Incidence and Pattern of Graft-versus-Host Disease in Patients Undergoing Allogeneic Transplantation after Nonmyeloablative Conditioning with Total Lymphoid Irradiation and Antithymocyte Globulin
Nonmyeloablative (NMA) conditioning with total lymphoid irradiation and antithymocyte globulin (TLI/ATG) has been shown to protect against acute graft-versus-host disease (GVHD). We report here our institutional experience with allogeneic transplantation following NMA conditioning with TLI/ATG ( ). GVHD prophylaxis consisted of a combination of a calcineurin inhibitor and mycophenolate mofetil. Median patient age was 59 years. The median followup of surviving patients is 545 days. One patient experienced primary graft rejection. The median time to neutrophil engraftment was 18 days and platelet engraftment was 9.5 days. The cumulative incidence (CI) of grade II–IV acute GVHD at day +100 was 28.6% and 38.1% at day +180. The CI for grade III-IV acute GVHD was 28.6% at day +180. CI of chronic GVHD was 45.2% at 1 year. The CI of disease relapse was 9.5% at 1 year. The rate of nonrelapse mortality (NRM) was 0% at day +100 and only 9.5% at 1 year. The overall and progression free survival at 1 year was 81% and 80.4%, respectively. Our limited, retrospective data show encouraging relapse and NRM rates with TLI/ATG-based NMA conditioning, but with higher than previously reported rates of acute and chronic GVHD, underscoring the need for novel strategies designed to effectively prevent GVHD. 1. Introduction Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative modality for a variety of hematological malignancies [1, 2]. However, the high rates of procedure-related toxicities and nonrelapse mortality (NRM) have limited the applicability of HCT following conventional myeloablative conditioning regimens, to select cohort of younger patients with few or no comorbidities [3–8]. Hematological malignancies disproportionately affect the elderly [3]. From 2010 to 2030, the percentage of all cancers diagnosed in older adults in the United States will increase from 61% to 70% [9]. This change in demographics places an even greater emphasis on creating less toxic conditioning regimens, suitable for elderly or less fit individuals. The introduction of nonmyeloablative (NMA) and reduced-intensity conditioning (RIC) regimens has extended the use of allogeneic HCT to patients otherwise ineligible for conventional myeloablative HCT due to age or comorbidities [3, 10]. However, even with the decline in transplant-related toxicities with the introduction of NMA regimens, graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality [11–16]. NMA conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) has been
References
[1]
E. A. Copelan, “Hematopoietic stem-cell transplantation,” The New England Journal of Medicine, vol. 354, no. 17, pp. 1813–1826, 2006.
[2]
M. Hamadani, F. T. Awan, and E. A. Copelan, “Hematopoietic stem cell transplantation in adults with acute myeloid leukemia,” Biology of Blood and Marrow Transplantation, vol. 14, no. 5, pp. 556–567, 2008.
[3]
M. L. Sorror, B. M. Sandmaier, B. E. Storer, et al., “Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies,” JAMA, vol. 306, no. 17, pp. 1874–1883, 2011.
[4]
M. L. Sorror, B. E. Storer, D. G. Maloney, B. M. Sandmaier, P. J. Martin, and R. Storb, “Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia,” Blood, vol. 111, no. 1, pp. 446–452, 2008.
[5]
S. Slavin, A. Nagler, E. Naparstek et al., “Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases,” Blood, vol. 91, no. 3, pp. 756–763, 1998.
[6]
H. G. Klingemann, R. Storb, and A. Fefer, “Bone marrow transplantation in patients aged 45 years and older,” Blood, vol. 67, no. 3, pp. 770–776, 1986.
[7]
P. A. McSweeney, D. Niederwieser, J. A. Shizuru et al., “Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects,” Blood, vol. 97, no. 11, pp. 3390–3400, 2001.
[8]
O. Ringden, M. M. Horowitz, R. P. Gale et al., “Outcome after allogeneic bone marrow transplant for leukemia in older adults,” Journal of the American Medical Association, vol. 270, no. 1, pp. 57–60, 1993.
[9]
B. D. Smith, G. L. Smith, A. Hurria, G. N. Hortobagyi, and T. A. Buchholz, “Future of cancer incidence in the United States: burdens upon an aging, changing nation,” Journal of Clinical Oncology, vol. 27, no. 17, pp. 2758–2765, 2009.
[10]
B. Gyurkocza, R. Storb, B. E. Storer et al., “Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia,” Journal of Clinical Oncology, vol. 28, no. 17, pp. 2859–2867, 2010.
[11]
V. T. Ho and R. J. Soiffer, “The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation,” Blood, vol. 98, no. 12, pp. 3192–3204, 2001.
[12]
M. Hamadani, W. Blum, G. Phillips et al., “Improved nonrelapse mortality and infection rate with lower dose of antithymocyte globulin in patients undergoing reduced-intensity conditioning allogeneic transplantation for hematologic malignancies,” Biology of Blood and Marrow Transplantation, vol. 15, no. 11, pp. 1422–1430, 2009.
[13]
M. Mielcarek, P. J. Martin, W. Leisenring et al., “Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation,” Blood, vol. 102, no. 2, pp. 756–762, 2003.
[14]
M. Mohty, J. O. Bay, C. Faucher et al., “Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen,” Blood, vol. 102, no. 2, pp. 470–476, 2003.
[15]
J. Pidala, J. Kim, H. Jim, et al., “A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation,” Haematologica, vol. 97, no. 12, pp. 1882–1889, 2012.
[16]
O. Sala-Torra, P. J. Martin, B. Storer et al., “Serious acute or chronic graft-versus-host disease after hematopoietic cell transplantation: a comparison of myeloablative and nonmyeloablative conditioning regimens,” Bone Marrow Transplantation, vol. 41, no. 10, pp. 887–893, 2008.
[17]
R. Lowsky, T. Takahashi, P. L. Yin et al., “Protective conditioning for acute graft-versus-host disease,” The New England Journal of Medicine, vol. 353, no. 13, pp. 1321–1331, 2005.
[18]
H. Kohrt and R. Lowsky, “Nonmyeloablative conditioning with total lymphoid irradiation and antithymocyte globulin: an update,” Current Opinion in Hematology, vol. 16, no. 6, pp. 460–465, 2009.
[19]
H. E. Kohrt, B. B. Turnbull, K. Heydari et al., “TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors,” Blood, vol. 114, no. 5, pp. 1099–1109, 2009.
[20]
F. Lan, D. Zeng, M. Higuchi, J. P. Higgins, and S. Strober, “Host conditioning with total lymphoid irradiation and antithymocyte globulin prevents graft-versus-host disease: the role of CD1-reactive natural killer T cells,” Biology of Blood and Marrow Transplantation, vol. 9, no. 6, pp. 355–363, 2003.
[21]
G. Messina, L. Giaccone, M. Festuccia, et al., “Multicenter experience using total lymphoid irradiation and antithymocyte globulin as conditioning for allografting in hematological malignancies,” Biology of Blood and Marrow Transplantation, vol. 18, no. 10, pp. 1600–1607, 2012.
[22]
A. B. Pillai, T. I. George, S. Dutt, and S. Strober, “Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4+CD25+Foxp3+ T regulatory cells that protects against graft-versus-host disease,” Blood, vol. 113, no. 18, pp. 4458–4467, 2009.
[23]
S. Strober, “Protective conditioning against GVHD and graft rejection after combined organ and hematopoietic cell transplantation,” Blood Cells, Molecules, and Diseases, vol. 40, no. 1, pp. 48–54, 2008.
[24]
M. L. Sorror, M. B. Maris, R. Storb et al., “Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT,” Blood, vol. 106, no. 8, pp. 2912–2919, 2005.
[25]
N. Flomenberg, L. A. Baxter-Lowe, D. Confer et al., “Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome,” Blood, vol. 104, no. 7, pp. 1923–1930, 2004.
[26]
D. Przepiorka, D. Weisdorf, P. Martin et al., “Consensus conference on acute GVHD grading,” Bone Marrow Transplantation, vol. 15, no. 6, pp. 825–828, 1995.
[27]
E. R. Farmer, “The histopathology of graft-versus-host disease,” Advances in dermatology, vol. 1, pp. 173–188, 1986.
[28]
H. M. Shulman, K. M. Sullivan, and P. L. Weiden, “Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 seattle patients,” American Journal of Medicine, vol. 69, no. 2, pp. 204–217, 1980.
[29]
K. M. Sullivan, E. Agura, C. Anasetti et al., “Chronic graft-versus-host disease and other late complications of bone marrow transplantation,” Seminars in Hematology, vol. 28, no. 3, pp. 250–259, 1991.
[30]
A. H. Filipovich, D. Weisdorf, S. Pavletic et al., “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,” Biology of Blood and Marrow Transplantation, vol. 11, no. 12, pp. 945–956, 2005.
[31]
T. A. Gooley, W. Leisenring, J. Crowley, and B. E. Storer, “Estimation of failure probabilities in the presence of competing risks: new representations of old estimators,” Statistics in Medicine, vol. 18, no. 6, pp. 695–706, 1999.
[32]
J. P. Fine and R. J. Gray, “A proportional hazards model for the subdistribution of a competing risk,” Journal of the American Statistical Association, vol. 94, no. 446, pp. 496–509, 1999.
[33]
P. J. Martin, G. B. McDonald, J. E. Sanders et al., “Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation,” Biology of Blood and Marrow Transplantation, vol. 10, no. 5, pp. 320–327, 2004.
[34]
R. A. Nash, J. H. Antin, C. Karanes et al., “Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors,” Blood, vol. 96, no. 6, pp. 2062–2068, 2000.
[35]
J. Finke, W. A. Bethge, C. Schmoor et al., “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,” The Lancet Oncology, vol. 10, no. 9, pp. 855–864, 2009.
[36]
B. George, I. H. Kerridge, N. Gilroy, et al., “A risk score for early cytomegalovirus reactivation after allogeneic stem cell transplantation identifies low-, intermediate-, and high-risk groups: reactivation risk is increased by graft-versus-host disease only in the intermediate-risk group,” Transplant Infectious Disease, vol. 14, no. 2, pp. 141–148, 2012.
[37]
P. Ljungman, C. Cordonnier, H. Einsele et al., “Use of intravenous immune globulin in addition to antiviral therapy in the treatment of CMV gastrointestinal disease in allogeneic bone marrow transplant patients: a report from the European group for blood and marrow transplantation (EBMT),” Bone Marrow Transplantation, vol. 21, no. 5, pp. 473–476, 1998.
[38]
A. H. Elmaagacli, N. K. Steckel, M. Koldehoff, et al., “Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients,” Blood, vol. 118, no. 5, pp. 1402–1412, 2011.
