FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN).
Checkpoint-inhibitor
Disease modification
Fedratinib
Myelofibrosis (MF)
Myeloproliferative Neoplasms (MPN)
Nivolumab
Journal
Annals of hematology
ISSN: 1432-0584
Titre abrégé: Ann Hematol
Pays: Germany
ID NLM: 9107334
Informations de publication
Date de publication:
05 Jul 2024
05 Jul 2024
Historique:
received:
24
05
2024
accepted:
25
06
2024
medline:
5
7
2024
pubmed:
5
7
2024
entrez:
5
7
2024
Statut:
aheadofprint
Résumé
Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.
Identifiants
pubmed: 38967662
doi: 10.1007/s00277-024-05867-w
pii: 10.1007/s00277-024-05867-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Perner F, Perner C, Ernst T, Heidel FH (2019) Roles of JAK2 in aging, inflammation, hematopoiesis and malignant transformation. Cells 8(8):E854. https://doi.org/10.3390/cells8080854
Palandri F, Palumbo GA, Bonifacio M, Breccia M, Latagliata R, Martino B, Polverelli N, Abruzzese E, Tiribelli M, Nicolosi M, Bergamaschi M, Tieghi A, Iurlo A, Sgherza N, Cavazzini F, Isidori A, Binotto G, Ibatici A, Crugnola M, Heidel F, Bosi C, Bartoletti D, Auteri G, Catani L, Cuneo A, Aversa F, Semenzato G, Cavo M, Vianelli N, Benevolo G (2018) Durability of spleen response affects the outcome of ruxolitinib-treated patients with myelofibrosis: results from a multicentre study on 284 patients. Leuk Res 74:86–88. https://doi.org/10.1016/j.leukres.2018.10.001
doi: 10.1016/j.leukres.2018.10.001
pubmed: 30321784
Palandri F, Palumbo GA, Bonifacio M, Elli EM, Tiribelli M, Auteri G, Trawinska MM, Polverelli N, Benevolo G, Tieghi A, Cavalca F, Caocci G, Beggiato E, Binotto G, Cavazzini F, Miglino M, Bosi C, Crugnola M, Bocchia M, Martino B, Pugliese N, Venturi M, Isidori A, Cattaneo D, Krampera M, Pane F, Cilloni D, Semenzato G, Lemoli RM, Cuneo A, Abruzzese E, Branzanti F, Vianelli N, Cavo M, Heidel F, Iurlo A, Breccia M (2023) A prognostic model to predict ruxolitinib discontinuation and death in patients with myelofibrosis. Cancers (Basel). 15(20):5027. https://doi.org/10.3390/cancers15205027
Jayavelu AK, Schnoder TM, Perner F, Herzog C, Meiler A, Krishnamoorthy G, Huber N, Mohr J, Edelmann-Stephan B, Austin R, Brandt S, Palandri F, Schroder N, Isermann B, Edlich F, Sinha AU, Ungelenk M, Hubner CA, Zeiser R, Rahmig S, Waskow C, Coldham I, Ernst T, Hochhaus A, Jilg S, Jost PJ, Mullally A, Bullinger L, Mertens PR, Lane SW, Mann M, Heidel FH (2020) Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms. Nature 588(7836):157–163. https://doi.org/10.1038/s41586-020-2968-3
doi: 10.1038/s41586-020-2968-3
pubmed: 33239784
Lussana F, Cattaneo M, Rambaldi A, Squizzato A (2018) Ruxolitinib-associated infections: a systematic review and meta-analysis. Am J Hematol 93(3):339–347. https://doi.org/10.1002/ajh.24976
doi: 10.1002/ajh.24976
pubmed: 29150886
Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Mesa R, He S, Jones MM, Garrett W, Li J, Pirron U, Habr D, Verstovsek S (2015) Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 372(5):426–435. https://doi.org/10.1056/NEJMoa1409002
doi: 10.1056/NEJMoa1409002
pubmed: 25629741
pmcid: 4358820
Keohane C, Kordasti S, Seidl T, Perez Abellan P, Thomas NS, Harrison CN, McLornan DP, Mufti GJ (2015) JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells. Br J Haematol 171(1):60–73. https://doi.org/10.1111/bjh.13519
doi: 10.1111/bjh.13519
pubmed: 26075866
Parampalli Yajnanarayana S, Stubig T, Cornez I, Alchalby H, Schonberg K, Rudolph J, Triviai I, Wolschke C, Heine A, Brossart P, Kroger N, Wolf D (2015) JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. Br J Haematol 169(6):824–833. https://doi.org/10.1111/bjh.13373
doi: 10.1111/bjh.13373
pubmed: 25824483
Massa M, Rosti V, Campanelli R, Fois G, Barosi G (2014) Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib. Leukemia 28(2):449–451. https://doi.org/10.1038/leu.2013.296
doi: 10.1038/leu.2013.296
pubmed: 24145312
Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, de Jong A, Harel S, DeStefano GM, Rothman L, Singh P, Petukhova L, Mackay-Wiggan J, Christiano AM, Clynes R (2014) Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 20(9):1043–1049. https://doi.org/10.1038/nm.3645
doi: 10.1038/nm.3645
pubmed: 25129481
pmcid: 4362521
Wang SP, Iwata S, Nakayamada S, Sakata K, Yamaoka K, Tanaka Y (2014) Tofacitinib, a JAK inhibitor, inhibits human B cell activation in vitro. Ann Rheum Dis 73(12):2213–2215. https://doi.org/10.1136/annrheumdis-2014-205615
doi: 10.1136/annrheumdis-2014-205615
pubmed: 25157177
Rizzi M, Lorenzetti R, Fischer K, Staniek J, Janowska I, Troilo A, Strohmeier V, Erlacher M, Kunze M, Bannert B, Kyburz D, Voll RE, Venhoff N, Thiel J (2017) Impact of tofacitinib treatment on human B-cells in vitro and in vivo. J Autoimmun 77:55–66. https://doi.org/10.1016/j.jaut.2016.10.005
doi: 10.1016/j.jaut.2016.10.005
pubmed: 27793425
Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, Wolf D, Brossart P (2013) The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 122(7):1192–1202. https://doi.org/10.1182/blood-2013-03-484642
doi: 10.1182/blood-2013-03-484642
pubmed: 23770777
Perner F, Schnoder TM, Ranjan S, Wolleschak D, Ebert C, Pils MC, Frey S, Polanetzki A, Fahldieck C, Schonborn U, Schraven B, Isermann B, Fischer T, Heidel FH (2016) Specificity of JAK-kinase inhibition determines impact on human and murine T-cell function. Leukemia 30(4):991–995. https://doi.org/10.1038/leu.2015.218
doi: 10.1038/leu.2015.218
pubmed: 26242463
Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Jones M, Kornacki D, Sun K, Kantarjian H, C.-I. investigators, (2017) Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol 10(1):55. https://doi.org/10.1186/s13045-017-0417-z
doi: 10.1186/s13045-017-0417-z
pubmed: 28228106
pmcid: 5322633
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger M, Miller C, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner E, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S, Koumenis IL, Sun W, Sandor V, Kantarjian HM (2012) A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366(9):799–807. https://doi.org/10.1056/NEJMoa1110557
doi: 10.1056/NEJMoa1110557
pubmed: 22375971
pmcid: 4822164
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S, Sun W, Sandor V, Kantarjian HM (2013) Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica 98(12):1865–1871. https://doi.org/10.3324/haematol.2013.092155
doi: 10.3324/haematol.2013.092155
pubmed: 24038026
pmcid: 3856961
Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P, Jourdan E, Winton E, Silver RT, Schouten HC, Passamonti F, Zweegman S, Talpaz M, Lager J, Shun Z, Mesa RA (2017) Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol 4(7):e317–e324. https://doi.org/10.1016/S2352-3026(17)30088-1
doi: 10.1016/S2352-3026(17)30088-1
pubmed: 28602585
pmcid: 8207822
Palandri F, Latagliata R, Polverelli N, Tieghi A, Crugnola M, Martino B, Perricone M, Breccia M, Ottaviani E, Testoni N, Merli F, Aversa F, Alimena G, Cavo M, Martinelli G, Catani L, Baccarani M, Vianelli N (2015) Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis. Leukemia 29(6):1344–1349. https://doi.org/10.1038/leu.2015.87
doi: 10.1038/leu.2015.87
pubmed: 25801912
Prestipino A, Emhardt AJ, Aumann K, O'Sullivan D, Gorantla SP, Duquesne S, Melchinger W, Braun L, Vuckovic S, Boerries M, Busch H, Halbach S, Pennisi S, Poggio T, Apostolova P, Veratti P, Hettich M, Niedermann G, Bartholoma M, Shoumariyeh K, Jutzi JS, Wehrle J, Dierks C, Becker H, Schmitt-Graeff A, Follo M, Pfeifer D, Rohr J, Fuchs S, Ehl S, Hartl FA, Minguet S, Miething C, Heidel FH, Kroger N, Triviai I, Brummer T, Finke J, Illert AL, Ruggiero E, Bonini C, Duyster J, Pahl HL, Lane SW, Hill GR, Blazar BR, von Bubnoff N, Pearce EL, Zeiser R (2018) Oncogenic JAK2(V617F) causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med 10(429). https://doi.org/10.1126/scitranslmed.aam7729
Medication Guide INREBIC®(fedratinib) (2019) [cited 2021 September]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212327s000lbl.pd f. Accessed 08.02.2021
Investigator's Brochure Nivolumab (2020) [cited 2021 September]; Available from: https://www.ctc.ucl.ac.uk/TrialDocuments/Uploaded/BMS%20Nivolumab%20IB%20v19_tracked%20changes_17112020_0.pdf . Accessed 19 Jun 2015
Animesh Pardanani RS, Talpaz M, Cortes J, Gotlib J, Jamieson C, Rose S, Berry T, Zhang J, Tefferi A (2020) Long-term safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF), in 62nd ASH annual meeting
Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Jourdan E, Silver RT, Schouten HC, Passamonti F, Zweegman S, Talpaz M, Verstovsek S, Rose S, Shen J, Berry T, Brownstein C, Mesa RA (2020) Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol 95(6):594–603. https://doi.org/10.1002/ajh.25777
doi: 10.1002/ajh.25777
pubmed: 32129512
pmcid: 7317815
Hotchkiss RS, Colston E, Yende S, Crouser ED, Martin GS, Albertson T, Bartz RR, Brakenridge SC, Delano MJ, Park PK, Donnino MW, Tidswell M, Mayr FB, Angus DC, Coopersmith CM, Moldawer LL, Catlett IM, Girgis IG, Ye J, Grasela DM (2019) Immune checkpoint inhibition in sepsis: a phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med 45(10):1360–1371. https://doi.org/10.1007/s00134-019-05704-z
doi: 10.1007/s00134-019-05704-z
pubmed: 31576433
pmcid: 9006384
Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, Masszi T, Mishchenko E, Jourdan E, Vannucchi AM, Drummond MW, Jurgutis M, Kuliczkowski K, Gheorghita E, Passamonti F, Neumann F, Patki A, Gao G, Tefferi A (2015) Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol 1(5):643–651. https://doi.org/10.1001/jamaoncol.2015.1590
doi: 10.1001/jamaoncol.2015.1590
pubmed: 26181658
Watanabe E, Nishida O, Kakihana Y, Odani M, Okamura T, Harada T, Oda S (2020) Pharmacokinetics, pharmacodynamics, and safety of Nivolumab in patients with Sepsis-Induced Immunosuppression: a multicenter, open-label phase 1/2 study. Shock 53(6):686–694. https://doi.org/10.1097/SHK.0000000000001443
doi: 10.1097/SHK.0000000000001443
pubmed: 31513050
Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly JT, Verstovsek S, Dupriez B, Silver RT, Odenike O, Cortes J, Wadleigh M, Solberg LA Jr., Camoriano JK, Gisslinger H, Noel P, Thiele J, Vardiman JW, Hoffman R, Cross NC, Gilliland DG, Kantarjian H, IWGfM Research, and Treatment (2006) International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood 108(5):1497–503. https://doi.org/10.1182/blood-2006-03-009746
doi: 10.1182/blood-2006-03-009746
pubmed: 16675707
Gale RP, Barosi G, Barbui T, Cervantes F, Dohner K, Dupriez B, Gupta V, Harrison C, Hoffman R, Kiladjian JJ, Mesa R, Mc Mullin MF, Passamonti F, Ribrag V, Roboz G, Saglio G, Vannucchi A, Verstovsek S (2011) What are RBC-transfusion-dependence and -independence? Leuk Res 35(1):8–11. https://doi.org/10.1016/j.leukres.2010.07.015
doi: 10.1016/j.leukres.2010.07.015
pubmed: 20692036
Gale RP, Barosi G, Barbui T, Cervantes F, Dohner K, Dupriez B, Gupta V, Harrison C, Hoffman R, Kiladjian JJ, Mesa R, Mc Mullin MF, Passamonti F, Ribrag V, Roboz G, Saglio G, Vannucchi A, Verstovsek S (2012) RBC-transfusion guidelines update. Leuk Res 36(5):659–660. https://doi.org/10.1016/j.leukres.2012.01.023
doi: 10.1016/j.leukres.2012.01.023
pubmed: 22336392
pmcid: 8162055
Pardanani A, Stone RM, Talpaz M, Cortes J, Gotlib J, Jamieson C, Rose SA, Berry T, Zhang J, Tefferi (2020) Long-term safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF). Hemasphere (EHA Annual Meeting Abstracts 2020). (Abstract release date: 05/14/20) EHA Library. 06/12/2020; 293585; EP1096
A’Hern RP (2001) Sample size tables for exact single-stage phase II designs. Stat Med 20(6):859–866. https://doi.org/10.1002/sim.721
doi: 10.1002/sim.721
pubmed: 11252008
Guglielmelli P, Lasho TL, Rotunno G, Mudireddy M, Mannarelli C, Nicolosi M, Pacilli A, Pardanani A, Rumi E, Rosti V, Hanson CA, Mannelli F, Ketterling RP, Gangat N, Rambaldi A, Passamonti F, Barosi G, Barbui T, Cazzola M, Vannucchi AM, Tefferi A (2018) MIPSS70: mutation-enhanced international prognostic score system for transplantation-age patients with primary myelofibrosis. J Clin Oncol 36(4):310–318. https://doi.org/10.1200/JCO.2017.76.4886
doi: 10.1200/JCO.2017.76.4886
pubmed: 29226763
Griesshammer M, Baerlocher GM, Döhner K, Gisslinger H, Koschmieder S, Petrides PE, Lengfelder E (2018) Primäre Myelofibrose (PMF). Onkopedia Leitlinien [cited 2021 August]; Available from: https://www.onkopedia.com/de/onkopedia/guidelines/primaere-myelofibrose-pmf/@@guideline/html/index.html . Accessed 31 Aug 2021
Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, Spoerl S, Ditschkowski M, Ecsedi M, Sockel K, Ayuk F, Ajib S, de Fontbrune FS, Na IK, Penter L, Holtick U, Wolf D, Schuler E, Meyer E, Apostolova P, Bertz H, Marks R, Lubbert M, Wasch R, Scheid C, Stolzel F, Ordemann R, Bug G, Kobbe G, Negrin R, Brune M, Spyridonidis A, Schmitt-Graff A, van der Velden W, Huls G, Mielke S, Grigoleit GU, Kuball J, Flynn R, Ihorst G, Du J, Blazar BR, Arnold R, Kroger N, Passweg J, Halter J, Socie G, Beelen D, Peschel C, Neubauer A, Finke J, Duyster J, von Bubnoff N (2015) Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 29(10):2062–2068. https://doi.org/10.1038/leu.2015.212
doi: 10.1038/leu.2015.212
pubmed: 26228813
pmcid: 4854652
Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socie G, Group RT (2020) Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med 382(19):1800–1810. https://doi.org/10.1056/NEJMoa1917635
doi: 10.1056/NEJMoa1917635
pubmed: 32320566
Ahsan A, La Motte-Mohs R, Hagner P, Thakurta A (2021) Fedratinib demonstrates limited suppression of t- and Natural Killer- (NK) cell activity ex vivo compared with ruxolitinib at clinically relevant doses. Hemasphere (EHA annual meeting abstracts 2021). EHA Library. Ahsan A. 06/09/21; 324785; EP1062
Abou Dalle I, Kantarjian H, Daver N, Masarova L, Pemmaraju N, Bose P, Garcia-Manero G, Verstovsek S (2021) Phase II study of single-agent nivolumab in patients with myelofibrosis. Ann Hematol 100(12):2957–2960. https://doi.org/10.1007/s00277-021-04618-5
doi: 10.1007/s00277-021-04618-5
pubmed: 34350483
Hobbs G, Cimen Bozkus C, Moshier E, Dougherty M, Bar-Natan M, Sandy L, Johnson K, Foster JE, Som T, Macrae M, Marble H, Salama M, El Jamal SM, Zubizarreta N, Wadleigh M, Stone R, Bhardwaj N, Iancu-Rubin C, Mascarenhas J (2021) PD-1 inhibition in advanced myeloproliferative neoplasms. Blood Adv 5(23):5086–5097. https://doi.org/10.1182/bloodadvances.2021005491
doi: 10.1182/bloodadvances.2021005491
pubmed: 34581778
pmcid: 9152999
England JT, Gupta V (2022) Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naive and exposed patients with myelofibrosis. Expert Opin Pharmacother 23(15):1677–1686. https://doi.org/10.1080/14656566.2022.2135989
doi: 10.1080/14656566.2022.2135989
pubmed: 36252265
Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G (2012) JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366(9):787–798. https://doi.org/10.1056/NEJMoa1110556
doi: 10.1056/NEJMoa1110556
pubmed: 22375970