Impact of graft-versus-host disease and graft-versus-leukemia effect based on minimal residual disease in Philadelphia chromosome-positive acute lymphoblastic leukemia
Yu Akahoshi
Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
Search for more papers by this authorAiko Igarashi
Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
Search for more papers by this authorTakahiro Fukuda
Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
Search for more papers by this authorNaoyuki Uchida
Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan
Search for more papers by this authorMasatsugu Tanaka
Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
Search for more papers by this authorYukiyasu Ozawa
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
Search for more papers by this authorYoshinobu Kanda
Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
Search for more papers by this authorMakoto Onizuka
Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan
Search for more papers by this authorTatsuo Ichinohe
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Search for more papers by this authorJunji Tanaka
Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan
Search for more papers by this authorYoshiko Atsuta
Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorCorresponding Author
Shinichi Kako
Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
Correspondence: Shinichi Kako, Division of Hematology, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama City, Saitama 330-8503, Japan.
E-mail: [email protected]
Search for more papers by this authorthe Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation
Search for more papers by this authorYu Akahoshi
Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
Search for more papers by this authorAiko Igarashi
Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
Search for more papers by this authorTakahiro Fukuda
Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
Search for more papers by this authorNaoyuki Uchida
Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan
Search for more papers by this authorMasatsugu Tanaka
Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
Search for more papers by this authorYukiyasu Ozawa
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
Search for more papers by this authorYoshinobu Kanda
Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
Search for more papers by this authorMakoto Onizuka
Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan
Search for more papers by this authorTatsuo Ichinohe
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Search for more papers by this authorJunji Tanaka
Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan
Search for more papers by this authorYoshiko Atsuta
Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorCorresponding Author
Shinichi Kako
Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
Correspondence: Shinichi Kako, Division of Hematology, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama City, Saitama 330-8503, Japan.
E-mail: [email protected]
Search for more papers by this authorthe Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation
Search for more papers by this authorSummary
The impacts of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect might differ depending on minimal residual disease (MRD). Therefore, we examined 1,022 recipients who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) in first complete remission. MRD status at HSCT was negative in 791 (77·4%) and positive in 231 (22·6%). The impact of GVHD as a time-dependent covariate on transplant outcomes were analyzed while adjusting for other possible variables. Mild acute GVHD [hazard ratio (HR), 0·90; 95% confidence interval (CI), 0·70–1·16; P = 0·901] and chronic GVHD (HR, 0·82, 95% CI, 0·58–1·14; P = 0·238) were not significantly associated with overall mortality, whereas severe acute GVHD (HR, 2·26, 95% CI, 1·64–3·11; P < 0·001) resulted in inferior overall survival due to high non-relapse mortality. Moreover, even in the subgroup analyses stratified according to MRD status, acute and chronic GVHD were not significantly associated with better overall survival. Therefore, less intensive GVHD prophylaxis to achieve a GVL effect is not recommended for Ph-positive ALL.
Conflict of interest
The authors declare no competing interests relevant to this article.
Supporting Information
| Filename | Description |
|---|---|
| bjh16540-sup-0001-TableS1-S2.docxWord document, 16 KB |
Table S1. Impact of aGVHD on transplant outcomes using landmark analyses. Table S2. Impact of aGVHD using the different classification on transplant outcomes in the multivariate analyses. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- Akahoshi, Y., Mizuta, S., Shimizu, H., Uchida, N., Fukuda, T., Kanamori, H., Onizuka, M., Ozawa, Y., Ohashi, K., Ohta, S., Eto, T., Tanaka, J., Atsuta, Y. & Kako, S. (2018) Additional cytogenetic abnormalities with Philadelphia chromosome-positive acute lymphoblastic leukaemia on allogeneic stem cell transplantation in the tyrosine kinase inhibitor era. Biology of Blood and Marrow Transplantation, 24, 2009–2016.
- Akahoshi, Y., Nishiwaki, S., Mizuta, S., Ohashi, K., Uchida, N., Tanaka, M., Fukuda, T., Ozawa, Y., Takahashi, S., Onizuka, M., Shiratori, S., Nakamae, H., Kanda, Y., Ichinohe, T., Atsuta, Y. & Kako, S. (2019) Tyrosine kinase inhibitor prophylaxis after transplant for Philadelphia chromosome-positive acute lymphoblastic leukaemia. Cancer Science, 110, 3255–3266.
- Atsuta, Y. (2016) Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). International Journal of Hematology, 103, 3–10.
- Bruggemann, M. & Kotrova, M. (2017) Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation. Blood Advances, 1, 2456–2466.
- Chhabra, S., Ahn, K.W., Hu, Z.H., Jain, S., Assal, A., Cerny, J., Copelan, E.A., Daly, A., DeFilipp, Z., Gadalla, S.M., Gale, R.P., Ganguly, S., Hamilton, B.K., Hildebrandt, G.C., Hsu, J.W., Inamoto, Y., Kanate, A.S., Khoury, H.J., Lazarus, H.M., Litzow, M.R., Nathan, S., Olsson, R.F., Pawarode, A., Ringden, O., Rowe, J.M., Saad, A., Savani, B.N., Schouten, H.C., Seo, S., Shah, N.N., Solh, M., Stuart, R.K., Ustun, C., Woolfrey, A.E., Yared, J.A., Alyea, E.P., Kalaycio, M.E., Popat, U., Sobecks, R.M. & Saber, W. (2018) Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukaemia. Blood Advances, 2, 2922–2936.
- Giebel, S., Czyz, A., Ottmann, O., Baron, F., Brissot, E., Ciceri, F., Cornelissen, J.J., Esteve, J., Gorin, N.C., Savani, B., Schmid, C., Mohty, M. & Nagler, A. (2016) Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a position statement of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer, 122, 2941–2951.
- Giralt, S., Ballen, K., Rizzo, D., Bacigalupo, A., Horowitz, M., Pasquini, M. & Sandmaier, B. (2009) Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biology of Blood and Marrow Transplantation, 15, 367–369.
- Hills, R.K. (2017) Statistical reporting in the BJH: some dos and don'ts. British Journal of Haematology, 176, 345–351.
- Iacobelli, S. (2013) Suggestions on the use of statistical methodologies in studies of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplantation, 48, S1–37.
- Jagasia, M.H., Greinix, H.T., Arora, M., Williams, K.M., Wolff, D., Cowen, E.W., Palmer, J., Weisdorf, D., Treister, N.S., Cheng, G.S., Kerr, H., Stratton, P., Duarte, R.F., McDonald, G.B., Inamoto, Y., Vigorito, A., Arai, S., Datiles, M.B., Jacobsohn, D., Heller, T., Kitko, C.L., Mitchell, S.A., Martin, P.J., Shulman, H., Wu, R.S., Cutler, C.S., Vogelsang, G.B., Lee, S.J., Pavletic, S.Z. & Flowers, M.E. (2015) National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biology of Blood and Marrow Transplantation, 21, e381.
- Kanda, Y. (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplantation, 48, 452–458.
- Kanda, J. (2016) Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. International Journal of Hematology, 103, 11–19.
- Kanda, Y., Izutsu, K., Hirai, H., Sakamaki, H., Iseki, T., Kodera, Y., Okamoto, S., Mitsui, H., Iwato, K., Hirabayashi, N., Furukawa, T., Maruta, A., Kasai, M., Atsuta, Y., Hamajima, N., Hiraoka, A. & Kawa, K. (2004) Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate. Leukaemia, 18, 1013–1019.
- Kanda, J., Morishima, Y., Terakura, S., Wake, A., Uchida, N., Takahashi, S., Ono, Y., Onishi, Y., Kanamori, H., Aotsuka, N., Ozawa, Y., Ogawa, H., Sakura, T., Ohashi, K., Ichinohe, T., Kato, K., Atsuta, Y., Teshima, T. & Murata, M. (2017) Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation. Leukaemia, 31, 663–668.
- Kato, M., Kurata, M., Kanda, J., Kato, K., Tomizawa, D., Kudo, K., Yoshida, N., Watanabe, K., Shimada, H., Inagaki, J., Koh, K., Goto, H., Cho, Y., Yuza, Y., Ogawa, A., Okada, K., Inoue, M., Hashii, Y., Teshima, T., Murata, M. & Atsuta, Y. (2019) Impact of graft-versus-host disease on relapse and survival after allogeneic stem cell transplantation for pediatric leukaemia. Bone Marrow Transplantation, 54, 68–75.
- Kawasaki, E.S., Clark, S.S., Coyne, M.Y., Smith, S.D., Champlin, R., Witte, O.N. & McCormick, F.P. (1988) Diagnosis of chronic myeloid and acute lymphocytic leukaemias by detection of leukaemia-specific mRNA sequences amplified in vitro. Proceedings of the National Academy of Sciences of the United States of America, 85, 5698–5702.
- Kolb, H.J. (2008) Graft-versus-leukaemia effects of transplantation and donor lymphocytes. Blood, 112, 4371–4383.
- Koyama, M. & Hill, G.R. (2016) Alloantigen presentation and graft-versus-host disease: fuel for the fire. Blood, 127, 2963–2970.
- Lussana, F., Intermesoli, T., Gianni, F., Boschini, C., Masciulli, A., Spinelli, O., Oldani, E., Tosi, M., Grassi, A., Parolini, M., Audisio, E., Cattaneo, C., Raimondi, R., Angelucci, E., Cavattoni, I.M., Scattolin, A.M., Cortelezzi, A., Mannelli, F., Ciceri, F., Mattei, D., Borlenghi, E., Terruzzi, E., Romani, C., Bassan, R. & Rambaldi, A. (2016) Achieving molecular remission before allogeneic stem cell transplantation in adult patients with philadelphia chromosome-positive acute lymphoblastic leukaemia: impact on relapse and long-term outcome. Biology of Blood and Marrow Transplantation, 22, 1983–1987.
- Mizuta, S., Matsuo, K., Nishiwaki, S., Imai, K., Kanamori, H., Ohashi, K., Fukuda, T., Onishi, Y., Miyamura, K., Takahashi, S., Onizuka, M., Atsuta, Y., Suzuki, R., Morishima, Y., Kato, K., Sakamaki, H. & Tanaka, J. (2014) Pretransplant administration of imatinib for allo-HSCT in patients with BCR-ABL-positive acute lymphoblastic leukaemia. Blood, 123, 2325–2332.
- Nishiwaki, S., Imai, K., Mizuta, S., Kanamori, H., Ohashi, K., Fukuda, T., Onishi, Y., Takahashi, S., Uchida, N., Eto, T., Nakamae, H., Yujiri, T., Mori, S., Nagamura-Inoue, T., Suzuki, R., Atsuta, Y. & Tanaka, J. (2016) Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ALL: a study from the adult ALL WG of the JSHCT. Bone Marrow Transplantation, 51, 43–50.
- Pfeifer, H., Wassmann, B., Bethge, W., Dengler, J., Bornhauser, M., Stadler, M., Beelen, D., Vucinic, V., Burmeister, T., Stelljes, M., Faul, C., Dreger, P., Kiani, A., Schafer-Eckart, K., Schwerdtfeger, R., Lange, E., Kubuschok, B., Horst, H.A., Gramatzki, M., Bruck, P., Serve, H., Hoelzer, D., Gokbuget, N. & Ottmann, O.G. (2013) Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukaemia. Leukaemia, 27, 1254–1262.
- Przepiorka, D., Weisdorf, D., Martin, P., Klingemann, H.G., Beatty, P., Hows, J. & Thomas, E.D. (1995) 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplantation, 15, 825–828.
- Ringden, O., Labopin, M., Ciceri, F., Velardi, A., Bacigalupo, A., Arcese, W., Ghavamzadeh, A., Hamladji, R.M., Schmid, C., Nagler, A. & Mohty, M. (2016) Is there a stronger graft-versus-leukaemia effect using HLA-haploidentical donors compared with HLA-identical siblings? Leukaemia, 30, 447–455.
- Simon, R. & Makuch, R.W. (1984) A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias. Statistics in Medicine, 3, 35–44.
- Stern, M., de Wreede, L.C., Brand, R., van Biezen, A., Dreger, P., Mohty, M., de Witte, T.M., Kroger, N. & Ruutu, T. (2014) Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukaemia, 28, 2235–2240.
- Storb, R., Gyurkocza, B., Storer, B.E., Sorror, M.L., Blume, K., Niederwieser, D., Chauncey, T.R., Pulsipher, M.A., Petersen, F.B., Sahebi, F., Agura, E.D., Hari, P., Bruno, B., McSweeney, P.A., Maris, M.B., Maziarz, R.T., Langston, A.A., Bethge, W., Vindelov, L., Franke, G.N., Laport, G.G., Yeager, A.M., Hubel, K., Deeg, H.J., Georges, G.E., Flowers, M.E., Martin, P.J., Mielcarek, M., Woolfrey, A.E., Maloney, D.G. & Sandmaier, B.M. (2013) Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. Journal of Clinical Oncology, 31, 1530–1538.
- Sullivan, K.M., Agura, E., Anasetti, C., Appelbaum, F., Badger, C., Bearman, S., Erickson, K., Flowers, M., Hansen, J. & Loughran, T. (1991) Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Seminars in Hematology, 28, 250–259.
- Thomas, D.A., Faderl, S., Cortes, J., O'Brien, S., Giles, F.J., Kornblau, S.M., Garcia-Manero, G., Keating, M.J., Andreeff, M., Jeha, S., Beran, M., Verstovsek, S., Pierce, S., Letvak, L., Salvado, A., Champlin, R., Talpaz, M. & Kantarjian, H. (2004) Treatment of Philadelphia chromosome-positive acute lymphocytic leukaemia with hyper-CVAD and imatinib mesylate. Blood, 103, 4396–4407.
- Towatari, M., Yanada, M., Usui, N., Takeuchi, J., Sugiura, I., Takeuchi, M., Yagasaki, F., Kawai, Y., Miyawaki, S., Ohtake, S., Jinnai, I., Matsuo, K., Naoe, T. & Ohno, R. (2004) Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukaemia. Blood, 104, 3507–3512.
- Weisdorf, D., Zhang, M.J., Arora, M., Horowitz, M.M., Rizzo, J.D. & Eapen, M. (2012) Graft-versus-host disease induced graft-versus-leukaemia effect: greater impact on relapse and disease-free survival after reduced intensity conditioning. Biology of Blood and Marrow Transplantation, 18, 1727–1733.
- Yanada, M., Takeuchi, J., Sugiura, I., Akiyama, H., Usui, N., Yagasaki, F., Kobayashi, T., Ueda, Y., Takeuchi, M., Miyawaki, S., Maruta, A., Emi, N., Miyazaki, Y., Ohtake, S., Jinnai, I., Matsuo, K., Naoe, T. & Ohno, R. (2006) High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukaemia: a phase II study by the Japan Adult Leukaemia Study Group. Journal of Clinical Oncology, 24, 460–466.
- Yeshurun, M., Weisdorf, D., Rowe, J.M., Tallman, M.S., Zhang, M.J., Wang, H.L., Saber, W., de Lima, M., Sandmaier, B.M., Uy, G., Kamble, R.T., Cairo, M.S., Cooper, B.W., Cahn, J.Y., Ganguly, S., Camitta, B., Verdonck, L.F., Dandoy, C., Diaz, M.A., Savani, B.N., George, B., Liesveld, J., McGuirk, J., Byrne, M., Grunwald, M.R., Drobyski, W.R., Pulsipher, M.A., Abdel-Azim, H., Prestidge, T., Wieduwilt, M.J., Martino, R., Norkin, M., Beitinjaneh, A., Seo, S., Nishihori, T., Wirk, B., Frangoul, H., Bashey, A., Mori, S., Marks, D.I. & Bachanova, V. (2019) The impact of the graft-versus-leukaemia effect on survival in acute lymphoblastic leukaemia. Blood Advances, 3, 670–680.
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