伊马替尼联合供者淋巴细胞输注治疗造血干细胞移植后慢性粒细胞白血病复发

Combination therapy of imatinib and donor lymphocyte infusion for chronic myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation

目的探讨伊马替尼联合供者淋巴细胞输注（Du）治疗异基因造血干细胞移植后慢性粒细胞白血病（CML）复发的效果。方法3例CML（慢性期）患者，在接受预处理后，例1接受其胞妹外周血造血干细胞移植，例2接受其胞兄的骨髓移植，例3接受其胞弟的骨髓与外周血造血干细胞联合移植。例1移植后采用环孢素A（CsA）和霉酚酸酯（MMF）预防移植物抗宿主病（GVHD），例2采用CsA、短程甲氨蝶呤（MTX）、抗胸腺细胞球蛋白及抗CD25单克隆抗体预防GVHD，例3应用CsA、MTX和MMF预防GVHD。采用细胞遗传学及荧光原位杂交技术动态监测治疗效果。移植后发生血液学复发时，给予伊马替尼口服，并行DLI。结果例1移植后30d行DLI，输注CD3^＋T淋巴细胞0．5×10^7／kg，移植后50d和70d，再次行DLI，分别输注CD3^＋T淋巴细胞1．0×10^7／kg和2．0×10^7／kg，短串联重复序列（STR）检测提示为完全供者嵌合（DC）。移植后120d，疾病进展，给予伊马替尼400mg／d，同时输注供者CD3^＋T淋巴细胞2．5×10^7／kg。移植后180d，STR检查提示仍为DC。患者最终于移植后17个月因髓外复发死亡。例2的染色体核型于移植后35d转变为46，XY，XY为100％，BCR-ABL融合基因阴性。移植后100d，原发病复发。停用免疫抑制剂，输入供者CD3^＋T淋巴细胞3．9×10^7／kg，同时口服伊马替尼500mg／d。DLI联合伊马替尼治疗后30d，患者的染色体核型为46，XY，XY为100％，BCR-ABL融合基因阴性，患者至今无病存活53个月。例3移植后5d造血功能获得重建，移植后60d，染色体核型为46，XY。移植后120d，确诊CML复发，遂给予伊马替尼400mg／d，并行DLI，共输注供者CD3^＋T淋巴细胞8×10^7／kg，1个月后，患者的染色体核型再次转为46，XY，患者至今无病存活50个月。结论伊马替尼联合DLI对造血干细胞移植后CML复发具有一定的治疗效果。

Objective To evaluate the efficiency of combination therapy of imatinib and donor lymphocyte infusion （DLI） for chronic myeloid leukemia （CML） relapse after allogeneic hematopoietic stem cell transplantation （allc-HSCT）. Methods Patient 1 received peripheral blood stem cell trans- plantation from her HLA-identical sister, patient 2 received bone marrow transplantation from her HLA-identical brother and patient 3 received the transplantation of bone marrow in combined with peripheral blood stem cells following a conditioning regimen. For the prophylaxis of graft-versus-host disease （GVHD）, patient 1 was treated with cyclosporine A （CsA） and mycophenolate mofetil （MMF）, patient 2 with CsA, short course methotrexate （MTX）, anti-thymocyte globulin and anti- CD25 monoclonal antibody, and patient 3 with CsA, MTX and MMF. They were treated with imatinib and DLI in hematologic relapse after HSCT. Results Patient 1 was treated with DLI on day ＋ 30, ＋ 50 and ＋ 70 after allo-HSCT,with CD3^＋ T lymphocyte cells of 0. 5 × 10^7/kg,1.0 × 10^7/kg and 2. 0 × 10^7/kg respectively. She obtained a full donor chimerism on short tandem repeats polymerase chain reaction （STR-PCR）. She was treated with imatinib 400 mg daily and DLI with CD3^＋ T lymphocyte cells of 2. 5 × 10^7/kg on day ＋ 120 days for progression of disease. The bone marrow on day ＋ 180 showed a full donor chimerism on STR-PCR. She died of extramedullary relapse 17 months after allo- HSCT. For patient 2, cytogenetic analysis of bone marrow showed a male karyotype of 46, XY without any cytogenetic abnormalities, 100% cells on interphase nuclei revealed the XY genotype in the sex chromosome fluorescence in site hybridization（FISH） analysis and BCR-ABL fusion gene was negative on day ＋ 35 after allo-HSCT. Patient 2 relapsed on day ＋ 100 after allo-HSCT, CsA was withdrawn and DLI with CD3^＋ T lymphocyte cells of 3. 9 × 10^7/kg in combination with imatinib 500 mg was given daily. After treatment with DLI and imatinib for 30 days, cytogenetic analysis of bone marrow showed a normal male karyotype, 100% cells on interphase nuclei revealed the XY genotype in the sex chromo-some FISH analysis and BCR-ABL fusion gene was negative. She has been disease-free survival for 53 months. Patient 3 was successfully engrafted on day ＋ 5 after allo-HSCT. Cytogenetic analysis showed 46,XY on day ＋ 60. She received DLI with CD3^＋ T lymphocyte cells of 8 × 10^7/kg and imatinib 400 mg daily after relapse on day ＋ 120. One month later, cytogenetic analysis of bone marrow showed a normal male karyotype. She has been disease-free survival for 50 months. Conclusion Combination therapy with imatinib and DLI could be beneficial for relapsed CML following allo-HSCT.