Page 183 - 2022_03-Haematologica-web

Letters to the Editor
activation, identified by the dual pyroptotic biomarkers (ASC specks and erythropoietin), may represent a distinct subset of patients among those with lower-risk MDS who could benefit more from treatment with lenalidomide and recombinant erythropoietin. Mechanistically, lenalido- mide was shown to reduce the steady-state S100A9 pro- duction by peripheral blood mononuclear cells from patients with non-del(5q) MDS and diminished the sup- pression of erythropoietin elaboration by S100A9.13 It could also stabilize the erythropoietin receptor by inhibit- ing the E3 ubiquitin ligase RNF41, to strengthen erythro- poietin receptor signaling.14 Practically, ASC speck is a rel- atively novel biomarker that is not yet available as a rou- tine diagnostic test. Additional studies are required to identify a clinically applicable cutoff to specifically recog- nize lower-risk MDS with inflammasome activation. Patients with these characteristics may also be optimal candidates for NLRP3 or other inflammasome-targeted therapy. In particular, targeting interleukin-1β represents a promising approach given the successful experience of interleukin-1β blockade (e.g., by canakinumab, an inter- leukin-1β neutralizing monoclonal antibody) in condi- tions with NLRP3 inflammasome activation, such as cry- opyrin-associated periodic syndrome and Schnitzler syn- drome.15 We recently launched a phase Ib/II trial (NCT04798339) to evaluate canakinumab plus recombi- nant erythropoietin in lower-risk MDS patients in whom prior treatment with an erythropoiesis-stimulating agent failed. This trial may provide more information on inflam- masome-targeted therapies in MDS patients in the near future.
Chen Wang,1,2 Kathy L. McGraw,2 Amy F. McLemore,2 Rami Komrokji,2 Ashley A. Basiorka,2 Najla Al Ali,2 Jeffrey E. Lancet,2 Eric Padron,2 Olivier Kosmider,3 Michaela Fontenay,3 Pierre Fenaux,4 Alan F. List2#
and David A. Sallman2#
1Department of Internal Medicine, University of South Florida, Morsani College of Medicine, Tampa, FL, USA; 2Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3Service d’Hématologie Biologique, Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Hôpital Cochin, Paris, France and 4Groupe Francophone des Myélodysplasies, Hopital Saint Louis, Paris, France
#AFL and DAS contributed equally as co-senior authors. Correspondence:
DAVID A. SALLMAN - david.sallman@moffitt.org doi:10.3324/haematol.2021.278855
Received: March 29, 2021. Accepted: June 11, 2021. Pre-published: August 5, 2021.
Disclosures: DAS has played a consulting or advisory role for Celyad, Agios, Abbvie, Aprea AB, Bristol-Myers Squibb, Gilead Sciences, Intellia Therapeutics, Kite Pharma, Magenta Therapeutics, Novartis, and Syndax; has sat on speakers' bureau for Agios, Incyte, and Bristol-Myers Squibb; has received research funding from Celgene and Jazz Pharmaceuticals; and is holder of an intellectual property patent for LB-100 in MDS. AFL has received honoraria from Celgene, Aileron Therapeutics and Cellular Biomedicine Group; has played a consulting or advisory role for Celgene, Cellular Biomedicine Group, Aileron Therapeutics, Acceleron Pharma, International Personalized Cancer Center, Precision Biosciences, CTI BioPharma Corp, and Prelude Therapeutics; has received research funding from Celgene;
has received travel, accommodation or other expenses from Celgene and Cellular Biomedicine Group; and is the holder of a Thousand
Talents Award. RSK has stock and other ownership interests in Abbvie; has played a consulting or advisory role for Novartis, Incyte, Bristol-Myers Squibb, Jazz Pharmaceuticals, Abbvie, Geron, and Acceleron Pharma; has sat on speakers' bureau for Jazz Pharmaceuticals, Bristol-Myers Squibb, and Agios; and has received travel, accommodation, or other expenses from Incy6te, Jazz Pharmaceuticals, Bristol-Myers Squibb, and Agios. JFL holds stock and other ownership interests in Arvinas, has played consulting or advisory roles for Jazz Pharmaceuticals, Astellas Pharma, Abbvie,Agios, BerGenBio, Daiichi Sankyo, and ElevateBioResearch; and has received funding from Pfizer. PF has received honoraria and research funding from Celgene. EP has received honoraria from Stemline Therapeutics and Blueprint Medicines; has received research funding from Incyte, Bristol-Myers Squibb, and Kura Oncology and sat on speakers' bureau for Novartis and Taiho Pharmaceutical. KLM has received research funding from Genentech and Celgene. MF has received research funding from Geron.
Contributions: CW conceived the study, analyzed the results, and wrote the manuscript; KLM, AFM and AAB managed the samples and performed the experiments; RK, NAA, JEL and EP involved in study design; OK, MF and PF were involved in study design and provided the samples; AFL and DAS conceived the study, analyzed the results and revised the manuscript.
References
1. List AF, Sun Z, Verma A, et al. Lenalidomide-epoetin alfa versus lenalidomide monotherapy in myelodysplastic syndromes refracto- ry to recombinant erythropoietin. J Clin Oncol. 2021;39(9):1001- 1009.
2. Toma A, Kosmider O, Chevret S, et al. Lenalidomide with or with- out erythropoietin in transfusion-dependent erythropoiesis-stimu- lating agent-refractory lower-risk MDS without 5q deletion. Leukemia. 2016;30(4):897-905.
3. Sallman DA, List A. The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes. Blood. 2019; 133(10):1039-1048.
4. Basiorka AA, McGraw KL, Eksioglu EA, et al. The NLRP3 inflam- masome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016;128(25):2960-2975.
5. Chen L, Chen JY, Huang YJ, et al. The augmented R-loop is a uni- fying mechanism for myelodysplastic syndromes induced by high- risk splicing factor mutations. Mol Cell. 2018;69(3):412-425.
6. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regu- lation and signalling. Nat Rev Immunol. 2016;16(7):407-420.
7. Lu A, Magupalli VG, Ruan J, et al. Unified polymerization mecha- nism for the assembly of ASC-dependent inflammasomes. Cell. 2014;156(6):1193-1206.
8.Rowczenio DM, Pathak S, Arostegui JI, et al. Molecular genetic investigation, clinical features, and response to treatment in 21 patients with Schnitzler syndrome. Blood. 2018;131(9):974-981.
9. Lachmann HJ, Lowe P, Felix SD, et al. In vivo regulation of inter- leukin 1beta in patients with cryopyrin-associated periodic syn- dromes. J Exp Med. 2009;206(5):1029-1036.
10.Basiorka AA, McGraw KL, Abbas-Aghababazadeh F, et al. Assessment of ASC specks as a putative biomarker of pyroptosis in myelodysplastic syndromes: an observational cohort study. Lancet Haematol. 2018;5(9):e393-e402.
11. Lee HM, Kim JJ, Kim HJ, Shong M, Ku BJ, Jo EK. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013;62(1):194-204.
12.Chesnais V, Renneville A, Toma A, et al. Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion. Blood. 2016;127(6):749-670.
13. Cluzeau T, McGraw KL, Irvine B, et al. Pro-inflammatory proteins S100A9 and tumor necrosis factor-α suppress erythropoietin elab- oration in myelodysplastic syndromes. Haematologica. 2017; 102(12):2015-2020.
14. Basiorka AA, McGraw KL, De Ceuninck L, et al. Lenalidomide sta- bilizes the erythropoietin receptor by inhibiting the E3 ubiquitin ligase RNF41. Cancer Res. 2016;76(12):3531-3540.
15. Jesus AA, Goldbach-Mansky R. IL-1 blockade in autoinflammatory syndromes. Annu Rev Med. 2014;65:223-244.
haematologica | 2022; 107(3)
739