Obesity is Associated with Higher Risk Disease State and Reduced Overall Survival in Females with MDS Free

Myelodysplastic Syndromes (MDS) are amongst the most prevalent hematological malignancies in the elderly, characterized by clonal proliferation of HSPCs and ineffective hematopoiesis with a 30-40% riskof evolution to acute myeloid leukemia (AML)¹. Numerous environmental and lifestyle factors have been implicated in the pathogenesis of MDS. Obesity, defined as a body mass index (BMI) >30 kg/m², has been shown in multiple epidemiological studies to increase the risk of developing MDS^2,3, but has not been studied extensively in the context of MDS prognosis. Our study's primary aim was to elucidate if BMI influences overall survival (OS) in the context of MDS and CMML and to identify factors that may contribute to this phenomenon.

We identified 1,246 patients at Memorial Sloan Kettering Hospital with MDS or CMML from whom 930 patients had BMI values associated with their initial diagnosis, which we used as our investigational cohort to investigate this question. The median OS for the entire cohort was 62.3 months. We divided the patients in 3 groups, BMI <25 kg/m² (healthy weight), BMI 25-30 kg/m² (overweight), and BMI >30 kg/m² (obese). Median OS for BMI <25 kg/m² was 74.8 months, which was significantly increased compared to both median OS for BMI 25-30 kg/m² of 52.4 months (p=0.0119) and median OS for BMI >30 kg/m² of 49.8 months (p=0.0219).

When assessing for covariates that could influence this finding, we compared if these survival differences persisted when dividing between genders. When we compared genders, median OS was no longer significantly influenced by BMI in males, but was in females. The entire female cohort was 353 patients with a median OS of 62 months (CI 46, 104). BMI <25 kg/m² had a median OS of 100 months (CI 64, -), which was significantly increased compared to median OS for BMI >30 kg/m² of 39 months (CI 31, 62, p=0.00445), and median OS for BMI 25-30 kg/m² was 46 months (CI 35, -, p=0.08407), which did not meet the threshold of significance. The hazard ratio in univariable analysis for OS for BMI >30 kg/m² was 2.06 (CI 1.37, 3.09, p<0.001).

Within this female cohort, we investigated characteristics that may contribute to reduced OS seen in MDS patients with obesity (BMI >30 kg/m²) compared to BMI <25 kg/m². Absolute neutrophil count, hemoglobin, bone marrow blast count, age, smoking history, and race were all statistically similar amongst the various BMI cohorts. Compared to patients with BMI <25 kg/m², those with BMI >30 kg/m² had differences in ECOG status scores (p=0.007), significantly lower platelets (133 versus 100, p=0.013), and significantly increased IPSSM scores (0.11 versus 0.54, p=0.018) and IPSSR scores (3.50 versus 4.5, p=0.032). However, when performing multivariable analysis for BMI in relation to ECOG status score and IPSSM score, it was found to be a highly significant independent predictor of OS (p=0.003). Interesting, mutational analysis showed an enrichment of STAG2 mutations, which is associated with worse MDS prognosis, in BMI >30 kg/m² compared to BMI <25 kg/m² (p=0.03).

Our results show that obesity is associated with reduced OS in MDS, particularly in females. Our data also identify that ECOG status scores and IPSSM/IPSSR scores are associated with obesity, but ultimately BMI is an independent predictor of OS. Surprisingly, obesity was associated with higher risk disease state based on both IPSSM and IPSSR scores, and showed a potential association with a specific mutation (STAG2).

References

• Cazzola, M. Myelodysplastic Syndromes. New England Journal of Medicine383, 1358–1374 (2020).

• Poynter, J. N. et al. Obesity over the Life Course and Risk of Acute Myeloid Leukemia and Myelodysplastic Syndromes. Cancer epidemiology40, 134 (2015).

• Ma, X. et al. Obesity, Lifestyle Factors, and Risk of Myelodysplastic Syndromes in a Large US Cohort. American Journal of Epidemiology169, 1492 (2009).