多种来源造血干细胞移植治疗重型再生障碍性贫血

背景：造血干细胞移植是年轻重型再生障碍性贫血患者首选方法,但在中国多数重型再生障碍性贫血患者无合适的供者,单倍体相合或非血缘造血干细胞移植国内外目前还处于探索阶段,联合间充质干细胞移植报道少见。 目的：观察不同干细胞来源造血干细胞移植治疗重型再生障碍性贫血的疗效。 方法：10例(3~52岁)重型再生障碍性贫血患者,分别接受了亲缘HLA相合(2例),单倍体相合(5例),非血缘(3例)的外周血和/或骨髓造血干细胞移植,其中5例患者同时联合了间充质干细胞共移植。预处理方案主要为环磷酰胺、氟达拉滨和抗人胸腺球蛋白,以霉酚酸酯、环孢素A加短疗程的甲氨蝶呤预防移植物抗宿主病,单倍体相合移植的患者在此基础上加马利兰和CD25单克隆抗体;同基因的例5患者预处理方案为抗人胸腺球蛋白+甲基泼尼龙。输注间充质干细胞的量为(0.27~1.85)×10⁶/kg。接受和未接受间充质干细胞组的患者回输的造血干细胞有核细胞分别为(7.4~17.38)×10⁸/kg和(6.09~13.68)×10⁸/kg。 结果与结论：除1例单倍体相合患者移植未成功,+36 d死于并发症外,余患者移植后染色体及DNA指纹检测等说明造血干细胞移植完全供者植入。移植后中性粒细胞达到0.5×10⁹ L^-1,血小板计数≥20×10⁹ L^-1中位时间分别为12 d和13 d;其中造血功能恢复快慢的趋势是同基因移植>外周血或/和骨髓+间充质干细胞移植>单纯外周血或/和骨髓干细胞移植,而亲缘HLA全相合的52岁患者造血恢复最慢。非血缘移植例1、6患者发生了Ⅰ度急性移植物抗宿主病,单倍体相合移植的例2和例10患者发生了Ⅱ度急性移植物抗宿主病后出现了局限性的慢性移植物抗宿主病,余下患者移植后生活质量良好,无慢性移植物抗宿主病;除未接受间充质干细胞的例3患者移植后出现严重感染外,其余患者移植后再未出现严重的感染和出血。结果提示造血干细胞是安全,高效治疗重型再生障碍性贫血的方法,联合应用间充质造血干细胞者患者造血恢复快,移植并发症少。     

ABO血型不合外周血造血干细胞移植10例

背景：ABO血型不合供受者之间进行外周血造血干细胞移植,面临受者血型的转变、移植后输血的选择等问题。 目的：观察ABO血型不合外周血造血干细胞移植治疗血液病的临床疗效和近远期并发症。 方法：回顾性分析了2005/2008武警总医院收治的10例ABO血型不合异基因外周血同胞供者造血干细胞移植患者的资料。总结植入效果,血型转变,移植物抗宿主病以及不良反应。 结果与结论：9例患者恢复造血功能,血型转变为完全供者型,1例患者白细胞血小板恢复,但红细胞植入延迟。所有患者在输注移植物时未出现短暂的血红蛋白尿,无严重急性溶血和迟发型溶血的发生,1例出现严重的移植物抗宿主病。可见ABO血型不合外周血造血干细胞移植对移植疗效无明显影响,红细胞植入延迟的预防和处理十分重要。     

A comparison of related donor peripheral blood and bone marrow transplants: importance of late-onset chronic graft-versus-host disease and infections.

Peripheral blood hematopoietic stem cell (PBSC) transplants have been shown to result in more rapid engraftment than standard bone marrow transplants (BMTs). Little comparative data exist regarding complications in patients receiving transplants using these stem cell sources. In our study, 97 adults with advanced hematologic malignancies who received allogeneic PBSC transplants were compared with 97 adults who received allogeneic BMTs using identical preparative regimens and support parameters. The incidence of systemic infections and other major complications occurring within the first year after transplantation were calculated in both groups. Proportional hazard analysis was used to examine risk factors for death and complications in both groups. Patients receiving PBSC transplants had more rapid neutrophil (17 days versus 24 days; P <.001) and platelet engraftment (28 days versus 47 days; P <.001) than BMT recipients. The survival rate at 2 years was 38% in PBSC transplant recipients and 28% in marrow recipients (P =.08). There was no difference in rates of grade II to IV acute graft-versus-host disease (GVHD) between groups (PBSC 46%, BMT 51%; P =.3). PBSC transplant recipients were more likely to develop chronic GVHD after 180 days (hazard ratio 2.2; P =.05). Accompanying this "late-onset chronic GVHD," a pattern of more frequent late systemic fungal and cytomegalovirus infections was observed in PBSC transplant recipients. In conclusion, although PBSC transplant recipients engraft more quickly than BMT recipients and have somewhat better 2-year survival rates, they develop more frequent late-onset chronic GVHD and may have more late fungal and cytomegalovirus infections than marrow recipients. Further studies must examine this late-onset chronic GVHD and better characterize immune reconstitution in PBSC transplant recipients to understand their effects on patient recovery.     

单倍体相合造血干细胞移植治疗高危白血病

背景：异基因造血干细胞移植是治疗高危白血病的主要方法,单倍体相合的造血干细胞移植扩展了移植的应用范围。 目的：观察“改良Bu/Cy+ATG”为预处理方案的单倍体相合造血干细胞移植治疗高危白血病的疗效。 方法：对19例高危白血病患者,均采用“改良Bu/Cy+ATG”预处理方案,采用外周血造血干细胞移植5例,外周血+骨髓造血干细胞移植14例。应用甲氨蝶呤,环孢素A,吗替麦考酚酯预防移植物抗宿主病。 结果与结论：①短期疗效：中性粒细胞恢复的中位时间为12(8~20) d;血小板恢复的中位时间为13(10~31) d;移植后100 d内,移植相关死亡率为(15.8±8.4)%。②移植物抗宿主病发生情况：Ⅰ~Ⅳ度急性移植物抗宿主病总发生率(63.1±11.1)%,慢性移植物抗宿主病发生率(54.54±15.0)%。③远期疗效：2年无病生存率为(28.2±15.5)%,2年总体生存率为(46.9±16.5)%。结果提示,高危白血病无人类白细胞抗原相合血缘供者及无人类白细胞抗原相合非血缘供者,而又急需进行挽救性移植时,“改良Bu/Cy+ATG”为预处理方案的单倍体相合造血干细胞移植是一种可行的选择。     

Fatal graft-versus-host disease following transfusion during open heart surgery

We report fatal transfusion-associated graft-versus-host disease (GVHD) in a patient who was not severely immunosuppressed. A 58-year-old man received 800 ml of fresh whole blood from his son and an unrelated volunteer donor during open heart surgery. On the 10th day after the operation, he suddenly had a high fever, followed by generalized skin rash and liver dysfunction. Pancytopenia due to bone marrow aplasia developed a week later. A skin biopsy revealed a cutaneous lesion highly compatible with acute GVHD. The patient did not respond to high-dose methylprednisolone therapy, and died of multiple organ failure on the 18th day after the operation.     

Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients.

Mesenchymal stem cells (MSCs) are found in a variety of tissues, including human bone marrow; secrete hematopoietic cytokines; support hematopoietic progenitors in vitro; and possess potent immunosuppressive properties. We hypothesized that cotransplantation of culture-expanded MSCs and hematopoietic stem cells (HSCs) from HLA-identical sibling donors after myeloablative therapy could facilitate engraftment and lessen graft-versus-host disease (GVHD); however, the safety and feasibility of this approach needed to be established. In an open-label, multicenter trial, we coadministered culture-expanded MSCs with HLA-identical sibling-matched HSCs in hematologic malignancy patients. Patients received either bone marrow or peripheral blood stem cells as the HSC source. Patients received 1 of 4 study-specified transplant conditioning regimens and methotrexate (days 1, 3, and 6) and cyclosporine as GVHD prophylaxis. On day 0, patients were given culture-expanded MSCs intravenously (1.0-5.0 x 10(6)/kg) 4 hours before infusion of either bone marrow or peripheral blood stem cells. Forty-six patients (median age, 44.5 years; range, 19-61 years) received MSCs and HLA-matched sibling allografts. MSC infusions were well tolerated, without any infusion-related adverse events. The median times to neutrophil (absolute neutrophil count > or = 0.500 x 10(9)/L) and platelet (platelet count > or = 20 x 10(9)/L) engraftment were 14.0 days (range, 11.0-26.0 days) and 20 days (range, 15.0-36.0 days), respectively. Grade II to IV acute GVHD was observed in 13 (28%) of 46 patients. Chronic GVHD was observed in 22 (61%) of 36 patients who survived at least 90 days; it was extensive in 8 patients. Eleven patients (24%) experienced relapse at a median time to progression of 213.5 days (range, 14-688 days). The probability of patients attaining disease- or progression-free survival at 2 years after MSC infusion was 53%. Cotransplantation of HLA-identical sibling culture-expanded MSCs with an HLA-identical sibling HSC transplant is feasible and seems to be safe, without immediate infusional or late MSC-associated toxicities. The optimal MSC dose and frequency of administration to prevent or treat GVHD during allogeneic HSC transplantation should be evaluated further in phase II clinical trials.     

Precursor lymphoblastic lymphoma reoccurring as a donor-derived neoplasm: a case report and review of the literature

Precursor lymphoblastic lymphoma is an uncommon neoplasm. We report the case of a man who presented with precursor T lymphoblastic lymphoma and ultimately received an allogeneic bone marrow transplant from his human leukocyte antigen-identical sister. Four years later he developed recurrent disease. By means of DNA probing for the amelogenin locus and fluorescence in situ hybridization, the neoplastic cells of the recurrent lesion were found to be of donor origin. We offer the report of a patient with an unusual lymphoblastic lymphoma who, after successful bone marrow transplantation, developed the same disease of donor cell origin; further, we offer a literature review on donor cell lymphoma.     

Allogeneic Th1 Cells Home to Host Bone Marrow and Spleen and Mediate IFNγ-Dependent Aplasia

Bone marrow graft failure and poor graft function are frequent complications after hematopoietic stem cell transplantation and result in significant morbidity and mortality. Both conditions are associated with graft-versus-host disease (GVHD), although the mechanism remains undefined. Here we show, in 2 distinct murine models of GVHD (complete MHC- and class II-disparate) that mimic human peripheral blood stem cell transplantation, that Th1 CD4⁺ cells induce bone marrow failure in allogeneic recipients. Bone marrow failure after transplantation of allogeneic naïve CD4⁺ T cells was associated with increased CD4⁺ Th1 cell development within bone marrow and lymphoid tissues. Using IFNγ-reporter mice, we found that Th1 cells generated during GVHD induced bone marrow failure after transfers into secondary recipients. Homing studies demonstrated that transferred Th1 cells express CXCR4, which was associated with accumulation within bone marrow and spleen. Allogeneic Th1 cells were activated by radiation-resistant host bone marrow cells and induced bone marrow failure through an IFNγ-dependent mechanism. Thus, allogeneic Th1 CD4⁺ cells generated during GVHD traffic to hematopoietic sites and induce bone marrow failure via IFNγ-mediated toxicity. These results have important implications for prevention and treatment of bone marrow graft failure after hematopoietic stem cell transplantation.     

第二次单倍体造血干细胞移植治疗首次移植失败再生障碍性贫血并发淋巴瘤1例

背景：急性重型再生障碍性贫血第一次异基因造血干细胞移植失败对患儿是严重致命的,若同时合并有继发性淋巴瘤等多种并发症,治疗就更为棘手,目前无成功方法可借鉴。 目的：探讨第二次HLA单倍体造血干细胞移植治疗首次移植失败且并发淋巴瘤的急性重型再生障碍性贫血患儿的有效性和安全性。 方法：回顾性分析1例急性重型再障患儿的二次造血干细胞移植的临床资料：患儿男,3岁,2011年11月25日行第一次非血缘异基因外周血干细胞移植(供受者HLA为8/10相合,血型主要不合),移植后粒细胞和血小板造血分别在11 d和14 d恢复,移植后30 d DNA移植植入鉴定和染色体检测均示移植成功植入,术后35 d出现皮肤Ⅰ度移植物抗宿主病,激素治疗后消失,术后54 d因出现自身免疫性溶血性贫血及纯红细胞再生障碍性贫血,给予大剂量丙种球蛋白冲击、激素及促红素等治疗好转,激素逐渐减量,EBV拷贝数逐渐升高,术后3个月患者出现发热、双侧颈部可触及数个肿大淋巴结,行B超引导下右侧颈部淋巴结穿刺活检,考虑移植后淋巴增殖性疾病,病理示：弥漫大B细胞淋巴瘤,治疗上减停免疫抑制剂,应用美罗华及CHOP方案化疗,淋巴结缩小,且EBV拷贝数下降,体温正常。移植术后5个月复查血象和骨髓象提示继发性植入失败,进而于2012年5月15日行第二次单倍体相合造血干细胞移植。供者为患儿的父亲,预处理方案为清髓性预处理方案：氟达拉滨+环磷酰胺+马利兰+米托蒽醌+抗CD52单克隆抗体。回输骨髓造血干细胞的同时输注脐带间充质干细胞。移植物抗宿主病预防：环孢素A+短程的甲氨喋呤+CD25单克隆抗体联合霉酚酸酯。回输的有核细胞分别为13.52×108/kg,CD34+细胞数为2.45×106/kg,无关供者脐带来源间充质干细胞的量为1×106/kg。随访时间为移植后24个月。 结果与结论：移植后中性粒细胞达到0.5×109 L-1,血小板计数≥20×109 L-1分别为14 d和30 d;二次移植后1个月DNA指纹检测说明造血干细胞移植成功植入。预处理后肿大淋巴结逐渐缩小,但术后2个月因淋巴结有增大趋势,停用免疫抑制剂并局部放疗后淋巴结缩小且稳定至今,PET无明显代谢异常区,移植后每半年定期随访,目前正常生活及上学。结果说明：单倍体造血干细胞联合脐带间充质干细胞共移植是安全、高效的治疗第一次移植失败重型再生障碍性贫血的方法,患儿可以耐受预处理毒性,造血恢复较快,移植物抗宿主病可控,值得进一步临床研究。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

Incidence and Outcome of Invasive Fungal Diseases after Allogeneic Stem Cell Transplantation: A Prospective Study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP-IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP-IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs.     

Induction of autologous graft-versus-host disease: results of a randomized prospective clinical trial in patients with poor risk lymphoma.

The results of blood or marrow transplantation in patients with chemorefractory aggressive lymphoma, that is, those not responding to conventional-dose chemotherapy at the time of transplant, have been poor. The relapse rate has been high after autologous bone marrow transplant, whereas allogeneic transplantation has been associated with excessive transplant-related toxicity. Administration of cyclosporine after autologous transplantation can induce an autoreactive syndrome that resembles graft-versus-host disease (GVHD). This syndrome, named autologous graft-versus-host disease, has clear antitumor activity in animal models that can be enhanced by the addition of cytokines such as gamma-interferon and interleukin-2. A randomized, prospective study was conducted to evaluate the antitumor effect of autologous graft-versus-host disease induced with cyclosporine, and augmented by the administration of gamma-interferon and interleukin-2 in patients with chemorefractory Hodgkin and aggressive non-Hodgkin lymphomas. Fifty-one patients were randomized, 24 to the autologous GVHD induction arm, and 27 to the noninduction arm after autologous transplant using mobilized peripheral blood stem cell (PBSC) grafts. There were no differences in treatment-related mortality, overall and event-free survival (OS, EFS) between both groups; however, in the induction arm, GVHD developed only in 4 patients. The administration of oral cyclosporine followed by interleukin-2 and gamma-interferon is generally not well tolerated, and does not appear to be an effective method to induce autologous GVHD in patients receiving autologous PBSC grafts.     

Non‐specific interstitial pneumonia as a manifestation of graft‐versus‐host disease following pediatric allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans (BO) is generally believed to be a marker of pulmonary manifestation of graft‐versus‐host disease (GVHD) in patients who have undergone bone marrow transplantation for hematological malignancy. Pulmonary manifestations reported as GVHD (other than BO) include lymphocytic bronchiolitis with cellular interstitial pneumonia, lymphoid interstitial pneumonia, veno‐occlusive disease, and diffuse alveolar damage. Morphological reactions in the lungs of bone marrow transplant recipients associated with interstitial pneumonia have not been described systematically. Reported herein is a fibrosing non‐specific interstitial pneumonia (NSIP) pattern together with BO in both lungs in an 8‐year‐old girl following a second allogeneic hematopoietic stem cell transplantation for relapsed neuroblastoma of adrenal origin. The course was complicated by bilateral pneumothoraces, and the patient underwent lung transplantation 3 years after the second stem cell transplantation. Because the patient had chronic GVHD of the skin and the liver preceeded by the development of pulmonary involvement, NSIP may represent one of the facets of pulmonary GVHD.     

Demodicidosis simulating acute graft-versus-host disease after allogeneic stem cell transplantation in one patient with acute lymphoblastic leukemia

One important differential diagnosis of facial erythema in a patient receiving an allogeneic bone marrow transplant (BMT) is acute graft-versus-host disease (GVHD). Demodex folliculorum has been rarely implicated in the development of facial rashes in immunosuppressed patients, including BMT recipients. We report the case of a patient, suffering from acute lymphoblastic leukemia, who after bone marrow transplantation developed a facial rash due to D. folliculorum mimicking GVHD. Differential diagnosis of facial rashes and demodicidosis after BMT is reviewed.     

不同干细胞骨髓腔内输注对移植物抗宿主病和免疫耐受的影响

观察不同来源的造血干细胞经髓腔内输注能否在减轻移植物抗宿主病(GVHD)的同时诱导稳定的免疫耐受。雌性C57BL/6小鼠接受全身照射(TBI)预处理后,输注雄性BABL/c小鼠来源的骨髓细胞或经rhG-CSF动员后的外周造血干细胞,2 d后腹腔注射环磷酰胺(CTX)。观察各组GVHD发生情况,并通过皮肤移植对受者耐受状态进行检测。结果显示,髓腔内骨髓移植组(IBM-BMT)的受鼠无1例发生GVHD,而髓腔内外周造血干细胞移植组(IBM-PBSCT)的受鼠GVHD发生率较尾静脉组(IV)明显减低(P<0.05);IBM-BMT和IBM-PBSCT组受鼠对供鼠皮肤移植物的存活时间均超过120 d,较IV组明显延长(P<0.01)。实验表明髓腔内输注在降低GVHD发生率的同时,有利于稳定的免疫耐受状态的形成。     

Current donor selection strategies for allogeneic hematopoietic cell transplantation

Since the first allogeneic hematopoietic stem cell transplantation (HCT) was performed by Dr. E. Donnall Thomas in 1957, the field has advanced with new stem cell sources, immune suppressive regimens, and transplant protocols. Stem cells may be collected from bone marrow, peripheral or cord blood from an identical twin, a sibling, or a related or unrelated donor, which can be human leukocyte antigen (HLA) matched, mismatched, or haploidentical. Although HLA matching is one of the most important criteria for successful allogeneic HCT (allo-HCT) to minimize graft vs host disease (GVHD), prevent relapse, and improve overall survival, the novel immunosuppressive protocols for GVHD prophylaxis offered improved outcomes in haploidentical HCT (haplo-HCT), expanding donor availability for the majority of HCT candidates. These immunosuppressive protocols are currently being tested with the HLA-matched and mismatched donors to improve HCT outcomes further. In addition, fine-tuning the DPB1 mismatching and discovering the B leader genotype and mismatching may offer further optimization of donor selection and transplant outcomes. While the decision about a donor type largely depends on the patient’s characteristics, disease status, and the transplant protocols utilized by an individual transplant center, there are general approaches to donor selection dictated by donor-recipient histocompatibility and the urgency for HCT. This review highlights recent advances in understanding critical factors in donor selection strategies for allo-HCT. It uses clinical vignettes to demonstrate the importance of making timely decisions for HCT candidates.     

Reconstitution in severe combined immunodeficiency by transplantation of marrow from an unrelated donor.

A patient with severe combined immunodeficiency received seven transplants of bone marrow from an HLA-B-compatible and HLA-D-compatible unrelated donor in an attempt to provide immunologic reconstitution. The first four transplants achieved restricted engraftment with evidence of rudimentary immunologic function. A fifth transplant, given after low-dose cyclophosphamide, produced reconstituion of cell-mediated immunity. Marrow aplasia developed after recontamination with a nonpathogenic microflora. Transplantation of marrow previously stored in liquid nitrogen was ineffective. A subsequent transplant, administered after high-dose cyclophosphamide, achieved durable engraftment, with complete hematopoietic and immunologic reconstitution. Seventeen months after transplantation, full functional engraftment persists. Graft-versus-host disease has been chronic and moderately severe, but limited to the skin and oral mucosa. Transplantation of marrow from unrelated histocompatible donors may provide a useful treatment for patients with severe combined immunodeficiency or aplastic anemia who lack a matched sibling or related donor.     

骨髓移植治疗重型地中海贫血

目的　探讨骨髓移植治疗重型地中海贫血的可行性。方法　对 1例确诊为重型 β地中海贫血的患儿进行骨髓移植 ,患儿基因突变型为 CD41- 42 /6 5 4,移植同胞哥哥的骨髓 85 0 m l,有核细胞 :5 .6×10 8/kg,CD34 细胞 :7.8× 10 6 /kg,粒 -巨噬细胞集落形成单位 :5 .7× 10 5 /kg,HL A- DR一个位点不合 ,血型相同 ,预处理方案为白消安 :16 mg/kg、环磷酰胺 :2 0 0 m g/kg、抗人胸腺细胞免疫球蛋白 :88mg/kg,环孢 A和甲氨喋呤预防移植物抗宿主病 (Graft- versus- hostdisease,GVHD)。结果　移植后出现 度急性 GVHD和巨细胞病毒间质性肺炎 ,均获得控制。白细胞 (WBC)移植后 14天为 1.1× 10 9/L,中性粒细胞 0 .4× 10 9/L ,18天 WBC 4.5× 10 9/L ,由于受更昔洛韦副作用影响 ,WBC曾一度下降 ,3个月后恢复正常 ,血小板(Plt)移植后 86天 >5 0× 10 9/L ,5个半月恢复正常 ,移植后 12 8天血红蛋白 (Hb)升至 10 6 g/L ,最后一次输血时间为移植后 10 3天。移植前平均每月输血 2 0 0 ml,移植 10 3天后至今 6个多月未输血 ,Hb保持在 110 g/L以上。地中海贫血基因型已转为供者的。结论　骨髓造血干细胞移植可根治重型地中海贫血 ,为该病的治疗提供了新思路与途径。治疗移植后巨细胞病毒感染 (间质性肺炎 ) ,更昔洛韦     

Comparable Outcomes of Allogeneic Peripheral Blood versus Bone Marrow Hematopoietic Stem Cell Transplantation in Major Thalassemia: A Multivariate Long-Term Cohort Analysis

Allogeneic hematopoietic stem cell transplantation (HSCT) currently is the only available curative option for transfusion-dependent thalassemia. Peripheral blood is a more convenient source for HSCT in comparison with bone marrow. Information about the relative success of transplantation with these 2 graft sources would help physicians and patients choose between them. The aim of this study was to evaluate the pros and cons of using peripheral blood instead of bone marrow as the graft source in thalassemia transplantation. We analyzed the transplant results of 567 transfusion-dependent thalassemia patients who received a transplant between 1998 and 2015 considering their stem cell source as a comparative variable. In multivariate Cox analysis the survival advantage for bone marrow compared with peripheral blood was not significant after adjusting for sex, age, and hepatic fibrosis presence. Rejection incidence was significantly lower in patients who used peripheral blood as their graft source. Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants, but the difference was not statistically significant. This study shows that peripheral blood could be an alternative stem cell source in patients undergoing allogeneic HSCT for thalassemia.     

Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation.

Methotrexate in combination with a calcineurin inhibitor is a standard graft-versus-host disease (GVHD) prophylactic regimen in allogeneic stem cell transplantation. However, methotrexate is associated with delayed engraftment, mucositis, idiopathic pneumonia syndrome, and other transplant-related complications. Sirolimus, a novel immunosuppressant without methotrexate's toxicities, has been used successfully in solid organ transplantation. We hypothesized that replacing methotrexate with sirolimus would preserve effective prophylaxis of GVHD while minimizing transplant-related toxicity after allogeneic peripheral blood stem cell transplantation. We enrolled 30 patients in a phase II study to test the efficacy of tacrolimus in combination with sirolimus in lieu of methotrexate in preventing GVHD after allogeneic peripheral blood stem cell transplantation from HLA-matched related donors. Grade II GVHD occurred in 3 patients (10%), and no patient developed grade III or IV GVHD. Neutrophil and platelet engraftment were prompt, occurring on days 14 and 13, respectively. All patients survived to hospital discharge (median, 18 days), and peritransplantation toxicity was mild. Four patients developed thrombotic microangiopathy, and 3 patients developed hepatic veno-occlusive disease. Chronic GVHD occurred in 11 patients. Relapse-free and overall survival at 100 days were 93% and 97%, respectively, and were 71% and 67% at 1 year. Causes of death included relapse (n = 6), veno-occlusive disease (n = 1), and late pulmonary toxicity (n = 1). Sirolimus in combination with tacrolimus is a promising alternative to methotrexate-based regimens for GVHD prophylaxis after matched related donor peripheral blood stem cell transplantation. Mucositis was modest, engraftment was prompt, and transplant-related toxicity was modest. Methotrexate-free, sirolimus-based GVHD prophylactic regimens should be tested in randomized trials against the current standard of care.     

异基因外周血造血干细胞移植及其联合骨髓移植后造血重建及移植物抗宿主病的比较

通过比较异基因外周血造血干细胞移植(PBSCT)与其联合骨髓移植(BMT)治疗白血病过程中造血重建时间、移植物抗宿主病(GVHD)发生率及生存率,探讨二者联合移植对白血病治疗的影响。回顾性分析2003年1月至2009年1月在郑州大学第一附属医院接受全相合异基因造血干细胞移植的152例患者,其中78例单纯接受外周血造血干细胞移植,74例接受外周血造血干细胞移植联合骨髓移植。预处理方案:152例患者均应用改良Bu/CY方案预处理,环孢素A(CsA)联合甲氨蝶呤(MTX)、吗替麦考酚酯(MMF)预防GVHD,流式细胞仪测定外周及骨髓造血干细胞计数。SPSS17.0统计分析两组患者移植后造血重建时间、GVHD的发生率及2年生存率。结果:1、移植后造血重建:接受外周血造血干细胞移植与联合骨髓移植患者的白细胞及血小板重建时间无显著性差异(血小板>20×109/L时间分别为(14.18±4.713)d和(12.55±6.552)d(P>0.05),中性粒细胞>0.5×109/L的时间分别为(12.08±3.586)d和(11.64±5.540)d(P>0.05);2、GVHD:接受PBSCT及联合BMT患者Ⅲ度到Ⅳ度急性GVHD(aGVHD)发生率比较有显著性差异(P=0.05)。两者慢性GVHD(cGVHD)发病率有显著性差异(P=0.01);3、2年生存率:接受外周血干细胞移植及其联合骨髓移植患者2年无病生存率和总生存率无显著性差异(P>0.05)。提示,异基因造血干细胞移植与其联合骨髓移植比较造血重建时间及2年生存率无明显差异,但前者GVHD发生率较高,因此外周血造血干细胞移植联合骨髓移植可能减少急性及慢性GVHD的发生。