Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia

OBJECTIVE To evaluate the effects of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for patients with chronic myeloid leukemia(CML).METHODS Fifty-seven patients with CML were treated by HSCT, including 8 cases treated with autologous transplantation purged in vivo and in vitro of minimal residual disease (MRD), 39 cases with related donor allogeneic HSCT (allo-HSCT) and 10 cases with unrelated donor alIo-HSCT. The conditioning regimen was a TBI (total-body irradiation) CY (cyclophosphamide, CTX) protocol in 32 patients, a modified BuCY (hydroxyurea, busulfan, Ara-C, CTX) protocal in 24 patients, and a MACC ( Melphalan, Ara-C, CTX and chlorethyl cyclohexyl nitrosourea ) protocol in one patient. Cyclosporine (CsA) and methotrexate (MTX) were used in patients with related-donor allo-HSCT, and CsA and MTX were added to mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) in unrelated donor allo-HSCT for graft versus host disease (GVHD) prophylaxis. Otherwise, CsA was only used for GVHD prophylaxis in patients with accelerated phase (AP) and blast crisis (BC). The Kaplan-Meier survival analysis model was used to estimate the overall survival (OS) and the disease-free survival (DSF) at 5 years after transplantation.RESULTS Eight patients with autologous transplantation, except for 1 case who died of transplantation-related complications, obtained cytogenetic part or complete remission (CR) within 3 months after transplantation. One patient, who was in BC and obtained CR in hematology before transplantation, had been in molecular CR for 92 months after autologous transplantation. Among the 49 patients treated with alIo-HSCT, all obtained CR, except for one patient who died of hepatic veno-occlusive disease (VOD) and one who had not obtained CR. The incidence of infection and VOD was 33.3% and 7.0%, respectively, during transplantation. After transplantation the incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) interstitial pneumonia (IP) was 22.8% and 8.8%, respectively. VOD, HC and CMV IP did not occur in patients with autologous transplantation. The incidence of acute GVHD and the frequency of chronic GVHD was 41.0% and 48.6%, respectively, in patients with related and unrelated transplantation. The rate of relapse in patients with autologous and allogeneic transplantation was 57.1% and 12.8%, respectively. The DFS at 5 years after transplantation was 25.0% and 61.7%, respectively, in patients with autologous and related donor transplantation. The DFS at 5 years was 70.7% and 34.1%, respectively, in patients with CP (chronic phase) or AP and BC before transplantation.CONCLUSION AIIo-HSCT may have a higher clinical cure rate for CML patients with CP. The CsA MTX MMF ATG protocol is more effective for acute GVHD prophylaxis and can decrease the incidence and degree of GVHD in patients with unrelated donor transplantation, Autologous transplantation with purged bone marrow can prolong the survival time of CML patients and some may be cured with transplants of this type.     

Rare myeloid sarcoma/acute myeloid leukemia with adrenal mass after allogeneic mobilization peripheral blood stem cell transplantation

Myeloid sarcoma （MS） is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia （AML）. This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission. A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010. After one month, bone marrow biopsy and aspiration confirmed the diagnosis ofAML. Allogeneic mobilization peripheral blood stem cell transplantation was performed, with the sister of the patient as donor, after complete remission （CR） was achieved by chemotherapy. Five months after treatment, an adrenal mass was detected by positron emission tomography-computed tomography （PET-CT）. Radiotherapy was performed for the localized mass after a multidisciplinary team （MDT） discussion. The patient is still alive as of May 2013, with no evidence of recurrent MS or leukemia.     

The occurrence of Philadelphia chromosome (Ph) negative leukemia after hematopoietic stem cell transplantation for Ph positive chronic myeloid leukemia: implications for disease monitoring and treatment

Chronic myeloid leukemia (CML) is a clonal neoplastic disorder, characterized by t(9;22)(q34;q11) that results in the formation of the Philadelphia chromosome (Ph) and the BCR/ABL fusion gene. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CML. Much of its therapeutic efficacy is attributed to a graft-versus-leukemia (GVL) effect exerted by donor-derived lymphoid cells against the Ph positive (Ph₊) clone. Post-HSCT monitoring by cytogenetic and molecular detection of the Ph₊ clone is necessary, so that pre-emptive immunologic or pharmacologic treatment may be administered at an early stage of relapse. However, under rare circumstances a second Ph negative (Ph_-) leukemia may evolve post-HSCT. The pathogenetic possibilities included leukemia arising from donor-derived hematopoietic stem cells (HSCs), or transformation of residual recipient-derived Ph_- HSCs that have survived the conditioning chemotherapy and radiotherapy. Recipient-derived Ph_- leukemia may be related to genetic alterations that precede the onset of CML, or myelotoxic effects of the HSCT conditioning regimen. The diagnosis of Ph_- relapses requires detailed investigations by conventional karyotyping, fluorescence in-situ hybridization (FISH), and molecular analysis; as well as chimerism studies that help to document the donor or recipient origin of the leukemia. Although uncommonly reported in the past, Ph_- relapses may in fact be more frequent if leukemic relapses post-HSCT are more thoroughly evaluated with these investigations. The recognition of Ph_- relapses are important in several ways. Ph_- relapses cannot be identified by monitoring investigations targeting the Ph₊ clone, so that the early detection of Ph_- leukemia is usually not possible. Furthermore, Ph_- relapses will not respond to therapeutic strategies effective against the Ph₊ CML clone.     

脐带血血清体外培养的人骨髓间充质干细胞对干细胞移植病人造血重建的影响

目的：观察脐带血血清体外培养体系培养的人骨髓间充质干细胞对干细胞移植病人造血重建的影响及不良反应。方法：用10%脐带血血清体外培养体系培养的人骨髓间充质干细胞联合自体外周血干细胞移植治疗3例恶性淋巴瘤患者,计数BM-MSC的数目,观察其造血重建时间、不良反应。结果：采用10%脐带血血清培养体系培养BM-MSC,回输时达到2.82-3.96×106/kg,3例患者中性粒细胞〉0.1×109/L的时间为移植后第9-12天,血小板〉20×109/L的时间为移植后第9-15天,无明显不良反应。结论：10%脐带血血清培养体系是一种基于临床移植需要的分离、培养人BM-MSC的方法,此法培养的BM-MSC联合APBSC移植治疗恶性淋巴瘤患者,加速了造血重建,未见明显不良反应,具有临床应用价值。     

Imatinib combined with myeloablative allogeneic hematopoietic stem cell transplantation for advanced phases of chronic myeloid leukemia

To evaluat the efficacy and safety of myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with imatinib for advanced chronic myeloid leukemia (CML), 15 patients with accelerated phase (n = 6) or blast crisis (n = 9) were enrolled in this study. All the patients were conditioned with cyclophosphamide and busulfan, and treated with cyclosporin (CsA)/methotrexate (MTX)/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. Eleven of these 15 patients (73.3%) achieved complete hematologic response to pre-transplant imatinib, and six (40%) achieved a cytogenetic response. No engraftment failure was observed and the early transplant-related mortality was only 6.7%. Grade 3/4 acute GVHD occurred in 13.3% of patients. Chronic GVHD was observed in 61.5%, including 23.1% suffered from extensive disease. The 5-year estimated rates of relapse, transplant-related mortality and overall survival were 21.0 ± 10.8% 13.7 ± 10.8% and 66.0 ± 12.4%, respectively. Ten (66.7%) of 15 patients are alive with complete molecular remission, even after a median follow-up of 25 months after withdrawal of imatinib. In conclusion, even CML in advanced phases may have a satisfactory outcome after myeloablative allo-HSCT combined with imatinib, which may provide good remission prior to transplantation and reduce relapse risk, with low toxicity.     

Treatment of chronic myeloid leukemia with imatinib mesylate

Philadelphia (Ph) chromosome is the cytogenetic hallmark of chronic myeloid leukemia (CML). The translocation forms a chimeric gene, bcr-abl, which generates BCR-ABL. This fusion protein constitutively activate ABL tyrosine kinase and causes CML. Imatinib mesylate is a selective tyrosine kinase inhibitor on ABL, c-Kit and PGDF-receptor, and functions through competitive inhibition at the ATP-binding site of the enzyme, which leads to growth arrest or apoptosis in cells that express BCR-ABL. Imatinib has revolutionized the management of patients with CML, and at a dose of 400 mg daily has become the current standard therapy for newly diagnosed patients with CML even when they have HLA-matched family donors. Although imatinib therapy has only a 5-year history, it is hoped that CML will be cured with this drug and with forthcoming second-generation tyrosine kinase inhibitors as well as by allogeneic stem cell transplantation in patients who have become resistant to these drugs.     

联合克拉屈滨预处理方案在难治/复发性急性髓系白血病患者异基因造血干细胞移植中的疗效观察

目的:评价联合克拉屈滨预处理方案在异基因造血干细胞移植（allo-HSCT）治疗难治/复发性急性髓系白血病（AML）中的疗效。方法:收集并分析2017年4月至2019年10月在我院层流病房行联合克拉屈滨预处理方案并行异基因造血干细胞移植治疗的17例难治/复发性AML患者的临床资料。结果:17例患者均完成造血重建,粒细胞植入中位时间为12(9~20）d,血小板植入中位时间为11(9~30)d。预处理过程中,1例患者出现出血性膀胱炎。4例出现Ⅰ-Ⅱ级急性移植物抗宿主病（aGVHD),随访结束时,11例存活患者中有8例出现局限型慢性移植物抗宿主病（cGVHD)。5例患者于移植后复发,中位复发时间为4（2~19）月。1年总生存率为57.2％,1年无病生存率为55.2％。结论:联合克拉屈滨预处理方案近期疗效较好,在不增加预处理相关不良反应的前提下,可有效提高患者生存率,改善患者的预后。     

慢性髓细胞白血病异基因外周血联合骨髓造血干细胞移植T淋巴细胞重建研究

 目的 观察慢性髓细胞白血病（CML）患者进行异基因外周血联合骨髓造血干细胞移植（allo-PBSCT+BMT）后T淋巴细胞的重建情况。方法 11例采用同胞异基因HLA6／6位点相合的allo-PBSCT+BMT的CML患者,监测移植后1年内血常规中淋巴细胞的总数和比例变化,并使用流式细胞术检测CD+3 T细胞、CD+4 T细胞、CD+8 T细胞在淋巴细胞中所占的比例及CD4／CD8比值的变化。结果 allo-PBSCT+BMT后淋巴细胞重建较快,在+60天淋巴细胞绝对值及比例就达到正常水平。早期T淋巴细胞以CD+8 T细胞为主导,在+60天达高峰,占淋巴细胞的（56.3±18.69）％,后逐渐降低。移植后1年CD+4 T细胞一直明显低于正常,导致CD4／CD8比值在移植后一年持续倒置,但比例逐渐向正常水平发展,到一年时CD4／CD8比值为0.79±0.38。结论 allo-PBSCT+BMT后T淋巴细胞重建及造血重建较快,同时不增加复发率和急慢性GVHD,是一种安全有效的移植方法。     

人骨髓间充质干细胞对慢性粒细胞白血病细胞增殖的影响及其机制探讨

背景与目的：我们先前的实验证明,在适宜的刺激下骨髓间充质干细胞（mesenchymal stem cells,MSCs）可分泌可溶性的细胞因子。本实验旨在研究MSCs对慢性粒细胞白血病（chronic myeloid leukemia,CML）细胞增殖的影响．并检测上清液中MSCs分泌的细胞因子。方法：采集健康供者骨髓培养MSCs,流式细胞仪检测第三代MSCs表面标记。将MSCs与不同浓度的CML患者的骨髓单个核细胞（chronic myeloid leukemia mononuclear cells,CML—MNC）共培养;每天收集各组CML—MNC计数取均值,绘制生长曲线。于实验的第3天和第6天收集各培养组的上清液,ELISA法测IFN-α。结果：原代和传代培养的细胞呈大的长梭形,增殖旺盛：细胞表面标记：CD44阳性,而CD45阴性。生长曲线示：与MSCs培养的CML—MNC增殖受抑。ELISA法检测结果示：对照组CML细胞生成IFN-α极低,显著低于各实验组,差异有统计学意义（P〈0．001）。MSCs与CML细胞共培养时可以分泌大量的IFN-α,且随着MSCs浓度的增加和共培养时间的延长,生成的IFN-α量增多。结论：MSCs与CML细胞共培养时能产生大量IFN-α抑制CML细胞增殖。     

异基因造血干细胞移植在急变期慢性粒细胞白血病治疗中的应用

 目前,急变期慢性粒细胞白血病的治疗仍然是一个较大的挑战,酪氨酸激酶抑制剂虽有一定的疗效,却并不持久,异基因造血干细胞移植是唯一可以根治该病并使患者长期生存的治疗方式。文章将对急变期慢性粒细胞白血病异基因造血干细胞移植前的治疗、预处理方案、供者、造血干细胞来源的选择、移植后微小残留病的监测、移植后复发的预防进行介绍。     

Myelodysplasia and acute myeloid leukemia occurring after autologous bone marrow transplantation for lymphoma

Secondary hematopoietic disease manifesting as acute myeloid leukemia, myelodysplastic syndrome or clonal karyotypic abnormalities, has been recently recognized as a relatively frequent and potentially serious complication of autologous bone marrow transplantation for both Hodgkin's disease and non-Hodgkin's lymphoma. The available evidence suggests the disease results primarily from repeated exposure of the host stem cells to therapeutic agents before the time of transplant, but a conspiratory role for the transplantation procedure itself cannot be entirely excluded. Strategies to decrease the incidence of secondary hematopoietic disease include earlier stem cell harvest and/or transplantation, and the performance of screening karyotypic studies on the bone marrow prior to autologous grafting.     

异基因造血干细胞移植治疗急性髓系白血病的现状

 异基因造血干细胞移植（allo-HSCT）是治疗急性髓系白血病（AML）的有效方法之一。allo-HSCT的治疗作用来自于预处理中的放疗和（或）化疗,以及供者免疫系统的移植物抗白血病（GVL）效应。近十年来,随着对白血病细胞生物学特性研究的不断深入,根据细胞遗传学和分子标志对AML进行危险程度分级,使我们能够挑选出哪些AML患者可以从allo-HSCT中获益。allo-HSCT治疗AML的临床疗效已有明显提高,并且适用范围也较前扩大,但在AML中的应用还存在一定差异。现对allo-HSCT治疗AML的机制、时机、疗效、供者选择及预处理方案进行讨论。     

Prognostic implication of gene mutations on overall survival in the adult acute myeloid leukemia patients receiving or not receiving allogeneic hematopoietic stem cell transplantations

Several gene mutations have been shown to provide clinical implications in patients with acute myeloid leukemia (AML). However, the prognostic impact of gene mutations in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively evaluated the clinical implications of 8 gene mutations in 325 adult AML patients; 100 of them received allo-HSCT and 225 did not. The genetic alterations analyzed included NPM1, FLT3-ITD, FLT3-TKD, CEBPA, RUNX1, RAS, MLL-PTD, and WT1. In patients who did not receive allo-HSCT, older age, higher WBC count, higher lactate dehydrogenase level, unfavorable karyotype, and RUNX1 mutation were significantly associated with poor overall survival (OS), while CEBPA double mutation (CEBPA^double-mut) and NPM1^mut/FLT3-ITD^neg were associated with good outcome. However, in patients who received allo-HSCT, only refractory disease status at the time of HSCT and unfavorable karyotype were independent poor prognostic factors. Surprisingly, RUNX1 mutation was an independent good prognostic factor for OS in multivariate analysis. The prognostic impact of FLT3-ITD or NPM1^mut/FLT3-ITD^neg was lost in this group of patients receiving allo-HSCT, while CEBPA^double-mut showed a trend to be a good prognostic factor. In conclusion, allo-HSCT can ameliorate the unfavorable influence of some poor-risk gene mutations in AML patients. Unexpectedly, the RUNX1 mutation showed a favorable prognostic impact in the context of allo-HSCT. These results need to be confirmed by further studies with more AML patients.     

伊马替尼联合造血干细胞移植治疗慢性粒细胞白血病

 目的 研究伊马替尼（商品名：格列卫）对异基因造血干细胞移植（allo-HSCT）和自体外周血造血干细胞移植（APBSCT）的影响。方法 18例慢性粒细胞白血病（CML）分为2组：①al-lo-HSCT组14例,其中10例为CML加速期（AP）和急变期（BP）,4例为CML慢性期（CP）,移植之前格列卫疗程中位数为25（7～60）d,供受者HLA完全相合,亲缘相关供者9例、非亲缘供者5例,预处理方案为TBI+Cy+VP16或Bu／Cy±ATG,GVHD预防按常规方案进行;②APBSC动员4例,均为CML-CP患者,格列卫治疗的中位数疗程5.5（4～26）个月,动员前反复IFISH-bcr／abl阳性率0～2%,动员方案CAE+G-CSF,其中3例经TBI+Cy+VP16预处理后进行了APBSCT。结果 4例患者经G-CSF动员第5天分离自体外周血干细胞（APBSC）1次,得CD+34细胞的中位数6.8（3.9～9.6）×106／kg,动员产品中IFISH-bcr／abl阳性细胞比例高于动员前骨髓细胞（2.8 %∶0.8 %）,4例动员PBSC的患者中3例进行了APBSCT,移植后随访中位时间24（18～28）个月,2例复发,1例持续IFISH-bcr／abl阴性。14例allo-HSCT患者中位随访8（4～20）个月,造血重建需要8～21 d,发生GVHD 8例,白血病复发2例,移植相关并发症死亡2例,复发死亡1例,无病生存9例。结论 格列卫治疗后对CML患者造血干细胞的动员、移植结果无明显影响。     

Immunotherapy in acute myeloid leukemia

Despite the remarkable progress made in some leukemias such as CML and CLL, cytotoxic treatment for AML remains essentially unchanged over the last 4 decades. Several lines of evidence, including the graft versus leukemia effect associated with allogeneic hematopoietic stem cell transplantation (HSCT), suggest that immunotherapy is an active modality in AML. Given the lack of progress for chemotherapy in this disease, many novel immunologic treatment approaches have been explored. The goals of non‐transplant‐based immune approaches have largely consisted of the stimulation or restoration of endogenous immune responses or the targeting of specific tumor antigens by immune cells. These strategies have been associated with less toxicity than allogeneic HSCT but typically have inferior efficacy. Allogeneic HSCT exploits major and minor histocompatibility differences between the donor and recipient in order to recognize and eradicate malignancy. With the recognition that the immune system itself provides a basis for treating AML, immunotherapy continues to be an attractive modality to exploit in the treatment of this disease. Cancer 2015;121:2689‐2704. © 2015 American Cancer Society     

α干扰素促进急性髓性白血病来源的树突状细胞的成熟分化

目的:研究α干扰素(interferon alpha,IFN-α)对不同亚型的急性髓性白血病(acute myeloid leukemia,AML)细胞来源的树突状细胞(dendritic cell,DC)免疫表型及功能的影响。方法:5例初发AML患者(其中M2 1例、M4 2例、M5 2例)的外周血单个核细胞,在含GM-CSF、IL-4、TNF-α的无血清培养液中培养11 d,其后加入IFN-α-2a(1 000 U/ml)继续培养3 d,获得DC(IFN-AML-DC),光镜下观察细胞形态,流式细胞仪测定细胞免疫表型,同种异体混和淋巴细胞反应检测DC的免疫功能。结果:所有患者白血病细胞培养14 d后均转化为IFN-AML-DC,与正常人外周血单核细胞由GM-CSF IL-4 TNF-α培养获得的DC(monocyte-derived DC,MoDC)及AML细胞由GM-CSF IL-4 TNF-α培养获得的DC(AML-DC)相比,IFN-AML-DC具有典型成熟形态的细胞明显增多,表达CD83 细胞的比例显著增加,HLA-DR、CD86分子的表达水平增高,对同种异体T淋巴细胞的激活能力明显高于MoDC及AML-DC。结论:IFN-α能够促进AML-DC的体外成熟,形成更强的免疫激活能力,为AML的免疫治疗提供更有力的手段。