapse after response
Median n. of AZA cycles
Transfusion dependence
2 (4%)
1 (2%) 11 (20%)
11 (20%)
4 (7%) 27 (48%) 23 (41%) 2 (4%)
4 (7%) 13 (23%) 34 (61%) 5 (9%)
15 (27%) 41 (73%)
13 [9-23]
43 (77%)
Data are median [range] or number (n) / (%); ECOG: Eastern Cooperative Oncology Group; WHO: World Health Organization; RCMD: refractory cytopenia with multilin- eage dysplasia; CMML: chronic myelomonocytic leukemia; RAEB: refractory anemia with excess blasts; RAEB-t: RAEB in transformation; AML: acute myeloid leukemia; IPSS: International Prognostic Scoring System; Int: intermediate; NA: not available; IPSS- R: revised IPSS; AZA: azacitidine.
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