Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia : a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation
Baron, Frédéric; Labopin, M.; Niederwieser, D.et al.
[en] This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of relapse (hazards ratio (HR)¼0.7, P¼0.02) translating into a trend for better overall survival (OS; HR¼1.3; P¼0.07). Grade II acute GVHD had no net impact on OS, while grade III–IV acute GVHD was associated with a worse OS (HR¼0.4, Po0.0.001) owing to high risk of nonrelapse mortality (NRM; HR¼5.2, Po0.0001). In time-dependent multivariate Cox analyses, limited chronic GVHD tended to be associated with a lower risk of relapse (HR¼0.72; P¼0.07) translating into a better OS (HR¼1.8; Po0.001), while extensive chronic GVHD was associated with a lower risk of relapse (HR¼0.65; P¼0.02) but also with higher NRM (HR¼3.5; Po0.001) and thus had no net impact on OS. In-vivo T-cell depletion with antithymocyte globulin (ATG) or alemtuzumab was successful at preventing extensive chronic GVHD (Po0.001), but without improving OS for ATG and even with worsening OS for alemtuzumab (HR¼0.65; P¼0.001). These results highlight the role of the immune-mediated graft-versus-leukemia effect in the RIC allo-SCT setting, but also the need for improving the prevention and treatment of severe GVHD.
Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia : a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation
Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453-474.
Gupta V, Tallman MS, Weisdorf DJ. Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood 2011; 117: 2307-2318.
Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989; 73: 1720-1728.
Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb H-J et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555-562.
Blaise D, Vey N, Faucher C, Mohty M. Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 2007; 92: 533-541.
Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb H-J et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia 2005; 19: 2304-2312.
Ringden O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009; 27: 4570-4577.
Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA et al. Non-myeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol 2010; 28: 2859-2867.
Valcarcel D, Martino R, Caballero D, Martin J, Ferra C, Nieto JB et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26: 577-584.
Blaise DP, Michel BJ, Faucher C, Mohty M, Bay JO, Bardoux VJ et al. Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment. Cancer 2005; 104: 1931-1938.
de Lima M, Giralt S. Allogeneic transplantation for the elderly patient with acute myelogenous leukemia or myelodysplastic syndrome. Semin Hematol 2006; 43: 107-117.
van Besien K, Artz A, Smith S, Cao D, Rich S, Godley L et al. Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23: 5728-5738.
Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23: 9387-9393.
Lazarus HM, Rowe JM. Reduced-intensity conditioning for acute myeloid leukemia: is this strategy correct. Leukemia 2006; 20: 1673-1682.
Estey E, de Lima M, Tibes R, Pierce S, Kantarjian H, Champlin R et al. Prospective feasibility analysis of reduced-intensity conditioning (RIC) regimens for hemato-poietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood 2007; 109: 1395-1400.
McClune BL, Weisdorf DJ, Pedersen TL, Tunes da Silva G, Tallman MS, Sierra J et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 2010; 28: 1878-1887.
Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia 2006; 20: 322-328.
Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 2005; 23: 1993-2003.
Oran B, Giralt S, Saliba R, Hosing C, Popat U, Khouri I et al. Allogeneic hemato-poietic stem cell transplantation for the treatment of high-risk acute myelo-genous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant 2007; 13: 454-462.
Craddock C, Nagra S, Peniket A, Brookes C, Buckley L, Nikolousis E et al. Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 2010; 95: 989-995.
van Besien K, Kunavakkam R, Rondon G, de Lima M, Artz A, Oran B et al. Fludarabine-melphalan conditioning for AML and MDS: alemtuzumab reduces acute and chronic GVHD without affecting long-term outcomes. Biol Blood Marrow Transplant 2009; 15: 610-617.
Weisdorf DJ, Zhang MJ, Arora M, Rizzo JD, Horowitz MM, Eapen M. Graft-versus-host disease (GVHD) induced graft-versus-leukemia (GVL) effect: more impact on later relapse and disease-free survival following reduced intensity conditioning. ASH Ann Meeting Abstracts 2011; 118: 1014.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295-304.
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: 695-706.
Giebel S, Labopin M, Mohty M, Blaise D, Craddock C, Nagler A et al. The impact of center experience on results of reduced intensity\allogeneic hematopoietic stem cell transplantation. A survey from the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT). Blood 2010; 11: 1445-1446.
Baron F, Storb R. Hematopoietic cell transplantation after reduced-intensity conditioning for older adults with acute myeloid leukemia in complete remission. Curr Opin Hematol 2007; 14: 145-151.
Storer BE. Statistical considerations in studies of late effects in HCT. Biol Blood Marrow Transplant 2009; 15(1 Suppl): 25-28.
Soiffer RJ, Lerademacher J, Ho V, Kan F, Artz A, Champlin RE et al. Impact of immune modulation with anti-T cell antibodies on outcomes of reduced intensity allogeneic hematopoietic cell transplantation for hematologic malignancies. Blood 2011; 117: 6963-6970.
Chevallier P, Labopin M, Milpied N, Cornelissen JJ, Blaise D, Petersen E et al. Impact of cytogenetics risk on outcome after reduced intensity conditioning allo-SCT from an HLA-identical sibling for patients with AML in first CR: a report from the Acute Leukemia Working Party of EBMT. Bone Marrow Transplant 2012; e-pub ahead of print 16 April 2012; doi:10.1038/bmt.2012.55.
Luger SM, Ringden O, Zhang MJ, Perez WS, Bishop MR, Bornhauser M et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant 2012; 47: 203-211.
Pidala J, Kim J, Jim H, Fernandez HF, Tomblyn M, Kharfan-Dabaja MA et al. Sirolimus/tacrolimus facilitates preferential recovery of regulatory T cells (Treg) after allogeneic hematopoietic cell transplantation (HCT), and is more effective than methotrexate/tacrolimus in preventing grade II-IV acute graft vs host disease (GVHD) and moderate to severe chronic GVHD. Blood 2011; Annual ASH meeting supplement: 323a.
Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea III EP et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011; 365: 2055-2066.
