In a letter to the editor published in the journal Haematologica, researchers described biomarkers that may be predictive of erythroid response in patients with lower-risk myelodysplastic syndromes (MDS) without a chromosome 5q deletion (del[5q]) who received treatment with lenalidomide and with or without recombinant erythropoietin.
The researchers explained in their report that fewer than half of patients with this condition show a response to combined therapy with lenalidomide and recombinant erythropoietin. The researchers had an aim of identifying biomarkers that may be related to response to treatment with this combination. They postulated that NLRP3 inflammasome-directed pyroptosis may be a factor.
The apoptosis-associated speck-like protein containing a CARD domain (ASC speck) binds to NLRP3. The researchers undertook the current analysis to determine whether the circulating level of ASC speck could function as a biomarker of response in patients with non-del(5q) lower-risk MDS treated with lenalidomide with or without epoetin b.
The research team evaluated 99 patients who had transfusion-dependent, low or intermediate-1 risk (based on International Prognostic Scoring System scores), non-del(5q) MDS and who were enrolled in the phase 3 GFM-Len-Epo-08 trial (ClinicalTrials.gov Identifier: NCT01718379). In this trial, lenalidomide treatment was compared with the combination of lenalidomide with epoetin b, with hematologic improvement of erythroid lineage (HI-E) as the trial’s primary endpoint. Response in this biomarker analysis was analyzed in this patient population with respect to baseline ASC speck and serum erythropoietin levels in peripheral blood plasma, measured using flow cytometry.
From the study population, peripheral blood plasma samples were obtained from 69 patients who had a median age at enrollment of 73 years (range, 46-86). At a response assessment after 16 weeks on study treatment, responders (71.4%) demonstrated elevated baseline ASC speck levels at a higher rate than nonresponders (34.1%; P =.002) did. Responders (28.6%) also showed a lower rate of elevated serum erythropoietin than nonresponders did (60.0%; P =.029). In these analyses, an elevated ASC speck level was defined as being at a level greater than the median, and elevated serum erythropoietin was defined as a level of >200 mU/mL.
Multivariate analysis revealed that both biomarkers showed independent associations with HI-E. For the ASC speck level, the odds ratio for this association was 4.963 (95% CI, 1.445-17.045; P =.011), and for the serum erythropoietin level it was 0.119 (95% CI, 0.25-0.561; P =.007).
“Ineffective erythropoiesis is a hallmark of lower risk MDS, and NLRP3 inflammasome-directed pyroptosis serves as a common underlying driver licensed by both extrinsic proinflammatory cytokine milieu and intrinsic somatic mutations,” the researchers wrote in their report.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Wang C, McGraw KL, McLemore AF, et al. Dual pyroptotic biomarkers predict erythroid response in lower risk non-del(5q) myelodysplastic syndromes treated with lenalidomide and recombinant erythropoietin. Haematologica. Published July 29, 2021. doi:10.3324/haematol.2021.278855