Differences in Genomic Patterns and Clinical Outcomes Between African-American and White Patients with Myelodysplastic Syndromes (MDS)

Background:

African-American (AA) patients (pts) have a younger age at diagnosis and worse outcomes compared to whites (WTs) across many cancers, including acute myeloid and lymphoblastic leukemias. This difference may be related to disease biology rather than access to medical care or socioeconomic status. The incidence of MDS and age at diagnosis in national cancer registries in AAs is lower than in WTs. Detailed biological and clinical characteristics and outcome of AA pts with MDS compared to WTs have not been defined.

Methods:

We collected mutational and clinical data on MDS pts diagnosed from 1/2000-1/2012. Next-generation gene-targeted deep sequencing of 62 common gene mutations (selected based on frequencies established in a separate cohort of MDS pts studied by whole exome sequencing) were analyzed as individual mutations and then grouped into several functional pathways which were hypothesized to characterize MDS pathogenesis. International Prognostic Scoring System-Revised (IPSS-R) score was calculated as described previously. Overall survival (OS) was measured from the time of diagnosis to time of death or last follow up. Time-to-event analyses were performed by the Kaplan-Meier method, with curves compared by log rank test. Differences among variables were evaluated by the Fisher’s exact test and Mann-Whitney U test for categorical and continuous variables, respectively.

Results:

Of 341 pts, 44 (13%) were AA. Comparing WTs to AAs, pts had a similar median age (68 for both), absolute neutrophil count (1.6 vs 2.23) X 10⁹/L, hemoglobin (9.7 vs 9.4) g/dL, platelets (93 vs 91) X 10⁹/L, and bone marrow blasts (2% vs 3%), respectively. IPSS-R risk category distribution for WTs and AA was: very low 15% vs 9%, low 35% vs 30%, intermediate 18% vs 18%, high 16% vs 23%, very high 10% vs 18%, and not applicable 6% vs 2%, respectively. Among AA pts, 25% had very poor risk cytogenetics per IPSS-R criteria (complex >3) compared to 10% of WTs (p=.008) which led to 41% of AA pts having high and very high risk IPSS-R scores compared to 26% of WTs (p=.035). Further, WTs were more likely to receive a treatment (86% vs 66%, p <0.001) and allogeneic bone marrow transplant (15% vs 5%) compared to AAs; however, AML transformation rate was similar (21% vs 25%, p= .31, respectively). With a median follow up of 36 months (mo) (range .9-128.5), the median OS for AAs was 17.9 mo vs. 27.5 mo for WTs (p=.03, Figure 1). In a multivariable Cox analysis that include age and IPSS-R, AA pts retained their worse outcome compared to WTs (HR 1.68, CI 1.17-2.41, p= .005). Somatic mutational data were available on 321 pts (24 AAs). Overall, the most frequently mutated genes were: TET2 (16%), SF3B1 (13%), ASXL1 (13%), DNMT3A (10%), BCOR/BCORL1 (10%), STAG2 (10%), U2AF1 (8%), ZRSR2 (7%), and TP53 (5%). AA pts were more likely to have Tp53 (17% vs 4%, p = .04), and ZRSR2 mutations (21% vs 6%, p = .02). As a group, mutations in transcription factors (including SETBP1,RUNX1, BCOR, BCORL1, ETV6, NPM1, and CEBPA) and chromatin modifications (including ASXL1, SUZ12, EZH2, MLL, and KDM6A) were more common in WTs compared to AA pts (p= .02 and .049, respectively).

Conclusion:

In our cohort, AA pts with MDS had worse OS compared to WTs. Adjusting for IPSS-R risk categories and age did not negate this poor outcome. On a molecular level, AAs are more likely to have poor-risk mutations such as TP53, and less likely to have mutations in transcription factors and chromatin modifications pathways, which may have contributed to their inferior outcomes, and suggests that treatments targeting these pathways in AA pts may have less benefit.

Figure 1:

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Overall survival by race

Figure 1:

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Overall survival by race

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