Improved Survival in Lymphoma Patients Receiving Sirolimus for Graft-versus-host Disease Prophylaxis After Allogeneic Hematopoietic Stem-cell Transplantation with Reduced-intensity Conditioning

Overview

Journal J Clin Oncol

Specialty Oncology

Date 2008 Nov 13

PMID 19001324

Citations 56

Authors

Philippe Armand

Supriya Gannamaneni

Haesook T Kim

Corey S Cutler

Vincent T Ho

John Koreth

Edwin P Alyea

Ann S LaCasce

Eric D Jacobsen

David C Fisher

Jennifer R Brown

George P Canellos

Arnold S Freedman

Robert J Soiffer

Joseph H Antin

Affiliations

Soon will be listed here.

Abstract

Purpose: Inhibitors of the mammalian target of rapamycin (mTOR) kinase have shown clinical activity in several lymphoma subtypes. Sirolimus, an mTOR inhibitor, also has activity in the treatment and prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem-cell transplantation (HSCT). We hypothesized that the use of sirolimus for GVHD prophylaxis in patients with lymphoma might lead to improved survival after transplantation through a decreased incidence of disease progression.

Patients And Methods: We retrospectively analyzed 190 patients who underwent transplantation for lymphoma. We compared the outcomes of patients who received sirolimus for GVHD prophylaxis with those of patients who received transplantation with a combination of a calcineurin inhibitor and methotrexate without sirolimus.

Results: Overall survival (OS) after transplantation was significantly superior in the sirolimus group, which was confirmed in multivariable analysis. The benefit was restricted to patients undergoing reduced-intensity conditioning (RIC) HSCT (3-year OS, 66% for sirolimus group v 38% for no-sirolimus group; P = .007; hazard ratio [HR] for mortality in multivariable analysis = 0.5, P = .042). Patients who received sirolimus had a similar incidence of nonrelapse mortality but a decreased incidence of disease progression compared with patients who did not receive sirolimus (3-year cumulative incidence of progression, 42% v 74%, respectively; P < .001; HR for progression in multivariable analysis = 0.4, P = .01). The effect of sirolimus persisted after adjusting for the occurrence of GVHD. No such survival advantage was apparent in a similar comparison of patients who underwent transplantation for diseases other than lymphoma.

Conclusion: This study suggests that sirolimus can independently decrease the risk of lymphoma progression after RIC HSCT, paving the way for prospective clinical trials.

Citing Articles

mTOR inhibitors potentially preserve fertility in female patients with haematopoietic malignancies: a narrative review.

Tanaka Y, Amano T, Nakamura A, Deguchi M, Takahashi A, Tsuji S Ann Hematol. 2024; 103(12):4953-4969.

PMID: 39537993 DOI: 10.1007/s00277-024-06090-3.

Engineering a solution for allogeneic CAR-T rejection.

Amini L, Peter L, Schmueck-Henneresse M Mol Ther. 2024; 32(10):3204-3206.

PMID: 39265578 PMC: 11489523. DOI: 10.1016/j.ymthe.2024.08.025.

Haematological Drugs Affecting Lipid Metabolism and Vascular Health.

Parrella A, Iannuzzi A, Annunziata M, Covetti G, Cavallaro R, Aliberti E Biomedicines. 2022; 10(8).

PMID: 36009482 PMC: 9405726. DOI: 10.3390/biomedicines10081935.

Sirolimus versus cyclosporine in haploidentical stem cell transplantation with posttransplant cyclophosphamide and mycophenolate mofetil as graft-versus-host disease prophylaxis.

Hernani R, Pinana J, Perez A, Quintero A, Montoro J, Hernandez-Boluda J EJHaem. 2022; 2(2):236-248.

PMID: 35845283 PMC: 9175741. DOI: 10.1002/jha2.183.

Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus-infected rhesus macaques on antiretroviral therapy.

Varco-Merth B, Brantley W, Marenco A, Duell D, Fachko D, Richardson B J Clin Invest. 2022; 132(10).

PMID: 35316218 PMC: 9106346. DOI: 10.1172/JCI156063.

References

Sehgal S . Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 1998; 31(5):335-40. DOI: 10.1016/s0009-9120(98)00045-9. View

Witzig T, Geyer S, Ghobrial I, Inwards D, Fonseca R, Kurtin P . Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005; 23(23):5347-56. DOI: 10.1200/JCO.2005.13.466. View

Sureda A, Robinson S, Canals C, Carella A, Boogaerts M, Caballero D . Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2007; 26(3):455-62. DOI: 10.1200/JCO.2007.13.2415. View

Cutler C, Li S, Ho V, Koreth J, Alyea E, Soiffer R . Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2006; 109(7):3108-14. PMC: 1852220. DOI: 10.1182/blood-2006-09-046219. View

Teachey D, Obzut D, Cooperman J, Fang J, Carroll M, Choi J . The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood. 2005; 107(3):1149-55. PMC: 1895910. DOI: 10.1182/blood-2005-05-1935. View

Mehrabi A, Fonouni H, Kashfi A, Schmied B, Morath C, Sadeghi M . The role and value of sirolimus administration in kidney and liver transplantation. Clin Transplant. 2006; 20 Suppl 17:30-43. DOI: 10.1111/j.1399-0012.2006.00598.x. View

Decker T, Hipp S, Ringshausen I, Bogner C, Oelsner M, Schneller F . Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin. Blood. 2002; 101(1):278-85. DOI: 10.1182/blood-2002-01-0189. View

Benito A, Furlong T, Martin P, Anasetti C, Appelbaum F, Doney K . Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation. 2002; 72(12):1924-9. DOI: 10.1097/00007890-200112270-00010. View

Haritunians T, Mori A, OKelly J, Luong Q, Giles F, Koeffler H . Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia. 2006; 21(2):333-9. DOI: 10.1038/sj.leu.2404471. View

10.

Couriel D, Saliba R, Escalon M, Hsu Y, Ghosh S, Ippoliti C . Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol. 2005; 130(3):409-17. DOI: 10.1111/j.1365-2141.2005.05616.x. View

11.

Johnston L, Brown J, Shizuru J, Stockerl-Goldstein K, Stuart M, Blume K . Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2004; 11(1):47-55. DOI: 10.1016/j.bbmt.2004.10.004. View

12.

Sehgal S . Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003; 35(3 Suppl):7S-14S. DOI: 10.1016/s0041-1345(03)00211-2. View

13.

Wanner K, Hipp S, Oelsner M, Ringshausen I, Bogner C, Peschel C . Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. Br J Haematol. 2006; 134(5):475-84. DOI: 10.1111/j.1365-2141.2006.06210.x. View

14.

Przepiorka D, Weisdorf D, MARTIN P, Klingemann H, Beatty P, Hows J . 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15(6):825-8. View

15.

Jurado M, Vallejo C, Perez-Simon J, Brunet S, Ferra C, Balsalobre P . Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2007; 13(6):701-6. DOI: 10.1016/j.bbmt.2007.02.003. View

16.

Brown V, Fang J, Alcorn K, Barr R, Kim J, Wasserman R . Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A. 2003; 100(25):15113-8. PMC: 299917. DOI: 10.1073/pnas.2436348100. View

17.

Sorror M, Storer B, Maloney D, Sandmaier B, Martin P, Storb R . Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood. 2007; 111(1):446-52. PMC: 2200822. DOI: 10.1182/blood-2007-07-098483. View

18.

Cutler C, Kim H, Hochberg E, Ho V, Alyea E, Lee S . Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2004; 10(5):328-36. DOI: 10.1016/j.bbmt.2003.12.305. View

19.

Marty F, Bryar J, Browne S, Schwarzberg T, Ho V, Bassett I . Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. Blood. 2007; 110(2):490-500. PMC: 1924486. DOI: 10.1182/blood-2007-01-069294. View

20.

Gomez-Almaguer D, Ruiz-Arguelles G, Tarin-Arzaga L, Gonzalez-Llano O, Gutierrez-Aguirre H, Cantu-Rodriguez O . Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2007; 14(1):10-5. DOI: 10.1016/j.bbmt.2007.08.052. View