A myelodysplastic neoplasm with del(5q) treated with luspatercept uncovers unexplored mechanisms of action for the drug

We would like to report the unique case of a 79-year-old man with myelodysplastic syndrome (MDS) with low blasts and isolated 5q deletion (Khoury et al., 2022)1 who was effectively treated with luspatercept. During the previous 10 months, he had received care at another healthcare facility with epoetin alpha and filgrastim, followed by five cycles of azacitidine, with no response, and he presented to us with severe pancytopenia. His past medical history was unremarkable except for heterozygous sickle cell disease. His bone marrow showed dyserythropoiesis, hypolobulated megakaryocytes and micromegakaryocytes, 2% myeloblasts, with no ring-shaped sideroblasts, with cytogenetics being 45,X,-Y,del(5)(q12q33)[12]/45,X,-Y[8] and no genomic alterations by next-generation sequencing. The revised International Prognostic Scoring System score was 3.5 (intermediate risk). The patient was started on lenalidomide at 10 mg qd for 21 days in 28-day cycles, along with deferasirox and filgrastim but due to ongoing grade 4 anaemia, neutropenia and thrombocytopenia, the lenalidomide dose was reduced and, finally, discontinued after 6 months, while he was heavily transfusion-dependent (Figure 1A). He was then started on off-label luspatercept at 1 mg/kg SC, increased after two 21-day cycles to 1.33 mg/kg subcutaneously. After five doses with no need to titrate to the maximum dose, treatment was discontinued due to a normal haemoglobin level and increased platelet and neutrophil counts (Figure 1B). The patient continued to increase his blood counts even off treatment. Fourteen months after luspatercept discontinuation, his marrow showed no dyserythropoiesis, normally maturing megakaryocytes and granulocytes, and blasts <1%, with a normal karyotype (45,X,-Y[30]), requiring no treatment, except for deferasirox (Figure 1C). Myelodysplastic syndrome with del(5q) constitutes approximately 5% of MDS and typically affects women, presenting with erythropoietin-refractory macrocytic anaemia, dyserythropoiesis, normal or elevated PLT counts, giant platelets, hypolobulated micromegakaryocytes and variable neutropenia. It is characterized by prolonged survival and a lower progression rate to acute myelogenous leukaemia,2 as well as high erythroid responses to lenalidomide,3 with frequent dose adjustments due to haematological toxicity.4 Luspatercept is an erythroid maturation agent that enhances late-stage erythropoiesis, reducing aberrant Smad2/3 signalling by binding transforming growth factor beta (TGFβ) superfamily ligands.5 It has been approved for anaemia in erythropoietin-naïve, transfusion-dependent adults with lower risk MDS, but it has not been tested in del(5q) patients.6 Regarding our patient, a trial of luspatercept was deemed well justified, since he did not benefit from a 6-month course of lenalidomide and experienced worsening pancytopenia, requiring regular red blood cell transfusions. In conclusion, the above preclinical data on the complex actions of the SMAD–TGFβ pathway on different blood cells as well as the limited clinical data on the effects of luspatercept on inflammatory pathways provide indirect clues that luspatercept's mechanism of action is more complex than a simple enhancement of late-stage erythropoiesis, spanning different haematopoietic cells and pathways that may affect haematopoiesis and inflammation, as a whole. Nevertheless, this data are still inadequate to guide further investigations, outside the context of clinical trials. I.P. performed data analysis and interpretation and wrote the main text. C.-N.K. contributed to drafting and writing the text. D.V., C.S, F.K. and A.A contributed to drafting sections of the document. M.M. reviewed and approved the final version of the document. P.D. coordinated the report, performed abstract and full-text screening, reviewed and revised the main document. This report did not receive any specific grant from funding agencies. None of the authors have a conflict of interest to disclosure. Not applicable to this study. Written informed consent was obtained from the patient for publication of this letter to the editor, a copy of which is available for review by the Senior Editor of British Journal of Haematology. All procedures followed were in accordance with the Helsinki Declaration. In the presence report since there are no photographs of any part of the body that could identify the patient, the IC will not be uploaded. Data that support the findings of this report are available from Prof. Panagiotis Diamantopoulos upon reasonable request. Due to clinical and ethical restrictions, patient identifiable information are not publicly available.