Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic neoplasm: a HARMONY Alliance study.

Journal

Leukemia

ISSN: 1476-5551

Titre abrégé: Leukemia

Pays: England

ID NLM: 8704895

Informations de publication

Date de publication:
05 Aug 2024

Historique:

received: 12 04 2024

accepted: 19 07 2024

revised: 11 07 2024

medline: 6 8 2024

pubmed: 6 8 2024

entrez: 5 8 2024

Statut: aheadofprint

Résumé

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.

Identifiants

DOI: 10.1038/s41375-024-02360-1 PMID: 39103678

pubmed: 39103678

doi: 10.1038/s41375-024-02360-1

pii: 10.1038/s41375-024-02360-1

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Informations de copyright

Références

Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood. 2007;110:4385–95.

doi: 10.1182/blood-2007-03-082404 pubmed: 17726160

Schanz J, Tüchler H, Solé F, Mallo M, Luño E, Cervera J, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30:820–9.

doi: 10.1200/JCO.2011.35.6394 pubmed: 22331955 pmcid: 4874200

Solé F, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Luño E, et al. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Español de Citogenética Hematológica. Br J Haematol. 2000;108:346–56.

doi: 10.1046/j.1365-2141.2000.01868.x pubmed: 10691865

List AF, Bennett JM, Sekeres MA, Skikne B, Fu T, Shammo JM, et al. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. Leukemia. 2014;28:1033–40.

doi: 10.1038/leu.2013.305 pubmed: 24150217

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

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

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

Ades L, Le Bras F, Sebert M, Kelaidi C, Lamy T, Dreyfus F, et al. Treatment with lenalidomide does not appear to increase the risk of progression in lower risk myelodysplastic syndromes with 5q deletion. A comparative analysis by the Groupe Francophone des Myelodysplasies. Haematologica. 2012;97:213–8.

doi: 10.3324/haematol.2011.045914 pubmed: 21993675 pmcid: 3269480

Sanchez-Garcia J, Del Canizo C, Lorenzo I, Nomdedeu B, Luno E, de Paz R, et al. Multivariate time-dependent comparison of the impact of lenalidomide in lower-risk myelodysplastic syndromes with chromosome 5q deletion. Br J Haematol. 2014;166:189–201.

doi: 10.1111/bjh.12876 pubmed: 24716538

Kuendgen A, Lauseker M, List AF, Fenaux P, Giagounidis AA, Brandenburg NA, et al. Lenalidomide does not increase AML progression risk in RBC transfusion-dependent patients with Low- or Intermediate-1-risk MDS with del(5q): a comparative analysis. Leukemia. 2013;27:1072–9.

doi: 10.1038/leu.2012.369 pubmed: 23257782 pmcid: 3650492

Komrokji RS, List AF. Short- and long-term benefits of lenalidomide treatment in patients with lower-risk del(5q) myelodysplastic syndromes. Ann Oncol. 2016;27:62–8.

doi: 10.1093/annonc/mdv488 pubmed: 26504152

Figaro MK, Clayton W, Usoh C, Brown K, Kassim A, Lakhani VT, et al. Thyroid abnormalities in patients treated with lenalidomide for hematological malignancies: results of a retrospective case review. Am J Hematol. 2011;86:467–70.

doi: 10.1002/ajh.22008 pubmed: 21544854

Zeidan AM, Gore SD, McNally DL, Baer MR, Hendrick F, Mahmoud D, et al. Lenalidomide performance in the real world: patterns of use and effectiveness in a Medicare population with myelodysplastic syndromes. Cancer. 2013;119:3870–8.

doi: 10.1002/cncr.28298 pubmed: 23922173

Dimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, et al. A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood. 2012;119:2764–7.

doi: 10.1182/blood-2011-08-373514 pubmed: 22323483

Rollison DE, Shain KH, Lee J-H, Hampras SS, Fulp W, Fisher K, et al. Subsequent primary malignancies and acute myelogenous leukemia transformation among myelodysplastic syndrome patients treated with or without lenalidomide. Cancer Med. 2016;5:1694–701.

doi: 10.1002/cam4.721 pubmed: 27098006 pmcid: 4944897

Scharenberg C, Giai V, Pellagatti A, Saft L, Dimitriou M, Jansson M, et al. Progression in patients with low- and intermediate-1-risk del(5q) myelodysplastic syndromes is predicted by a limited subset of mutations. Haematologica. 2017;102:498–508.

doi: 10.3324/haematol.2016.152025 pubmed: 27884971 pmcid: 5394951

Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011;29:1971–9.

doi: 10.1200/JCO.2010.31.8576 pubmed: 21519010

Mossner M, Jann JC, Nowak D, Platzbecker U, Giagounidis A, Götze K, et al. Prevalence, clonal dynamics and clinical impact of TP53 mutations in patients with myelodysplastic syndrome with isolated deletion (5q) treated with lenalidomide: results from a prospective multicenter study of the German MDS study group (GMDS). Leukemia. 2016;30:1956–9.

doi: 10.1038/leu.2016.111 pubmed: 27133825

Jadersten M, Saft L, Pellagatti A, Gohring G, Wainscoat JS, Boultwood J, et al. Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Haematologica. 2009;94:1762–6.

doi: 10.3324/haematol.2009.011528 pubmed: 19797731 pmcid: 2791931

Giagounidis AaN, Kulasekararaj A, Germing U, Radkowski R, Haase S, Petersen P, et al. Long-term transfusion independence in del(5q) MDS patients who discontinue lenalidomide. Leukemia. 2012;26:855–8.

doi: 10.1038/leu.2011.268 pubmed: 21960245

Vozella F, Latagliata R, Carmosino I, Volpicelli P, Montagna C, Romano A, et al. Lenalidomide for myelodysplastic syndromes with del(5q): how long should it last? Hematol Oncol. 2015;33:48–51.

doi: 10.1002/hon.2134 pubmed: 25950027

Hatzimichael E, Lagos K, Vassou A, Gougopoulou D, Papoudou-Bai A, Briasoulis E. Durable response to lenalidomide in a patient with myelodysplastic syndrome associated with isolated 5q deletion and JAK2 V617F mutation despite discontinuation of treatment. Mol Clin Oncol. 2016;5:23–6.

doi: 10.3892/mco.2016.866 pubmed: 27330758 pmcid: 4906970

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

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

Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.

doi: 10.1182/blood-2009-03-209262 pubmed: 19357394

Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.

doi: 10.1182/blood-2012-03-420489 pubmed: 22740453 pmcid: 4425443

Santini V, Giagounidis A, Pelligra CG, Franco-Villalobos C, Tang D, Morison J, et al. Impact of lenalidomide treatment on overall survival in patients with lower-risk, transfusion-dependent myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk. 2022;22:e874–e83.

doi: 10.1016/j.clml.2022.05.001 pubmed: 35710702

Ribezzo F, Snoeren IAM, Ziegler S, Stoelben J, Olofsen PA, Henic A, et al. Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome. Leukemia. 2019;33:1759–72.

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

Saußele S, Richter J, Hochhaus A, Mahon FX. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia. 2016;30:1638–47.

doi: 10.1038/leu.2016.115 pubmed: 27133824 pmcid: 4980559

Sperling AS, Guerra VA, Kennedy JA, Yan Y, Hsu JI, Wang F, et al. Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms. Blood. 2022;140:1753–63.

doi: 10.1182/blood.2021014956 pubmed: 35512188 pmcid: 9837415

López Cadenas F, Lumbreras E, González T, Xicoy B, Sánchez-García J, Coll R, et al. Evaluation of Lenalidomide (LEN) Vs placebo in non-transfusion dependent low risk del(5q) MDS patients. Final results of Sintra-REV phase III international multicenter clinical trial. Blood. 2022;140:1109–11.

doi: 10.1182/blood-2022-168718