Although recent improvements have been indicated in the outcome after allogeneic hematopoietic cell transplantation (allo-HCT), little information is available on how changes in transplant modalities have affected the outcomes after allo-HCT in non-remission, based on patient age, donor source and disease type. We compared the incidence and causes of non-relapse mortality (NRM) after allo-HCT in non-remission among three consecutive four-year periods using a nationwide transplant outcome registry database. A total of 3308 patients with acute leukemia in non-remission were analyzed. The risk of NRM decreased over the three periods, and the hazard ratios (HRs) in 2001–2004 and 2005–2008 compared with 1997–2000 were 0.86 (95% CI, 0.70–1.06; P=0.16) and 0.65 (95% CI, 0.53–0.80; P<0.01), respectively. A significant decrease in the HR for overall mortality was also observed in 2005–2008 (HR 0.85; 95% CI, 0.75–0.97; P=0.02). We found that a decrease in the incidences of death due to GVHD and infection contributed to the reduction in NRM, to which high-resolution donor-recipient HLA matching and other improvements may have contributed. As none of the subgroups showed improved survival without a reduction in NRM, the effective prevention of transplant-related complications appears to be necessary for improving outcomes after allo-HCT in non-remission.
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Giebel S, Labopin M, Holowiecki J, Labar B, Komarnicki M, Koza V et al. Outcome of HLA-matched related allogeneic hematopoietic stem cell transplantation for patients with acute leukemia in first complete remission treated in Eastern European centers. Better results in recent years. Ann Hematol 2009; 88: 1005–1013.
Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091–2101.
Gratwohl A, Brand R, Frassoni F, Rocha V, Niederwieser D, Reusser P et al. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant 2005; 36: 757–769.
Horan JT, Logan BR, Agovi-Johnson MA, Lazarus HM, Bacigalupo AA, Ballen KK et al. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol 2011; 29: 805–813.
Remberger M, Ackefors M, Berglund S, Blennow O, Dahllof G, Dlugosz A et al. Improved survival after allogeneic hematopoietic stem cell transplantation in recent years. A single-center study. Biol Blood Marrow Transplant 2011; 17: 1688–1697.
Kurosawa S, Yakushijin K, Yamaguchi T, Atsuta Y, Nagamura-Inoue T, Akiyama H et al. Changes in incidence and causes of non-relapse mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia/myelodysplastic syndrome: an analysis of the Japan Transplant Outcome Registry. Bone Marrow Transplant 2013; 48: 529–536.
Barrett AJ . Conditioning regimens for allogeneic stem cell transplants. Curr Opin Hematol 2000; 7: 339–342.
Feinstein L, Storb R . Reducing transplant toxicity. Curr Opin Hematol 2001; 8: 342–348.
Sayer HG, Kroger M, Beyer J, Kiehl M, Klein SA, Schaefer-Eckart K et al. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor. Bone Marrow Transplant 2003; 31: 1089–1095.
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.
Shimoni A, Nagler A . Optimizing the conditioning regimen for allogeneic stem-cell transplantation in acute myeloid leukemia; dose intensity is still in need. Best Pract Res Clin Haematol 2011; 24: 369–379.
Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol 2007; 86: 269–274.
Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009; 15: 367–369.
Mizuta S, Matsuo K, Yagasaki F, Yujiri T, Hatta Y, Kimura Y et al. Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute lymphoblastic leukemia. Leukemia 2011; 25: 41–47.
Yanada M, Ohno R, Naoe T . Recent advances in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol 2009; 89: 3–13.
Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 2006; 24: 460–466.
Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE et al. Age and acute myeloid leukemia. Blood 2006; 107: 3481–3485.
Andersson BS, Valdez BC, de Lima M, Wang X, Thall PF, Worth LL et al. Clofarabine +/- fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS. Biol Blood Marrow Transplant 2011; 17: 893–900.
Chevallier P, Prebet T, Turlure P, Hunault M, Vigouroux S, Harousseau JL et al. Prior treatment with gemtuzumab ozogamicin and the risk of veno-occlusive disease after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 2010; 45: 165–170.
Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: A Multicenter, Randomized Phase III Study. J Clin Oncol 2012; 30: 2441–2448.
Iravani M, Evazi MR, Mousavi SA, Shamshiri AR, Tavakoli M, Ashouri A et al. Fludarabine and busulfan as a myeloablative conditioning regimen for allogeneic stem cell transplantation in high- and standard-risk leukemic patients. Bone Marrow Transplant 2007; 40: 105–110.
Kantarjian HM, Erba HP, Claxton D, Arellano M, Lyons RM, Kovascovics T et al. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol 2010; 28: 549–555.
Lowenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009; 361: 1235–1248.
Magenau J, Tobai H, Pawarode A, Braun T, Peres E, Reddy P et al. Clofarabine and busulfan conditioning facilitates engraftment and provides significant antitumor activity in nonremission hematologic malignancies. Blood 2011; 118: 4258–4264.
Tran H, Yang D . Clofarabine in the treatment of newly diagnosed acute myeloid leukemia in older adults. Ann Pharmacother 2012; 46: 89–96.
Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M 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 2004; 104: 1923–1930.
Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.
Yanada M, Emi N, Naoe T, Sakamaki H, Takahashi S, Hirabayashi N et al. Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan. Bone Marrow Transplant 2004; 34: 331–337.
Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM 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 2000; 96: 2062–2068.
Hiraoka A, Ohashi Y, Okamoto S, Moriyama Y, Nagao T, Kodera Y et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 28: 181–185.
Martin PJ, McDonald GB, Sanders JE, Anasetti C, Appelbaum FR, Deeg HJ et al. Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2004; 10: 320–327.
Fuji S, Kim SW, Mori S, Fukuda T, Kamiya S, Yamasaki S et al. Hyperglycemia during the neutropenic period is associated with a poor outcome in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation. Transplantation 2007; 84: 814–820.
Hahn T, McCarthy PL Jr, Zhang MJ, Wang D, Arora M, Frangoul H et al. Risk factors for acute graft-versus-host disease after human leukocyte antigen-identical sibling transplants for adults with leukemia. J Clin Oncol 2008; 26: 5728–5734.
Oh H, Loberiza FR Jr, Zhang MJ, Ringden O, Akiyama H, Asai T et al. Comparison of graft-versus-host-disease and survival after HLA-identical sibling bone marrow transplantation in ethnic populations. Blood 2005; 105: 1408–1416.
Paulin T, Ringden O, Nilsson B . Immunological recovery after bone marrow transplantation: role of age, graft-versus-host disease, prednisolone treatment and infections. Bone Marrow Transplant 1987; 1: 317–328.
Sayer HG, Longton G, Bowden R, Pepe M, Storb R . Increased risk of infection in marrow transplant patients receiving methylprednisolone for graft-versus-host disease prevention. Blood 1994; 84: 1328–1332.
Upton A, Kirby KA, Carpenter P, Boeckh M, Marr KA . Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin Infect Dis 2007; 44: 531–540.
Lee JL, Gooley T, Bensinger W, Schiffman K, McDonald GB . Veno-occlusive disease of the liver after busulfan, melphalan, and thiotepa conditioning therapy: incidence, risk factors, and outcome. Biol Blood Marrow Transplant 1999; 5: 306–315.
Baker KS, Gurney JG, Ness KK, Bhatia R, Forman SJ, Francisco L et al. Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study. Blood 2004; 104: 1898–1906.
Khera N, Storer B, Flowers ME, Carpenter PA, Inamoto Y, Sandmaier BM et al. Nonmalignant late effects and compromised functional status in survivors of hematopoietic cell transplantation. J Clin Oncol 2012; 30: 71–77.
Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 2010; 28: 3730–3738.
This work was supported by grants from the Japanese Ministry of Health, Labor and Welfare and the National Cancer Research and Development Fund (23-A-28). The results were presented at the 52nd Annual Meeting of the American Society of Hematology in Orlando, FL, 7 December, 2010.
The authors declare no conflicts of interest.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
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Prognostic index for patients with relapsed or refractory acute myeloid leukemia who underwent hematopoietic cell transplantation: a KSGCT multicenter analysis
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