allogeneic hematopoietic stem cell transplantation allo-hsct chronic myeloid leukemia CML 1 1 FISH Major-bcr/abl 90% 10 30%

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1 chronic myeloid leukemia CML imatinib complete cytogenetic response CCR allogeneic hematopoietic stem cell transplantation allo-hsct HLA rpbsct 6 imatinib dasatinib 9 17 donor lymphocyte infusion DLI CML Key Wordschronic myeloid leukemia CMLallogeneic hematopoietic stem cell transplantation allo-hsctdonor lymphocyte infusion DLItyrosine kinase inhibitor allogeneic hematopoietic stem cell transplantation allo-hsct chronic myeloid leukemia CML 1 imatinib imatinib allo-hsct 1 CML 10 30% donor lymphocyte infusion DLI 80% 1 DLI dasatinib nirotinib bcr/abl CML dasatinib DLI CML FISH Major-bcr/abl 90% 6 STI 7 Ph FISH complete cytogenetic response CCR 10 blastic crisis biphenotype 11 JALSG ALL-97 like 2 HLA rpbsct cm 68.8 kg 37.0 C 88 / 106/70 mmhg

2 1 blast G 20/20 bcr/abl FISH 1/100 1% Major bcr/abl PCR copy/µg RNA bright liver 1 WBC 2700 /µl CRP 0.3 mg/dl IgG 671 mg/dl stab 5% TP 6.1 g/dl IgA 101 mg/dl seg 45% Alb 4.0 g/dl IgM 19 mg/dl lym 37% T-Bil 0.6 mg/dl βd <5 pg/ml mono 10% AST 20 IU/l HBs Ag - eos 1% ALT 29 IU/l HBs Ab - baso 2% ALP 148 IU/l HCV Ab - RBC 288 x 10 4 /µl γgtp 27 IU/l HTLV-1 - Hb 10.6 g/dl LDH 241 IU/l HIV - Ht 31.8% BUN 14 mg/dl Plt 27.7 x 10 4 /µl Cre 0.74 mg/dl Ret 12.9 UA 3.8 mg/dl Na 142 meq/l PT-INR 0.93 K 4.2 meq/l APTT 29.9 sec Cl 103 meq/l FBG 200 mg/dl ng/ml FDP 3.7 µg/ml 1 2 day 0 imatinib failure 2 PCR FISH major partial cytogenetic response MCRallo-HSCT imatinib 800 mg/day day -8 Busulfex 0.8 mg/kg/ x 4 /day -8-5; Cyclophosphamide 60 mg/kg/day -4-3 CD x 10 6 /kg matchgvhd graft-versus-host disease cyclosporine A CsA methotrexate 10 mg/m 2 day 1 7 mg/m 2 day 3 5 CsA ng/ml polymyxin B sulfate acyclovir fluconazole hepatic venoocclusive disease ursodeoxycholic acid 600 mg/day day 1 GCSF day -5 polymyxin B sulfate LVFX day 4 grade 3 grade 2 grade 1 CTCAE ver. 3.0 day 14 day 21 veno-occulusive disease day 21 mpsl 1 mg/kg/day gabexate mesilate antithrombin Ⅲ glycyrrhizin day 23 AST 1226 IU/L ALT 742 IU/L PT-INR 2.01 day mg/dl 9% moderate GVHD day 60 day 90 T type day Major bcr/abl PCR copy/µg RNA

3 1 CyA; cyclosporine A, mpsl; methylprednisolone, PSL; prednisolone, FN; febrile neutropenia, allo-pbsct; allogeneic peripheral blood stem cell transplantation, VOD; veno-occlusive disease 2 HSV; herpes simplex, CD; clostridium difficile, FN; febrile neutropenia, CVAD; cyclophosphamide, vincristine, cytarabine and dexamethasone, DLI; donor lymphocyte infusion

4 day 30 GVHD day 115 day 116 day 119 9% day /µl blast 66% Major bcr/abl CD7 CD10 CD19 CD13 CD33 CD34 HLA-DR biphenotype imatinib 600 mg/day CsA day 126 day /µl blast 87% hyper CVAD imatinib 253Y H imatinib day 132 dasatinib 140 mg/day day 134 day 139 dasatinib dasatinib day L/min acyclovir 10 mg/kg/ x 3 /day Major bcr/abl PCR day copy /µg RNA day copy/µg RNA day 174 HLA GVL day 203 DLI CD3 1.3 x 10 8 /kg DLI day 222 TNC 63000/µl blast 16% Major bcr/abl PCR 56 copy/µg RNA day 244 TNC /µl blast 86% Major bcr/abl PCR 240 copy/µg RNA GVHD dasatinib day 298 Enterococcus faecium Trichosporon asahii day 301 Martínez 107 CML % 49.8% 25% 0% CML DLI 58 91% 20 80% 1 DLI 28 79% 0 25% 3 DLI CML imatinib 4 DLI 3 72% vs 20% 5 imatinib dasatinib imatinib imatinib CML blastic crisis major cytogenetic response myeloid leukemia 31% lymphoid leukemia 50% % 6 dasatinib 70 mg/ x 3 O'Hare T imatinib dasatinib 7 dasatinib CML DLI DLI dose

5 blastic crisis 1) Baccarani M, et al. (European LeukemiaNet): Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108: , ) Martínez C, et al.: Relapse of chronic myeloid leukemia after allogeneic stem cell transplantation: outcome and prognostic factors: the Chronic Myeloid Leukemia Subcommittee of the GETH (Grupo Español de Trasplante Hemopoyético). Bone Marrow Transplant 36: , ) :.,, ) Olavarria E, et al. Chronic Leukaemia Working Party of the European Group of Bone and Marrow Transplantation (EBMT)): Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia 17: , ) Weisser M, et al.: A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation. Haematologica 91: , ) Cortes J, et al.: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109: , ) O'Hare T, et al.: Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110: ,