Efficacy of ruxolitinib in the treatment of relapsed/refractory large granular lymphocytic leukaemia.
T‐cell lymphoma
chronic T cell leukaemia
clinical studies
lymphoproliferative disease
molecular biology
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
19 Apr 2024
19 Apr 2024
Historique:
revised:
03
04
2024
received:
09
02
2024
accepted:
07
04
2024
medline:
19
4
2024
pubmed:
19
4
2024
entrez:
19
4
2024
Statut:
aheadofprint
Résumé
Large granular lymphocytic (LGL) leukaemia is a rare chronic lymphoproliferative disorder characterized by an expansion of cytotoxic T or NK cells. Despite a usually indolent evolution, most patients will require a treatment over the course of the disease because of cytopenia or symptomatic associated autoimmune disorders. First-line treatment is based on immunosuppressive agents, namely cyclophosphamide, methotrexate and ciclosporin. However, relapses are frequent, and there is no consensus on the management of relapsed/refractory patients. The implication of the JAK/STAT pathway in the pathogenesis of this disease has prompted our group to propose treatment with ruxolitinib. A series of 21 patients who received this regimen is reported here. Ten patients (47.6%) were refractory to the three main immunosuppressive drugs at the time of ruxolitinib initiation. Ruxolitinib yielded an overall response rate of 86% (n = 18/21), including 3 complete responses and 15 partial responses. With a median follow-up of 9 months, the median response duration was 4 months. One-year event-free survival and 1-year overall survival were 57% and 83% respectively. Mild side effects were observed. Biological parameters, notably neutropenia and anaemia, improved significantly, and complete molecular responses were evidenced. This study supports ruxolitinib as a valid option for the treatment of relapsed/refractory LGL leukaemia.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Références
Dinmohamed AG, Brink M, Visser O, Jongen‐Lavrencic M. Population‐based analyses among 184 patients diagnosed with large granular lymphocyte leukemia in the Netherlands between 2001 and 2013. Leukemia. 2016;30(6):1449–1451.
Loughran TP Jr. Clonal diseases of large granular lymphocytes [see comments]. Blood. 1993;82(1):1–14.
Lamy T, Moignet A, Loughran TP Jr. LGL leukemia: from pathogenesis to treatment. Blood. 2017;129(9):1082–1094.
Drillet G, Pastoret C, Moignet A, Lamy T, Marchand T. Large granular lymphocyte leukemia: an indolent clonal proliferative disease associated with an array of various immunologic disorders. Rev Med Interne. 2023;44(6):295–306.
Moignet A, Hasanali Z, Zambello R, Pavan L, Bareau B, Tournilhac O, et al. Cyclophosphamide as a first‐line therapy in LGL leukemia. Leukemia. 2014;28(5):1134–1136.
Lamy T, Loughran TP Jr. How I treat LGL leukemia. Blood. 2011;117(10):2764–2774.
Sanikommu SR, Clemente MJ, Chomczynski P, Afable MG II, Jerez A, Thota S, et al. Clinical features and treatment outcomes in large granular lymphocytic leukemia (LGLL). Leuk Lymphoma. 2018;59(2):416–422.
Dumitriu B, Ito S, Feng X, Stephens N, Yunce M, Kajigaya S, et al. Alemtuzumab in T‐cell large granular lymphocytic leukaemia: interim results from a single‐arm, open‐label, phase 2 study. Lancet Haematol. 2016;3(1):e22–e29.
Zaja F, Baldini L, Ferreri AJ, Luminari S, Grossi A, Salvi F, et al. Bendamustine salvage therapy for T cell neoplasms. Ann Hematol. 2013;92(9):1249–1254.
Osuji N, Matutes E, Tjonnfjord G, Grech H, del Giudice I, Wotherspoon A, et al. T‐cell large granular lymphocyte leukemia: a report on the treatment of 29 patients and a review of the literature. Cancer. 2006;107(3):570–578.
Marchand T, Lamy T, Finel H, Arcese W, Choquet S, Finke J, et al. Hematopoietic stem cell transplantation for T‐cell large granular lymphocyte leukemia: a retrospective study of the European Society for Blood and Marrow Transplantation. Leukemia. 2016;30(5):1201–1204.
Fasan A, Kern W, Grossmann V, Haferlach C, Haferlach T, Schnittger S. STAT3 mutations are highly specific for large granular lymphocytic leukemia. Leukemia. 2013;27(7):1598–1600.
Jerez A, Clemente MJ, Makishima H, Koskela H, LeBlanc F, Peng Ng K, et al. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T‐cell large granular lymphocyte leukemia. Blood. 2012;120(15):3048–3057.
Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012;366(20):1905–1913.
Pastoret C, Desmots F, Drillet G, le Gallou S, Boulland ML, Thannberger A, et al. Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells. Blood. 2021;137(23):3237–3250.
Cheon H, Xing JC, Moosic KB, Ung J, Chan VW, Chung DS, et al. Genomic landscape of TCRalphabeta and TCRgammadelta T‐large granular lymphocyte leukemia. Blood. 2022;139(20):3058–3072.
Olson TL, Cheon H, Xing JC, Olson KC, Paila U, Hamele CE, et al. Frequent somatic TET2 mutations in chronic NK‐LGL leukemia with distinct patterns of cytopenias. Blood. 2021;138:662–673.
Isabelle C, Boles A, Chakravarti N, Porcu P, Brammer J, Mishra A. Cytokines in the pathogenesis of large granular lymphocytic leukemia. Front Oncol. 2022;12:849917.
Bilori B, Thota S, Clemente MJ, Patel B, Jerez A, Afable M II, et al. Tofacitinib as a novel salvage therapy for refractory T‐cell large granular lymphocytic leukemia. Leukemia. 2015;29(12):2427–2429.
Harrison C, Kiladjian JJ, Al‐Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798.
Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, et al. Ruxolitinib for glucocorticoid‐refractory chronic graft‐versus‐host disease. N Engl J Med. 2021;385(3):228–238.
Moignet A, Pastoret C, Cartron G, Coppo P, Lamy T. Ruxolitinib for refractory large granular lymphocyte leukemia. Am J Hematol. 2021;96(10):E368–E370.
Moskowitz AJ, Ghione P, Jacobsen E, Ruan J, Schatz JH, Noor S, et al. A phase 2 biomarker‐driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T‐cell lymphomas. Blood. 2021;138(26):2828–2837.
Rausch C, Rothenberg‐Thurley M, Buerger SA, Tschuri S, Dufour A, Neusser M, et al. Double drop‐off droplet digital PCR: a novel, versatile tool for mutation screening and residual disease monitoring in acute myeloid leukemia using cellular or cell‐free DNA. J Mol Diagn. 2021;23(8):975–985.
Kim D, Park G, Huuhtanen J, Ghimire B, Rajala H, Moriggl R, et al. STAT3 activation in large granular lymphocyte leukemia is associated with cytokine signaling and DNA hypermethylation. Leukemia. 2021;35(12):3430–3443.
Teramo A, Gattazzo C, Passeri F, Lico A, Tasca G, Cabrelle A, et al. Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T‐type large granular lymphocyte leukemia. Blood. 2013;121(19):3843–3854, S3841.
Ravandi F, Aribi A, O'Brien S, Faderl S, Jones D, Ferrajoli A, et al. Phase II study of alemtuzumab in combination with pentostatin in patients with T‐cell neoplasms. J Clin Oncol. 2009;27(32):5425–5430.
Loughran TP Jr, Zickl L, Olson TL, Wang V, Zhang D, Rajala HLM, et al. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia. 2015;29(4):886–894.
Rajala HL, Olson T, Clemente MJ, Lagström S, Ellonen P, Lundan T, et al. The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia. Haematologica. 2015;100(1):91–99.
Moskowitz A, Rahman J, Ganesan N, Hannigan K, Ksanznak K, Bitton H, et al. Ruxolitinib promotes clinical responses in large granular lymphocytic leukemia via suppression of JAK/STAT‐dependent inflammatory cascades. Blood. 2023;142(Suppl 1):183.
Thursky KA, Worth LJ, Seymour JF, Miles Prince H, Slavin MA. Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab. Br J Haematol. 2006;132(1):3–12.
Tadmor T. Purine analog toxicity in patients with hairy cell leukemia. Leuk Lymphoma. 2011;52(Suppl 2):38–42.
Cheson BD, Vena DA, Foss FM, Sorensen JM. Neurotoxicity of purine analogs: a review. J Clin Oncol. 1994;12(10):2216–2228.
Aribi A, Huh Y, Keating M, O'Brien S, Ferrajoli A, Faderl S, et al. T‐cell large granular lymphocytic (T‐LGL) leukemia: experience in a single institution over 8 years. Leuk Res. 2007;31(7):939–945.
Fortune AF, Kelly K, Sargent J, O'brien D, Quinn F, Chadwick N, et al. Large granular lymphocyte leukemia: natural history and response to treatment. Leuk Lymphoma. 2010;51(5):839–845.
Subbiah V, Viny AD, Rosenblatt S, Pohlman B, Lichtin A, Maciejewski JP. Outcomes of splenectomy in T‐cell large granular lymphocyte leukemia with splenomegaly and cytopenia. Exp Hematol. 2008;36(9):1078–1083.
Prince HM. Blocked addiction to IL‐15 for treating T‐LGLL. Blood. 2023;142(15):1258–1260.
Mease P, Charles‐Schoeman C, Cohen S, Fallon L, Woolcott J, Yun H, et al. Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real‐world data. Ann Rheum Dis. 2020;79(11):1400–1413.
Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R, Rivas JL, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316–326.
Brammer JE, Ballen K, Sokol L, Querfeld C, Nakamura R, Mishra A, et al. Effective treatment with the selective cytokine inhibitor BNZ‐1 reveals the cytokine dependency of T‐LGL leukemia. Blood. 2023;142(15):1271–1280.
Wang TT, Yang J, Zhang Y, Zhang M, Dubois S, Conlon KC, et al. IL‐2 and IL‐15 blockade by BNZ‐1, an inhibitor of selective gamma‐chain cytokines, decreases leukemic T‐cell viability. Leukemia. 2019;33(5):1243–1255.
Chan HW, Kurago ZB, Stewart CA, Wilson MJ, Martin MP, Mace BE, et al. DNA methylation maintains allele‐specific KIR gene expression in human natural killer cells. J Exp Med. 2003;197(2):245–255.
Zawit M, Gurnari C, Pagliuca S, Awada H, Maciejewski JP, Saunthararajah Y. A non‐cytotoxic regimen of decitabine to treat refractory T‐cell large granular lymphocytic leukemia. Clin Case Rep. 2021;9(9):e04533.