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Study Characterizes Mutational Pattern of Non-Immune Hemolytic Anemia in MDS

January 18, 2023

February 2023

Brandon May

Brandon May is a medical journalist based in Detroit.

Patients with myelodysplastic syndromes (MDS) and non-immune hemolysis were more likely to have EZH2 and U2AF1 mutations, according to a retrospective, single-center study. The study findings, published in Blood Advances, may have implications for treatment response.

Lead author Rami Komrokji, MD, of Moffitt Cancer Center in Tampa, explained that in patients with MDS, non-immune hemolysis is typically associated with ineffective intramedullary erythropoiesis, but few studies have fully characterized the underlying pathophysiology of hemolysis in MDS and its correlation with treatment responses.

Researchers retrospectively identified 519 patients who presented to a single center with an MDS diagnosis. Serum haptoglobin was measured in these patients at the time of diagnosis or referral. Patients with hemolysis (n=53) were compared with a non-hemolysis group (n=462) with respect to baseline characteristics, treatment response, and survival. Additionally, investigators compared the mutational landscape of MDS in patients with and without hemolysis. Next-generation sequencing panels targeting up to 406 genes were used to perform molecular profiling of all patients.

Approximately one in 10 patients (n=54) had hemolysis, as defined by serum haptoglobin levels below 10 mg/dL. Additional laboratory markers associated with hemolysis that were significantly elevated in the group of patients with and without hemolysis included total bilirubin (1.4 vs. 0.7; p<0.005) and elevated lactate dehydrogenase (p<0.005). Patients with hemolysis were younger (68 vs. 71; p=0.02) and had lower platelet counts (86,000 vs. 135,000; p=0.002) than those without.

Only a small proportion of patients with reduced haptoglobin were Coombs-positive (13% vs. 9% of those with normal haptoglobin; p=0.3), which led the researchers to conclude that hemolysis is not predominantly immune-mediated in MDS. The presence of small paroxysmal nocturnal hemoglobinuria clones was similar in both groups (4% vs. 3%; p=0.7)

No statistically significant differences were observed between the hemolysis and non-hemolysis groups with respect to overall survival (OS). There was a trend toward inferior survival in patients with hemolysis who were in the lower and intermediate Revised International Prognostic Scoring System risk subgroups, but the survival differences between groups were not statistically significant.

Erythropoiesis-stimulating agents (ESAs) were received by 19 patients (35%) with and 130 patients (87.2%) without hemolysis. While patients without hemolysis had a higher hematologic improvement (HI) rate with ESA therapy compared to patients with hemolysis, there was no statistical difference between the groups (30% vs. 16%; p=0.2). At best response with hypomethylating agents, the HI rate was 70% in the hemolysis group versus 45% in the non-hemolysis group (p=0.05).

Patients with hemolysis had significantly more U2AF1 and EZH2 hotspot mutations (p<0.05). Nearly all of the 16 patients in the hemolysis group who harbored U2AF1 mutations harbored a hotspot mutation at serine 34 (94%), while 40% of patients in the non-hemolysis cohort harbored this hotspot mutation. The researchers commented that this finding suggests “the association between U2AF1 and hemolysis is variant specific.”

A limitation of the study was the small number of patients with hemolysis, which the investigators noted may have hindered their ability to identify significant differences between groups regarding measurements such as treatment response, OS, and leukemia-free interval.

The researchers also explained that they “did not capture additional co-mutation patterns involving synchronic canonical mutations of potential interest nor identified whether the size of the dominant clones alluded to ancestral or subclonal ontogenies.”

Despite the study limitations, Dr. Komrokji said the findings may have future clinical implications, particularly if the data are confirmed.

“If we understand further the mechanism of hemolysis and confirm it’s related to a certain molecular profile in the future,” he said, “perhaps there would be likely inhibitors that could be used for the treatment of patients who have this hemolysis profile in MDS.”

Any conflicts of interest declared by the authors can be found in the original article.


Komrokji RS, Aguirre LE, Al-Ali N, et al. U2AF1 and EZH2 mutations are associated with nonimmune hemolytic anemia in myelodysplastic syndromes [published online ahead of print, 2023 Jan 10]. Blood Adv. doi: 10.1182/bloodadvances.2022007504.


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