Abstract
Azacitidine (aza) was the first drug to demonstrate a survival benefit for MDS patients (pts) in a randomized trial [Fenaux, Lancet Oncol 2009]. However, only about half of the pts respond and even after achieving complete remission (CR) and with sustained treatment, pts usually relapse. To date, limited data is available on prognostic factors influencing response. Therefore, until now we have analyzed 71 pts with MDS or AML, treated with at least 3 cycles of aza, to identify prognostic indicators that might help to improve treatment decisions.
71 cases were included and characterized by cytogenetics and various molecular assays including sensitive next-generation sequencing for mutations in ASXL1, DNMT3A, EZH2, FLT3-LM, IDH1, IDH2, KRAS, MLL-PTD, NRAS, RUNX1, SF3B1, SRSF2, TET2, and TP53. Median age was 71 (50-84) years. 38 pts had MDS (8 RAEB I, 26 RAEB II, 4 RCMD), 28 had AML (6 dysplastic, 16 sAML/MDS, and 6 tAML/MDS), and 5 pts had MDS/MPD. The IPSS [Greenberg, Blood 1997] was low in one, intermediate (int) 1 in 4, int 2 in 26, and high in 14 pts. Regarding cytogenetic risk groups we found 39 low, 11 int and 20 high risk pts according to IPSS and 49 int vs 21 high risk pts according to AML criteria [Grimwade, Blood 2010].
Median time from diagnosis to treatment was 122 days (0-2348). With a median follow up of 1091 days from start of treatment median survival was 530 days (95% CI 412-874). Pts received a median number of 6 cycles (3-43). 12 pts have received allogeneic transplantation after aza treatment and were censored at that date. To assess the impact of biomarkers, Kaplan-Meier curves and Cox models were estimated from the first day of treatment. Variables were considered for multivariate analysis if the univariate p value was <0.1.
Regarding cytogenetics, 47% of pts exhibited a normal karyotype, 17% had chromosome 7 abnormalities, 13% of karyotypes included del5q, 13% +8, 7% del20q, and 13% were complex. All except one case showed molecular aberrations. The most frequently mutated gene was ASXL1 (42%), followed by RUNX1 (38%), SRSF2 (38%), TET2 (30%), TP53 (18%), DNMT3A (16%), IDH2 (13%), NRAS (13%), EZH2 (12%), SF3B1 (11%), IDH1 (9%), FLT3-ITD (8%), MLL-PTD (7%), and KRAS (6%).
Responses were observed in 33 pts (46%; 4 CR, 3 marrow CR with hematological improvement, 8 partial remission, and 18 HI). When cytogenetic abnormalities were examined, responses were seen in 45% of pts with normal karyotype, in 50% of pts with chromosome 7 aberrations, in 33% with del5q, in 67% with +8, in 56% with complex karyotype, and in all 5 cases with del20q (p=0.02).
Regarding molecular abnormalities response rate was highest in pts with mutations in NRAS (67%) and IDH2 (63%), followed by RUNX1 (56%), ASXL1 (54%), SF3B1 (43%), TP53 (42%), SRSF2 (36%), TET2 (30%), DNMT3A (30%), MLL-PTD (25%), KRAS (25%), FLT3-ITD (20%), IDH1 (17%), and EZH2 (13%). However none of these mutations had a significant impact on response rate, possibly due to limited statistical power. The only p-value <0.1 was seen for EZH2 (p=0.08).
Finally we analyzed the influence of prognostic markers on survival in aza treated pts. In univariate analysis potential candidate variables were: TP53 (p=<0.01, HR: 3.63), cytogenetic group according to AML (p=0.02, HR 2.02) or IPSS (p=0.07, HR (high-low) 1.92, (int-low) 0.86), complex karyotype (p<0.01, HR: 3.17), age [yrs] (p=0.01, HR: 1.08), Hb [g/dl] (p=0.078, HR: 0.836), time to start of aza [yrs] (p=0.01, HR: 0.753), MLL-PTD (p=0.07, HR: 2.87), and AML vs MDS (p=0.01, HR: 2.13).
In multivariate analysis TP53 retained a significant influence on survival (HR: 4.99 [CI: 2.20-11.31], p<0.01), accompanied by age (HR:1.10 [CI: 1.03-1.16], p<0.01), Hb (HR: 0.69 [CI: 0.52-0.93], p=0.01), AML vs. MDS (HR: 2.42 [CI: 1.21-4.84], p=0.01), and time to start of aza (HR: 0.70 [CI: 0.52-0.94], p=0.02).
TP53 mutations negatively influenced survival, although response rates were comparable to other pts. Response duration was often short. However, pts might still benefit from aza treatment, if combination therapy (e.g. lenalidomide in del5q and TP53 positive pts) or allogeneic transplantation consolidate and prolong treatment results
After the analysis of 71 pts, TP53 mutations represent the only somatic mutations with a significant negative impact on survival in aza treated pts. The small group of pts with del20q might have higher response rates. The analysis of further pts is ongoing.
Kuendgen:Celgene: Honoraria, Research Funding. Off Label Use: Azacitidine in AML >30% marrow blasts. Lauseker:Celgene: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Albuquerque:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Gattermann:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding. Götze:Celgene Corp: Honoraria.
Author notes
Asterisk with author names denotes non-ASH members.
