Clinical characteristics and treatment outcome in 65 cases with refractory cytopenia of childhood defined according to the WHO 2008 classification
Corresponding Author
Daisuke Hasegawa
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Correspondence: Daisuke Hasegawa, Department of Paediatrics, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan.
E-mail: [email protected]
Search for more papers by this authorXiaojuan Chen
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Department of Paediatrics, Institute of Haematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, Tianjin, China
Search for more papers by this authorShinsuke Hirabayashi
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Division of Paediatric Haematology and Oncology, Department of Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
Search for more papers by this authorYasushi Ishida
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Search for more papers by this authorShizuka Watanabe
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Search for more papers by this authorYuji Zaike
Clinical Laboratory, Research Hospital, The Institution of Medical Science, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorMasahiro Tsuchida
Paediatric Haematology/Oncology, Ibaraki Children's Hospital, Mito, Japan
Search for more papers by this authorAtsuko Masunaga
Department of Surgical Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan
Search for more papers by this authorAyami Yoshimi
Division of Paediatric Haematology and Oncology, Department of Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
Search for more papers by this authorAsahito Hama
Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorSeiji Kojima
Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorMasafumi Ito
Department of Pathology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
Search for more papers by this authorTatsutoshi Nakahata
Centre for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
Search for more papers by this authorAtsushi Manabe
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Daisuke Hasegawa
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Correspondence: Daisuke Hasegawa, Department of Paediatrics, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan.
E-mail: [email protected]
Search for more papers by this authorXiaojuan Chen
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Department of Paediatrics, Institute of Haematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, Tianjin, China
Search for more papers by this authorShinsuke Hirabayashi
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Division of Paediatric Haematology and Oncology, Department of Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
Search for more papers by this authorYasushi Ishida
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Search for more papers by this authorShizuka Watanabe
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Search for more papers by this authorYuji Zaike
Clinical Laboratory, Research Hospital, The Institution of Medical Science, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorMasahiro Tsuchida
Paediatric Haematology/Oncology, Ibaraki Children's Hospital, Mito, Japan
Search for more papers by this authorAtsuko Masunaga
Department of Surgical Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan
Search for more papers by this authorAyami Yoshimi
Division of Paediatric Haematology and Oncology, Department of Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
Search for more papers by this authorAsahito Hama
Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorSeiji Kojima
Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorMasafumi Ito
Department of Pathology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
Search for more papers by this authorTatsutoshi Nakahata
Centre for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
Search for more papers by this authorAtsushi Manabe
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan
Search for more papers by this authorSummary
This study analysed 65 children who were prospectively registered between 1999 and 2008 and fulfilled the World Health Organization 2008 criteria of refractory cytopenia of childhood (RCC). First-line therapy was determined by the treating physicians: 25 patients received immunosuppressive therapy (IST), 12 patients received haematopoietic stem cell transplantation (HSCT) and one patient received intensive chemotherapy. The remaining 27 patients were followed without treatment for more than 2 years (watch and wait; WW). In the WW group, 18 patients had stable disease without further intervention. Thirteen of 29 patients (45%) who ended up receiving IST showed response. The combination of ciclosporin and antithymocyte globulin was not shown to be superior to ciclosporin alone with regard to response rate or survival. Of 28 patients who ended up undergoing HSCT, 17 patients are alive in complete remission, whereas nine patients died mostly due to transplantation-related mortality. The 5-year overall survival for all patients was 82 ± 5%. Eight patients suffered from disease progression. Patients with monosomy 7 or multilineage-dysplasia had a significantly higher incidence of disease progression. This analysis revealed heterogeneity in the clinical course of RCC, varying from those who remained stable for long periods to those who progressed to advanced disease.
Supporting Information
| Filename | Description |
|---|---|
| bjh12955-sup-0001-tableS1-S5.docxWord document, 98.4 KB | Table SI. Comparison of characteristics according to the initial treatment strategy. Table SII. Comparison of characteristics of patients who received IST (n = 29) according to the IST regimen. Table SIII. Comparison of characteristics between responder and non-responder to IST at 6 months. Table SIV. Univariate analyses of the probability of 5-year event-free survival (EFS) after HSCT. Table SV. Summary of eight cases who suffered from disease progression. |
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
- Baumann, I., Niemeyer, C.M. & Benett, J. (2008) Childhood myelodysplastic syndrome. In: WHO Classification of Tumours of Haematopoietic and Lymphoid tissues (eds by S. Swerdlow, E. Campo, N. Harris, E.S. Jaffe, S.A. Pileri, H. Stein, J. Thiele & J.W. Vardiman), pp. 104–107. IARC Press, Lyon.
- Baumann, I., Führer, M., Behrendt, S., Campr, V., Csomor, J., Furlan, I., de Haas, V., Kerndrup, G., Leguit, R.J., De Paepe, P., Noellke, P., Niemeyer, C. & Schwarz, S. (2012) Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria. Histopathology, 61, 10–17.
- Calado, R.T. (2011) Immunologic aspects of hypoplastic myelodysplastic syndrome. Seminars in Oncology, 38, 667–672.
- Cantù Rajnoldi, A., Fenu, S., Kerndrup, G., van Wering, E.R., Niemeyer, C.M. & Baumann, I. (2005) Evaluation of dysplastic features in myelodysplastic syndromes: experience from the morphology group of the European Working Group of MDS in Childhood (EWOG-MDS). Annals of Hematology, 84, 429–433.
- Cutler, C.S., Lee, S.J., Greenberg, P., Deeg, H.J., Pérez, W.S., Anasetti, C., Bolwell, B.J., Cairo, M.S., Gale, R.P., Klein, J.P., Lazarus, H.M., Liesveld, J.L., McCarthy, P.L., Milone, G.A., Rizzo, J.D., Schultz, K.R., Trigg, M.E., Keating, A., Weisdorf, D.J., Antin, J.H. & Horowitz, M.M. (2004) A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood, 104, 579–585.
- Filipovich, A.H., Weisdorf, D., Pavletic, S., Socie, G., Wingard, J.R., Lee, S.J., Martin, P., Chien, J., Przepiorka, D., Couriel, D., Cowen, E.W., Dinndorf, P., Farrell, A., Hartzman, R., Henslee-Downey, J., Jacobsohn, D., McDonald, G., Mittleman, B., Rizzo, J.D., Robinson, M., Schubert, M., Schultz, K., Shulman, H., Turner, M., Vogelsang, G. & Flowers, M.E. (2005) 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, 11, 945–956.
- Germing, U., Strupp, C., Kuendgen, A., Isa, S., Knipp, S., Hildebrandt, B., Giagounidis, A., Aul, C., Gattermann, N. & Haas, R. (2006) Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes. Haematologica, 91, 1596–1604.
- Haase, D., Germing, U., Schanz, J., Pfeilstöcker, M., Nösslinger, T., Hildebrandt, B., Kundgen, A., Lübbert, M., Kunzmann, R., Giagounidis, A.A., Aul, C., Trümper, L., Krieger, O., Stauder, R., Müller, T.H., Wimazal, F., Valent, P., Fonatsch, C. & Steidl, C. (2007) New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood, 110, 4385–4395.
- Hasegawa, D., Manabe, A., Yagasaki, H., Ohtsuka, Y., Inoue, M., Kikuchi, A., Ohara, A., Tsuchida, M., Kojima, S. & Nakahata, T. (2009) Treatment of children with refractory anemia: the Japanese Childhood MDS Study Group Trial (MDS99). Pediatric Blood & Cancer, 53, 1011–1015.
- Hasle, H., Niemeyer, C.M., Chessells, J.M., Baumann, I., Bennett, J.M., Kerndrup, G. & Head, D.R. (2003) A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia, 17, 277–282.
- Hasle, H., Baumann, I., Bergstrasser, E., Fenu, S., Fischer, A., Kardos, G., Kerndrup, G., Locatelli, F., Rogge, T., Schultz, K.R., Stary, J., Trebo, M., van den Heuvel-Eibrink, M.M., Harbott, J., Nollke, P. & Niemeyer, C.M. (2004) The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML). Leukemia, 18, 2008–2014.
- Howard, S.C., Naidu, P.E., Hu, X.J., Jeng, M.R., Rodriguez-Galindo, C., Rieman, M.D. & Wang, W.C. (2004) Natural history of moderate aplastic anemia in children. Pediatric Blood & Cancer, 43, 545–551.
- Jonásova, A., Neuwirtová, R., Cermák, J., Vozobulová, V., Mociková, K., Sisková, M. & Hochová, I. (1998) Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. British Journal of Haematology, 100, 304–309.
- Kardos, G., Baumann, I., Passmore, S.J., Locatelli, F., Hasle, H., Schultz, K.R., Stary, J., Schmitt-Graeff, A., Fischer, A., Harbott, J., Chessells, J.M., Hann, I., Fenu, S., Rajnoldi, A.C., Kerndrup, G., Van Wering, E., Rogge, T., Nollke, P. & Niemeyer, C.M. (2003) Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. Blood, 102, 1997–2003.
- Kojima, S., Hibi, S., Kosaka, Y., Yamamoto, M., Tsuchida, M., Mugishima, H., Sugita, K., Yabe, H., Ohara, A. & Tsukimoto, I. (2000) Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood, 96, 2049–2054.
- Luger, S.M., Ringdén, O., Zhang, M.J., Pérez, W.S., Bishop, M.R., Bornhauser, M., Bredeson, C.N., Cairo, M.S., Copelan, E.A., Gale, R.P., Giralt, S.A., Gulbas, Z., Gupta, V., Hale, G.A., Lazarus, H.M., Lewis, V.A., Lill, M.C., McCarthy, P.L., Weisdorf, D.J. & Pulsipher, M.A. (2012) Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplantation, 47, 203–211.
- Malcovati, L., Germing, U., Kuendgen, A., Della Porta, M.G., Pascutto, C., Invernizzi, R., Giagounidis, A., Hildebrandt, B., Bernasconi, P., Knipp, S., Strupp, C., Lazzarino, M., Aul, C. & Cazzola, M. (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. Journal of Clinical Oncology, 25, 3503–3510.
- Matsuda, A., Germing, U., Jinnai, I., Iwanaga, M., Misumi, M., Kuendgen, A., Strupp, C., Miyazaki, Y., Tsushima, H., Sakai, M., Bessho, M., Gattermann, N., Aul, C. & Tomonaga, M. (2007) Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification. Leukemia, 21, 678–686.
- Mehta, P.A., Harris, R.E., Davies, S.M., Kim, M.O., Mueller, R., Lampkin, B., Mo, J., Myers, K. & Smolarek, T.A. (2010) Numerical chromosomal changes and risk of development of myelodysplastic syndrome–acute myeloid leukemia in patients with Fanconi anemia. Cancer Genetics and Cytogenetics, 203, 180–186.
- Molldrem, J.J., Caples, M., Mavroudis, D., Plante, M., Young, N.S. & Barrett, A.J. (1997) Antithymocyte globulin for patients with myelodysplastic syndrome. British Journal of Haematology, 99, 699–705.
- Molldrem, J.J., Leifer, E., Bahceci, E., Saunthararajah, Y., Rivera, M., Dunbar, C., Liu, J., Nakamura, R., Young, N.S. & Barrett, A.J. (2002) Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Annals of Internal Medicine, 137, 156–163.
- Niemeyer, C.M. & Kratz, C.P. (2008) Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options. British Journal of Haematology, 140, 610–624.
- Nishio, N., Yagasaki, H., Takahashi, Y., Muramatsu, H., Hama, A., Yoshida, N., Kudo, K. & Kojima, S. (2009) Natural history of transfusion-independent non-severe aplastic anemia in children. International Journal of Hematology, 89, 409–413.
- Passmore, S.J., Chessells, J.M., Kempski, H., Hann, I.M., Brownbill, P.A. & Stiller, C.A. (2003) Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. British Journal of Haematology, 121, 758–767.
- 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.
- Sasaki, H., Manabe, A., Kojima, S., Tsuchida, M., Hayashi, Y., Ikuta, K., Okamura, I., Koike, K., Ohara, A., Ishii, E., Komada, Y., Hibi, S. & Nakahata, T. (2001) Myelodysplastic syndrome in childhood: a retrospective study of 189 patients in Japan. Leukemia, 15, 1713–1720.
- Shimamoto, T., Tohyama, K., Okamoto, T., Uchiyama, T., Mori, H., Tomonaga, M., Asano, Y., Niho, Y., Teramura, M., Mizoguchi, H., Omine, M. & Ohyashiki, K. (2003) Cyclosporin A therapy for patients with myelodysplastic syndrome: multicenter pilot studies in Japan. Leukemia Research, 27, 783–788.
- Sloand, E.M. (2009) Hypocellular myelodysplasia. Hematology/Oncology Clinics of North America, 23, 347–360.
- Sloand, E.M. & Rezvani, K. (2008) The role of the immune system in myelodysplasia: implications for therapy. Seminars in Hematology, 45, 39–48.
- Sloand, E.M., Wu, C.O., Greenberg, P., Young, N. & Barrett, J. (2008) Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. Journal of Clinical Oncology, 26, 2505–2511.
- Strahm, B., Locatelli, F., Bader, P., Ehlert, K., Kremens, B., Zintl, F., Fuhrer, M., Stachel, D., Sykora, K.W., Sedlacek, P., Baumann, I. & Niemeyer, C.M. (2007) Reduced intensity conditioning in unrelated donor translantation for refractory cytopenia in childhood. Bone Marrow Transplantation, 40, 329–333.
- Vardiman, J.W., Harris, N.L. & Brunning, R.D. (2002) The World Health Organization (WHO) classification of the myeloid neoplasms. Blood, 100, 2292–2302.
- Verburgh, E., Achten, R., Louw, V.J., Brusselmans, C., Delforge, M., Boogaerts, M., Hagemeijer, A., Vandenberghe, P. & Verhoef, G. (2007) A new disease categorization of low-grade myelodysplastic syndromes based on the expression of cytopenia and dysplasia in one versus more than one lineage improves on the WHO classification. Leukemia, 21, 668–677.
- de Vries, A.C., Langerak, A.W., Verhaaf, B., Niemeyer, C.M., Stary, J., Schmiegelow, K., van Wering, E.R., Zwaan, C.M., Beishuizen, A., Pieters, R. & van den Heuvel-Eibrink, M.M. (2008) T-cell receptor Vbeta CDR3 oligoclonality frequently occurs in childhood refractory cytopenia (MDS-RC) and severe aplastic anemia. Leukemia, 22, 1170–1174.
- Yoshimi, A., Baumann, I., Führer, M., Bergsträsser, E., Göbel, U., Sykora, K.W., Klingebiel, T., Gross-Wieltsch, U., van den Heuvel-Eibrink, M.M., Fischer, A., Nöllke, P. & Niemeyer, C. (2007) Immunosuppressive therapy with anti-thymocyte globulin and cyclosporine A in selected children with hypoplastic refractory cytopenia. Haematologica, 92, 397–400.
Citing Literature
