Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
31 Jan 2024
31 Jan 2024
Historique:
received:
30
06
2023
accepted:
17
01
2024
revised:
11
01
2024
medline:
1
2
2024
pubmed:
1
2
2024
entrez:
31
1
2024
Statut:
aheadofprint
Résumé
A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).
Identifiants
pubmed: 38297135
doi: 10.1038/s41375-024-02161-6
pii: 10.1038/s41375-024-02161-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : 2008-4333
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : 2008-4333
Informations de copyright
© 2024. The Author(s).
Références
Malcovati L, Hellstrom-Lindberg E, Bowen D, Ades L, Cermak J, Del Canizo C, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122:2943–64.
doi: 10.1182/blood-2013-03-492884
pubmed: 23980065
pmcid: 3811170
Jadersten M, Malcovati L, Dybedal I, Della Porta MG, Invernizzi R, Montgomery SM, et al. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol. 2008;26:3607–13.
doi: 10.1200/JCO.2007.15.4906
pubmed: 18559873
Hellström-Lindberg E, van de Loosdrecht A. Erythropoiesis stimulating agents and other growth factors in low-risk MDS. Best Pract Res Clin Haematol. 2013;26:401–10.
doi: 10.1016/j.beha.2013.09.007
pubmed: 24507816
Park S, Greenberg P, Yucel A, Farmer C, O’Neill F, De Oliveira Brandao C, et al. Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review. Br J Haematol. 2019;184:134–60.
doi: 10.1111/bjh.15707
pubmed: 30549002
Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118:3765–76.
doi: 10.1182/blood-2011-01-330126
pubmed: 21753188
Santini V, Almeida A, Giagounidis A, Gröpper S, Jonasova A, Vey N, et al. Randomized phase III study of lenalidomide versus placebo in RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes and ineligible for or refractory to erythropoiesis-stimulating agents. J Clin Oncol. 2016;34:2988–96.
doi: 10.1200/JCO.2015.66.0118
pubmed: 27354480
Toma A, Kosmider O, Chevret S, Delaunay J, Stamatoullas A, Rose C, et al. Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. Leukemia. 2016;30:897–905.
doi: 10.1038/leu.2015.296
pubmed: 26500139
List AF, Sun Z, Verma A, Bennett JM, Komrokji RS, McGraw K, et al. Lenalidomide-epoetin alfa versus lenalidomide monotherapy in myelodysplastic syndromes refractory to recombinant erythropoietin. J Clin Oncol. 2021;39:1001–9.
doi: 10.1200/JCO.20.01691
pubmed: 33439748
pmcid: 8274743
Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–5.
doi: 10.1126/science.1244851
pubmed: 24292625
Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015;523:183–8.
doi: 10.1038/nature14610
pubmed: 26131937
pmcid: 4853910
McGraw KL, Basiorka AA, Johnson JO, Clark J, Caceres G, Padron E, et al. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors. PLoS ONE. 2014;9:e114249.
doi: 10.1371/journal.pone.0114249
pubmed: 25469886
pmcid: 4254997
Basiorka AA, McGraw KL, De Ceuninck L, Griner LN, Zhang L, Clark JA, et al. Lenalidomide stabilizes the erythropoietin receptor by inhibiting the E3 ubiquitin ligase RNF41. Cancer Res. 2016;76:3531–40.
doi: 10.1158/0008-5472.CAN-15-1756
pubmed: 27197154
pmcid: 4911265
Semeraro M, Vacchelli E, Eggermont A, Galon J, Zitvogel L, Kroemer G, et al. Trial watch: lenalidomide-based immunochemotherapy. Oncoimmunology. 2013;2:e26494.
doi: 10.4161/onci.26494
pubmed: 24482747
pmcid: 3897503
Adema V, Palomo L, Toma A, Kosmider O, Fuster-Tormo F, Benito R, et al. Distinct mutational pattern of myelodysplastic syndromes with and without 5q- treated with lenalidomide. Br J Haematol. 2020;189:e133–7.
doi: 10.1111/bjh.16558
pubmed: 32147816
pmcid: 8370477
Santini V, Fenaux P, Giagounidis A, Platzbecker U, List AF, Haferlach T, et al. Impact of somatic mutations on response to lenalidomide in lower-risk non-del(5q) myelodysplastic syndromes patients. Leukemia. 2021;35:897–900.
doi: 10.1038/s41375-020-0961-3
pubmed: 32661294
Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–302.
doi: 10.1182/blood-2002-04-1199
pubmed: 12239137
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–25.
doi: 10.1182/blood-2005-10-4149
pubmed: 16609072
Westers TM, Ireland R, Kern W, Alhan C, Balleisen JS, Bettelheim P, et al. Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group. Leukemia. 2012;26:1730–41.
doi: 10.1038/leu.2012.30
pubmed: 22307178
Sandmann S, de Graaf AO, van der Reijden BA, Jansen JH, Dugas M. GLM-based optimization of NGS data analysis: a case study of Roche 454, Ion Torrent PGM and Illumina NextSeq sequencing data. PLoS ONE. 2017;12:e0171983.
doi: 10.1371/journal.pone.0171983
pubmed: 28222155
pmcid: 5319672
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.
doi: 10.1182/blood-2016-03-643544
pubmed: 27069254
Wells DA, Benesch M, Loken MR, Vallejo C, Myerson D, Leisenring WM, et al. Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation. Blood. 2003;102:394–403.
doi: 10.1182/blood-2002-09-2768
pubmed: 12649150
Della Porta MG, Picone C, Pascutto C, Malcovati L, Tamura H, Handa H, et al. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study. Haematologica. 2012;97:1209–17.
doi: 10.3324/haematol.2011.048421
pubmed: 22315489
pmcid: 3409819
Cremers EMP, Westers TM, Alhan C, Cali C, Visser-Wisselaar HA, Chitu DA, et al. Implementation of erythroid lineage analysis by flow cytometry in diagnostic models for myelodysplastic syndromes. Haematologica. 2017;102:320–6.
doi: 10.3324/haematol.2016.147843
pubmed: 27658438
pmcid: 5286939
List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456–65.
doi: 10.1056/NEJMoa061292
pubmed: 17021321
Giagounidis A, Mufti GJ, Mittelman M, Sanz G, Platzbecker U, Muus P, et al. Outcomes in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study. Eur J Haematol. 2014;93:429–38.
doi: 10.1111/ejh.12380
pubmed: 24813620
pmcid: 4232868
Schuler E, Giagounidis A, Haase D, Shirneshan K, Büsche G, Platzbecker U, et al. Results of a multicenter prospective phase II trial investigating the safety and efficacy of lenalidomide in patients with myelodysplastic syndromes with isolated del(5q) (LE-MON 5). Leukemia. 2016;30:1580–2.
doi: 10.1038/leu.2015.340
pubmed: 26668126
Platzbecker U, Fenaux P, Adès L, Giagounidis A, Santini V, van de Loosdrecht AA, et al. Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials. Blood. 2019;133:1020–30.
doi: 10.1182/blood-2018-06-857102
pubmed: 30404811
pmcid: 7042664
Santini V, Schemenau J, Levis A, Balleari E, Sapena R, Adès L, et al. Can the revised IPSS predict response to erythropoietic-stimulating agents in patients with classical IPSS low or intermediate-1 MDS? Blood. 2013;122:2286–8.
doi: 10.1182/blood-2013-07-512442
pubmed: 24072851
Kerdivel G, Chesnais V, Becht E, Toma A, Cagnard N, Dumont F, et al. Lenalidomide-mediated erythroid improvement in non-del(5q) myelodysplastic syndromes is associated with bone marrow immuno-remodeling. Leukemia. 2018;32:558–62.
doi: 10.1038/leu.2017.305
pubmed: 28972593
Kahn JD, Chamuleau ME, Westers TM, Van de Ven PM, van Dreunen L, van Spronsen M, et al. Regulatory T cells and progenitor B cells are independent prognostic predictors in lower risk myelodysplastic syndromes. Haematologica. 2015;100:e220–2.
doi: 10.3324/haematol.2014.116657
pubmed: 25749828
pmcid: 4450633
van de Loosdrecht AA, Kern W, Porwit A, Valent P, Kordasti S, Cremers EMP, et al. Clinical application of flow cytometry in patients with idiopathic cytopenias and suspected myelodysplastic syndrome: a report of the International Consortium and the European LeukemiaNet Working Group. Cytometry B Clin Cytom. 2023;104:77–86.
doi: 10.1002/cyto.b.22044
pubmed: 34897979
Malcovati L, Stevenson K, Papaemmanuil E, Neuberg D, Bejar R, Boultwood J, et al. SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS. Blood. 2020;136:157–70.
doi: 10.1182/blood.2020004850
pubmed: 32347921
pmcid: 7362582
Meggendorfer M, Haferlach C, Kern W, Haferlach T. Molecular analysis of myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5 reveals a specific spectrum of molecular mutations with prognostic impact: a study on 123 patients and 27 genes. Haematologica. 2017;102:1502–10.
doi: 10.3324/haematol.2017.166173
pubmed: 28642303
pmcid: 5685225
Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science. 2019;366:eaan4673.
doi: 10.1126/science.aan4673
pubmed: 31672865
pmcid: 8050831
Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382:140–51.
doi: 10.1056/NEJMoa1908892
pubmed: 31914241
Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36:1703–19.
doi: 10.1038/s41375-022-01613-1
pubmed: 35732831
pmcid: 9252913
Komrokji R, Melody M, Al Ali N, Chan O, Klimek V, Ball BJ, et al. Treatment outcomes for patients with myelodysplastic syndrome/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis. Leuk Lymphoma. 2022;63:199–204.
doi: 10.1080/10428194.2021.1971217
pubmed: 34448437
Oelschlaegel U, Westers TM, Mohr B, Kramer M, Parmentier S, Sockel K, et al. Myelodysplastic syndromes with a deletion 5q display a characteristic immunophenotypic profile suitable for diagnostics and response monitoring. Haematologica. 2015;100:e93–6.
doi: 10.3324/haematol.2014.115725
pubmed: 25425689
pmcid: 4349286
Duetz C, Westers TM, In ‘t Hout FEM, Cremers EMP, Alhan C, Venniker-Punt B, et al. Distinct bone marrow immunophenotypic features define the splicing factor 3B subunit 1 (SF3B1)-mutant myelodysplastic syndromes subtype. Br J Haematol. 2021;193:798–803.
doi: 10.1111/bjh.17414
pubmed: 33765355
pmcid: 8252736
Weiß E, Walter W, Meggendorfer M, Baer C, Haferlach C, Haferlach T, et al. Identification of a specific immunophenotype associated with a consistent pattern of genetic mutations including SRFS2 and gene expression profile in MDS. Cytometry B Clin Cytom. 2023;104:173–82.
doi: 10.1002/cyto.b.22057
pubmed: 35088567