Survival Trends in Primary Myelodysplastic Syndromes: A Comparative Analysis of 1000 Patients By Year of Diagnosis and Treatment

 

Background: Over the last decade there have been three FDA-approved agents available for the treatment of myelodysplastic syndromes (MDS); azacitidine was approved in 2004 for all subtypes of MDS; lenalidomide in 2005 for MDS with del(5q); and decitabine in 2006 for intermediate/high risk MDS. However the ability of these drugs to improve survival outside of clinical trials remains controversial (Neukirchen J, Leuk Res 2015, Bernal T, Leukemia 2015).

Objectives:

i)        Evaluate trends in overall survival (OS) and leukemic transformation (LT) rate amongst primary MDS patients (pts) by year of diagnosis and,

ii)      Evaluate trends in OS by treatment received.

Methods: The Mayo Clinic database was used to identify pts with primary MDS in whom bone marrow histologic and cytogenetic information was obtained at the time of diagnosis. WHO criteria were used for MDS diagnosis and LT. A comparative analysis was performed based on year of diagnosis commensurate with the approval of the aforementioned drugs (Group 1- diagnosis prior to the year 2000, Group 2- year 2001-2004, Group 3- year 2005-2009, and Group 4- year 2010-2014).

Results:

i) Patient characteristics: A total of 1000 pts met the above-stipulated criteria. 85% of pts were above 60 years of age (median 72 years) with 69% being males. The distribution of pts by year of diagnosis was as follows: Group 1 (n=281)(28%), Group 2 (n=250)(25%), Group 3 (n=264)(26%), and Group 4 (n=205 (21%). Median follow-up of our cohort was 27 months (range; 0-300 months) during which time 808 (81%) deaths and 129 (13%) LT were documented.

ii) Comparison of patient characteristics by year of diagnosis: Pts in group 1 and 2 compared with groups 3 and 4 were more likely to present with anemia defined as hemoglobin < 10 g/dl (61%/59% vs 50%/55%)(P=.04). In addition, groups 1 and 2 displayed a higher incidence of RA (5%/4% vs 1% each), and RARS (17%/16% vs 9%/8%), compared to groups 3 and 4 that had a higher incidence of RCMD (37%/44% vs 17%/28%) (P<.001). The IPSS-R risk distribution was not significantly different; 17%  very low, 36% low, 21% intermediate, 15% high and 11% very high risk with median survivals of 72, 43, 24, 18 and 7 months, respectively (P<.001). As expected, a higher proportion of pts in groups 3 and 4 (41% and 57% respectively) received “disease-modifying” therapy including allogeneic transplant and hypomethylating agents as opposed to only 6% and 22% in groups 1 and 2 respectively (P<.001).

iii)Trends in OS and LT rate by year of diagnosis: The median OS of the entire cohort was 30 months, with median OS and LT rates being similar amongst groups 1 through 4 at 31 vs 33 vs 30 vs 27 months (P=.79) (Figure) and 10% vs 16% vs 12% vs 15% (P=.25), respectively.

iv)Trends in OS by treatment received: In univariate analysis survival was significantly better in pts who underwent allogeneic transplant (n=65) with median survival of 55 months vs 26 months for non-transplant pts (P<.001); and among non-transplant lenalidomide-treated pts (n=44) with median survival of 54 months vs 26 months for the remainder of pts (P=.02).  However, these results lost significance on multivariable analysis with the addition of age as a co-variate for transplant pts (P=.28), and IPSS-R as a co-variate for lenalidomide treated pts (P=.10). Excluding transplant pts, pts that received hypomethylating agents (n=158) had similar survival to pts not treated with hypomethylating agents (27 vs 29 months; P=.19, age-adjusted P=.11). In addition, the 54 pts who received other chemotherapeutic agents had similar survival to pts not treated with these agents (33 vs 26 months; P=.57, age-adjusted P=.80). Supportive care alone was utilized in 702 pts that had comparable survival to the 298 pts that received “disease-modifying” therapy (27 months vs 34 months; P=.05, age-adjusted P=.11).

Conclusions: In this single center analysis of 1000 pts with primary MDS, stratified by year of diagnosis, the poor outcome of these pts has not improved over the last two decades, in spite of the significantly higher utilization of “disease-modifying” therapy, including hypomethylating agents since 2005. The lack of improvement in survival with hypomethylating therapy is consistent with recently published results from the Spanish MDS registry (Bernal T, Leukemia 2015). However, our retrospective study is not designed to detect marginal survival benefit, which has thus far been reported in only one clinical trial.