A prospective single-center study on CNI-free GVHD prophylaxis with everolimus plus mycophenolate mofetil in allogeneic HCT

Henning Schäfer, Jacqueline Blümel-Lehmann, Gabriele Ihorst, Hartmut Bertz, Ralph Wäsch, Robert Zeiser, Jürgen Finke, Reinhard Marks, Henning Schäfer, Jacqueline Blümel-Lehmann, Gabriele Ihorst, Hartmut Bertz, Ralph Wäsch, Robert Zeiser, Jürgen Finke, Reinhard Marks

Abstract

We report a single-center phase I/II trial exploring the combination of everolimus (EVE) and mycophenolate mofetil (MMF) as calcineurin inhibitor (CNI)-free GVHD prophylaxis for 24 patients with hematologic malignancies and indication for allogeneic HCT after a high dose or reduced-intensity ablative conditioning. The study was registered as EudraCT-2007-001892-12 and Clinicaltrials.gov as NCT00856505. All patients received PBSC grafts and no graft failure occurred. 7/24 patients (29%) developed acute grades III and IV GVHD (aGVHD), 16/19 evaluable patients (84%) developed chronic GVHD (cGVHD) of all grades, and 6/19 (31.6%) of higher grades. No severe toxicities related to study medication were observed. The median follow-up of all surviving patients is 2177 days. The 3-year OS was 45.2% (95% CI: 27.4-61.4%), and the 3-year PFS was 38.7% (95% CI: 22.0-55.1%). The cumulative incidence of relapse at 1 year and 3 year was 25% (95% CI: 12.5-50.0%), and 33.3% (95% CI: 18.9-58.7%), the cumulative incidence of NRM at 1 year and 3 years was 20.8% (95%CI: 9.6-45.5%), and 29.2% (95%CI: 15.6-54.4%), respectively. The utilization of CNI-free GVHD prophylaxis with EVE+MMF resulted in high rates of acute and chronic GVHD. Therefore, we do not recommend a CNI-free combination of mTOR inhibitor EVE with MMF as the sole GVHD prophylaxis. In subsequent studies, this combination should be modified, e.g., with further components like post-transplant cyclophosphamide (PTCy) or anti-thymocyte globulin (ATG).

Keywords: Allogeneic transplantation; Clinical trial; Everolimus; Graft versus host disease prophylaxis; Mycophenolate mofetil.

Conflict of interest statement

HS received travel grants and research honoraria from Roche and BMS. JF received research support and speakers honoria from Medac, Neovii, Novartis, Riemser. RM received speakers honoria from Novartis. All other authors declare no conflict of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Quantitative analysis of reconstitution of CD4+ T cell subsets in patients receiving EVE+MMF or CsA+MTX/MMFas GVHD prophylaxis. Numbers indicate timepoints after HCT in days. *Statistical difference p < 0.05; **p < 0.005. Ev, everolimus; MMF, mycophenolate mofetil; CsA, cyclosporine; MTX, methotrexate
Fig. 2
Fig. 2
Overall survival, progression-free survival, cumulative incidence of relapse and non-relapse mortality. Cumulative incidence (%) of a overall survival, b progression-free survival, c incidence of relapse, and d non-relapse mortality in 24 patients treated with EVE + MMF for GVHD prophylaxis
Fig. 3
Fig. 3
Acute and chronic GVHD. Cumulative incidence (%) of a aGVHD grade II-IV and b aGVHD grade III-IV and c cGVHD all grades and d cGVHD NIH3 with death as a competing risk in 24 patients treated with EVE + MMF for GVHD prophylaxis

References

    1. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, Buckner CD, Clift R, Doney K, Farewell V. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986;314(12):729–735. doi: 10.1056/NEJM198603203141201.
    1. Kharfan-Dabaja M, Mhaskar R, Reljic T, Pidala J, Perkins JB, Djulbegovic B, Kumar A. Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2014;7:CD010280. doi: 10.1002/14651858.CD010280.pub2.
    1. Piñana JL, Valcárcel D, Fernández-Avilés F, Martino R, Rovira M, Barba P, Martínez C, Brunet S, Sureda A, Carreras E, Sierra J. MTX or mycophenolate mofetil with CsA as GVHD prophylaxis after reduced-intensity conditioning PBSCT from HLA-identical siblings. Bone Marrow Transplant. 2010;45(9):1449–1456. doi: 10.1038/bmt.2009.362.
    1. Bolwell B, Sobecks R, Pohlman B, Andresen S, Rybicki L, Kuczkowski E, Kalaycio M. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;34(7):621–625. doi: 10.1038/sj.bmt.1704647.
    1. Yerushalmi R, Shem-Tov N, Danylesko I, Shouval R, Nagler A, Shimoni A. The combination of cyclosporine and mycophenolate mofetil is less effective than cyclosporine and methotrexate in the prevention of acute graft-versus host disease after stem-cell transplantation from unrelated donors. Am J Hematol. 2017;92(3):259–268. doi: 10.1002/ajh.24631.
    1. Perkins J, Field T, Kim J, Kharfan-Dabaja MA, Fernandez H, Ayala E, Perez L, Xu M, Alsina M, Ochoa L, Sullivan D, Janssen W, Anasetti C. A randomized phase II trial comparing tacrolimus and mycophenolate mofetil to tacrolimus and methotrexate for acute graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2010;16(7):937–947. doi: 10.1016/j.bbmt.2010.01.010.
    1. Chhabra S, Liu Y, Hemmer MT, Costa L, Pidala JA, Couriel DR, Alousi AM, Majhail NS, Stuart RK, Kim D, Ringden O, Urbano-Ispizua A, Saad A, Savani BN, Cooper B, Marks DI, Socie G, Schouten HC, Schoemans H, Abdel-Azim H, Yared J, Cahn J-Y, Wagner J, Antin JH, Verdonck LF, Lehmann L, Aljurf MD, MacMillan ML, Litzow MR, Solh MM, Qayed M, Hematti P, Kamble RT, Vij R, Hayashi RJ, Gale RP, Martino R, Seo S, Hashmi SK, Nishihori T, Teshima T, Gergis U, Inamoto Y, Spellman SR, Arora M, Hamilton BK. Comparative analysis of calcineurin inhibitor-based methotrexate and mycophenolate mofetil-containing regimens for prevention of graft-versus-host disease after reduced-intensity conditioning allogeneic transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2019;25(1):73–85. doi: 10.1016/j.bbmt.2018.08.018.
    1. Cutler C, Li S, Ho VT, Koreth J, Alyea E, Soiffer RJ, Antin JH. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007;109(7):3108–3114. doi: 10.1182/blood-2006-09-046219.
    1. Pidala J, Kim J, Jim H, Kharfan-Dabaja MA, Nishihori T, Fernandez HF, Tomblyn M, Perez L, Perkins J, Xu M, Janssen WE, Veerapathran A, Betts BC, Locke FL, Ayala E, Field T, Ochoa L, Alsina M, Anasetti C. A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. Haematologica. 2012;97(12):1882–1889. doi: 10.3324/haematol.2012.067140.
    1. Armand P, Kim HT, Sainvil M-M, Lange PB, Giardino AA, Bachanova V, Devine SM, Waller EK, Jagirdar N, Herrera AF, Cutler C, Ho VT, Koreth J, Alyea EP, McAfee SL, Soiffer RJ, Chen Y-B, Antin JH. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial. Br J Haematol. 2016;173(1):96–104. doi: 10.1111/bjh.13931.
    1. Kornblit B, Maloney DG, Storer BE, Maris MB, Vindeløv L, Hari P, Langston AA, Pulsipher MA, Bethge WA, Chauncey TR, Lange T, Petersen FB, Hübel K, Woolfrey AE, Flowers MED, Storb R, Sandmaier BM. A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after nonmyeloablative unrelated donor transplantation. Haematologica. 2014;99(10):1624–1631. doi: 10.3324/haematol.2014.108340.
    1. Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, Raetz E, Gardner S, Gastier-Foster JM, Howrie D, Goyal RK, Douglas JG, Borowitz M, Barnes Y, Teachey DT, Taylor C, Grupp SA. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children’s Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014;123(13):2017–2025. doi: 10.1182/blood-2013-10-534297.
    1. Hoda D, Pidala J, Salgado-Vila N, Kim J, Perkins J, Bookout R, Field T, Perez L, Ayala E, Ochoa-Bayona JL, Raychaudhuri J, Alsina M, Greene J, Janssen W, Fernandez HF, Anasetti C, Kharfan-Dabaja MA. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant. 2010;45(8):1347–1351. doi: 10.1038/bmt.2009.343.
    1. Sandmaier BM, Kornblit B, Olesen G, Storer BE. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019;6(8):e409–e418. doi: 10.1016/S2352-3026(19)30088-2.
    1. Al-Kadhimi Z, Gul Z, Chen W, Smith D, Abidi M, Deol A, Ayash L, Lum L, Waller EK, Ratanatharathorn V, Uberti J. High incidence of severe acute graft-versus-host disease with tacrolimus and mycophenolate mofetil in a large cohort of related and unrelated allogeneic transplantation patients. Biol Blood Marrow Transplant J AmSoc Blood Marrow Transplant. 2014;20(7):S979–S985. doi: 10.1016/j.bbmt.2014.03.016.
    1. Mielke S, Lutz M, Schmidhuber J, Kapp M, Ditz D, Ammer J, Einsele H, Grigoleit GU, Holler E, Wolff D. Salvage therapy with everolimus reduces the severity of treatment-refractory chronic GVHD without impairing disease control: a dual center retrospective analysis. Bone Marrow Transplant. 2014;49(11):1412–1418. doi: 10.1038/bmt.2014.170.
    1. Platzbecker U, von Bonin M, Goekkurt E, Radke J, Binder M, Kiani A, Stoehlmacher J, Schetelig J, Thiede C, Ehninger G, Bornhäuser M (2009) Graft-versus-host disease prophylaxis with everolimus and tacrolimus is associated with a high incidence of sinusoidal obstruction syndrome and microangiopathy: results of the EVTAC trial. Biol Blood Marrow Transpl 15(1):101–108. 10.1016/j.bbmt.2008.11.004
    1. Zeiser R, Nguyen VH, Beilhack A, Buess M, Schulz S, Baker J, Contag CH, Negrin RS. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood. 2006;108(1):390–399. doi: 10.1182/blood-2006-01-0329.
    1. Zeiser R, Leveson-Gower DB, Zambricki EA, Kambham N, Beilhack A, Loh J, Hou J-Z, Negrin RS (2008) Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 111(1):453–462. 10.1182/blood-2007-06-094482
    1. Segundo DS, Ruiz JC, Izquierdo M, Fernández-Fresnedo G, Gómez-Alamillo C, Merino R, Benito MJ, Cacho E, Rodrigo E, Palomar R, López-Hoyos M, Arias M. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation. 2006;82(4):550–557. doi: 10.1097/01.tp.0000229473.95202.50.
    1. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18(4):295–304. doi: 10.1097/00007890-197410000-00001.
    1. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers MED. National Institutes of Health consensus development project on criteria for Clinical trials in chronic graft-versus-host disease: I. diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945–956. doi: 10.1016/j.bbmt.2005.09.004.
    1. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18(6):695–706. doi: 10.1002/(SICI)1097-0258(19990330)18:6<695::AID-SIM60>;2-O.
    1. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496–509. doi: 10.1080/01621459.1999.10474144.
    1. Marks R, Potthoff K, Hahn J, Ihorst G, Bertz H, Spyridonidis A, Holler E, Finke JM. Reduced-toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: particular activity against advanced hematologic malignancies. Blood. 2008;112(2):415–425. doi: 10.1182/blood-2007-08-104745.
    1. Christopoulos P, Schmoor C, Waterhouse M, Marks R, Wäsch R, Bertz H, Finke J. Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML. Bone Marrow Transplant. 2013;48(7):901–907. doi: 10.1038/bmt.2012.267.
    1. Grüllich C, Bertz H, Spyridonidis A, Müller CI, Finke J. A fludarabine, thiotepa reduced toxicity conditioning regimen designed specifically for allogeneic second haematopoietic cell transplantation after failure of previous autologous or allogeneic transplantation. Bone Marrow Transplant. 2008;41(10):845–850. doi: 10.1038/sj.bmt.1705989.
    1. Spyridonidis A, Labopin M, Savani BN, Niittyvuopio R, Blaise D, Craddock C, Socié G, Platzbecker U, Beelen D, Milpied N, Cornelissen JJ, Ganser A, Huynh A, Griskevicius L, Giebel S, Aljurf M, Brissot E, Malard F, Esteve J, Peric Z, Baron F, Ruggeri A, Schmid C, Gilleece M, Gorin N-C, Lanza F, Shouval R, Versluis J, Bug G, Fløisand Y, Ciceri F, Sanz J, Bazarbachi A, Nagler A, Mohty M. Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients. Bone Marrow Transplant. 2020;55(6):1114–1125. doi: 10.1038/s41409-020-0803-y.
    1. Armand P, Gibson CJ, Cutler C, Ho VT, Koreth J, Alyea EP, Ritz J, Sorror ML, Lee SJ, Deeg HJ, Storer BE, Appelbaum FR, Antin JH, Soiffer RJ, Kim HT. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood. 2012;120(4):905–913. doi: 10.1182/blood-2012-03-418202.
    1. Tenderich G, Fuchs U, Zittermann A, Muckelbauer R, Berthold HK, Koerfer R. Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart transplant recipients. Clin Transpl. 2007;21(4):536–543. doi: 10.1111/j.1399-0012.2007.00686.x.
    1. Schleuning M, Judith D, Jedlickova Z, Stübig T, Heshmat M, Baurmann H, Schwerdtfeger R. Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study. Bone Marrow Transplant. 2009;43(9):717–723. doi: 10.1038/bmt.2008.377.
    1. Ruutu T, de Wreede LC, van Biezen A, Brand R, Mohty M, Dreger P, Duarte R, Peters C, Garderet L, Schönland S, Gratwohl A, Niederwieser D, de Witte T, Kröger N, European Society for Blood and Marrow Transplantation (EBMT) (2015) Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT. Bone Marrow Transplant. 10.1038/bmt.2015.186
    1. Kato K, Yonemoto K, Miyamoto T, Uchida N. Second allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for relapse of hematological malignancies after first Allo-HSCT. Blood. 2014;124(21):3947–3947. doi: 10.1182/blood.V124.21.3947.3947.
    1. Fedele R, Martino M, Garreffa C, Messina G, Console G, Princi D, Dattola A, Moscato T, Massara E, Spiniello E, Irrera G, Iacopino P. The impact of early CD4+ lymphocyte recovery on the outcome of patients who undergo allogeneic bone marrow or peripheral blood stem cell transplantation. Blood Transfus. 2012;10(2):174–180. doi: 10.2450/2012.0034-11.
    1. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb H-J, Bertz H, Egger M, Grishina O, Socié G, ATG-Fresenius Trial Group Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10(9):855–864. doi: 10.1016/S1470-2045(09)70225-6.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다