Soluble Interleukin-2 Receptor Index Predicts Outcomes After Cord Blood Transplantation

BackgroundOur previous study demonstrated that the soluble interleukin-2 receptor (sIL-2R) index, defined as the ratio of serum sIL-2R levels at neutrophil engraftment to that before conditioning, is a biomarker that can predict acute graft-vs-host disease (GVHD) after unrelated bone marrow transplantation. In the present study, we evaluated the significance of the sIL-2R index among patients who underwent cord blood transplantation (CBT).MethodsWe retrospectively analyzed 31 patients who underwent single-unit CBT as their first transplantation for hematologic malignancies.ResultsThe median sIL-2R index was 4.2. The cumulative incidence of grade II to IV acute GVHD was not associated with the sIL-2R index. However, the cumulative incidence of relapse at 3 years after transplantation was significantly lower, with an sIL-2R index ≥ 3.7 than with an index < 3.7 (12.8% vs 50.0%; P = .04). As a result, the probability of overall survival at 3 years after transplantation was significantly higher in the former group than in the latter (79.8% vs 20.0%; P < .01). Only the dose of corticosteroid administered in the pre-engraftment period influenced the sIL-2 index.ConclusionThe sIL-2R index can predict the incidence of relapse and probability of survival after CBT, possibly reflecting a graft-vs-leukemia effect.     

Myeloablative Cord Blood Transplantation for Adults With Hematological Malignancies Using Tacrolimus and Short-Term Methotrexate for Graft-Versus-Host Disease Prophylaxis: Single-Institution Analysis

We studied clinical outcomes of 25 adult patients with hematological malignancies who underwent cord blood transplantation (CBT) after a myeloablative conditioning regimen, including high-dose cytosine arabinoside (CA) (8 g/m²), cyclophosphamide (CY) (120 mg/kg), and total-body irradiation (TBI) (12 Gy). For graft-versus-host disease (GVHD) prophylaxis, all patients received a combination of tacrolimus and short-term methotrexate (sMTX). Neutrophil engraftment was achieved in 20 of 25 patients. Of the 22 evaluable patients, 2 and 7 had grades I and II acute GVHD, respectively, and only 1 developed grade III acute GVHD after discontinuation of tacrolimus due to encephalopathy. Chronic GVHD developed in 13 of 19 evaluable patients, including 4 with the extensive type. However, the Karnofsky scores of survivors at 1 year after CBT were 90% or 100%. Eight of 25 patients died of nonrelapse causes (n = 4) and relapse/progressive disease (n = 4); 17 patients are currently alive with 15 free of disease at the present time (median follow-up, 24 months). The probability of disease-free survival at 2 years among patients with standard risk was 89% and that of high-risk patients was 30%. Transplantation-related mortality within 100 days was 12%. These results suggested that the CA/CY/TBI combination is a promising conditioning regimen for myeloablative CBT. Furthermore, tacrolimus and sMTX seemed to have suppressed severe acute GVHD and chronic GVHD, which may also contribute to the favorable results.     

非血缘脐血造血干细胞移植治疗恶性血液病50例临床观察

目的 回顾性分析非血缘脐血移植(UCBT)治疗恶性血液病患者的植入、移植相关并发症及存活情况.方法 2000年4月至2009年8月,单中心进行UCBT治疗恶性血液病患者50例,其中高危难治性患者39例(78%),中位年龄19岁(3～48岁),中位体重53 kg(15～76 kg).进行单份脐血移植24例,双份脐血移植26例.移植前采用清髓性预处理方案45例,减低强度预处理方案5例.采用环孢素A(CsA)联合吗替麦考酚酯(MMF)预防移植物抗宿主病(GVHD).结果 全部受者按自身的体重计算,输注的脐血总有核细胞数(TNC)中位值为4.0(1.95～16.24)×10~7/kg,其中CD34~+细胞数为2.74(0.67～29.28)×10~5/kg.50例受者中,除1例移植后16 d死亡外,可评估的49例中有42例获得稳定造血功能重建,植入率为86%.中性粒细胞绝对计数(ANC)≥0.5×10~9/L和血小板≥20×10~9/L的中位时间分别为移植后19 d和34 d,移植后42 d时,中性粒细胞恢复率为86.3%(95%可信区间为0.769～0.957).移植后120 d时,血小板恢复率为72.3%(95%可信区间为0.620～0.821).在42例植入的受者中,发生急性GVHD 20例,其中Ⅲ～Ⅳ度3例(发生率为7.1%).移植后2年时,慢性GVHD发生率为17.4%.中位随访时间22个月(4～116个月),移植后180 d时的总存活率为66.2%(95%可信区间为0.590～0.734),1年时的总存活率为57.4%(95%可信区间为0.496～0.652),2年时的总存活率为54.2%(95%可信区间为0.462～0.622).非疾病进展期行移植的受者,180 d时的总存活率为73.2%(95%可信区间为0.659～0.805),1年时的总存活率为66.1%(95%可信区间为0.579～0.743),2年时的总存活率为62.2%(95%可信区间为0.542～0.682).移植后原发病复发5例,2年累计复发率为16.2%(95%可信区间为0.099～0.225).移植后死亡21例,感染为主要死亡原因.结论 UCBT治疗恶性血液病是安全和有效的.     

Modified donor lymphocyte infusion‐associated acute graft‐versus‐host disease after haploidentical T‐cell‐replete hematopoietic stem cell transplantation: incidence and risk factors

We performed a study to investigate the profile of donor lymphocyte infusion (DLI)‐associated acute graft‐versus‐host disease (GVHD) in haploidentical T‐cell‐replete hematopoietic stem cell transplantation (HSCT). A total of 124 patients receiving modified DLI after haploidentical T‐cell‐replete HSCT were enrolled. The cumulative incidence of DLI‐associated acute GVHD was 53.2% for grades II–IV and 28.4% for grades III–IV. The duration of GVHD prophylaxis after DLI was the only risk factor for DLI‐associated grades III–IV acute GVHD (p < 0.05). The cumulative incidence of grades III–IV acute GVHD in patients with prophylaxis more than six, four to six, two to four, and <2 wk were 9.3%, 14.4%, 31.6%, and 49.5%, respectively (p = 0.018). Furthermore, DLI‐associated grades III–IV acute GVHD was the only risk factor for overall survival (p = 0.038, OR   = 2.869) and transplant‐related mortality (p = 0.018, OR = 3.296) but not a risk factor for relapse after DLI (p = 0.840). This study confirms for the first time that the duration of GVHD prophylaxis after DLI is the only risk factor for the development of grades III–IV acute GVHD. Donor lymphocyte infusion with prophylaxis more than six wk was associated with a lower incidence of grades III–IV acute GVHD.     

Outcomes of Busulfan,Fludarabine, and 400 cGy Total Body Irradiation Compared With Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Adult Patients With Hematologic Diseases: A Single-Center Experience

BackgroundReduced intensity conditioning (RIC) regimens decrease the risk for nonrelapse mortality (NRM) in adult patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies but increase the risk for relapse. The aim of this study was to compare the outcomes of fludarabine–total body irradiation (TBI) with fludarabine among patients with hematologic diseases.Patients and MethodsThis retrospective study of 137 patients with different hematologic malignancies compared the outcomes of 63 patients who received a conventional RIC regimen with 2 days of IV busulfan (3.2 mg/kg/d × 2 days) and fludarabine with 74 patients who received the same regimen plus 400 cGy of fludarabine and busulfan (FB)-TBI divided in 2 doses over 1 day (200 cGy BID). Median follow-up was 4.62 years.ResultsThe donors were either HLA-matched siblings (36%) or HLA-matched unrelated donors (64%). The FB-TBI showed trends toward improvement in progression-free survival (PFS) and overall survival (OS) over FB (5-year PFS rates 50% vs 34%, P = .06, and 5-year OS rate 53% vs 39%, P = .13). Acute graft-vs-host disease (aGVHD), relapse, and NRM were similar between the 2 groups. The 5-year cumulative incidence of chronic GVHD (cGVHD) was lower in the FB-TBI group compared with the FB group (29% vs 52%, P = .003). Multivariable analysis revealed that grade III-IV aGVHD was the only independent risk factor for worse OS (P = .001) in both groups. A high disease risk index was possibly associated with inferior OS (P = .07) in both groups.ConclusionsThe FB-TBI is a safe and effective intensified RIC regimen for adult patients with hematologic malignancies. It predicted a lower risk for cGVHD and showed possibly improved PFS and OS compared with FB.     

Improved survival after bone marrow transplantation for early leukemia using busulfan-cyclophosphamide and individualized prophylaxis against graft-versus-host disease: a long-term follow-up

To minimize immunosuppression, allow a graft-versus-leukemia (GVL) effect, and reduce relapse incidence, 73 leukemic recipients of human leukocyte antigens-identical sibling marrow were given graft-versus-host disease (GVHD) prophylaxis based on the estimated risk of GVHD development. Methotrexate (MTX) monotherapy was given to patients with an estimated low risk of developing GVHD, whereas MTX + cyclosporine (CsA) was given to 'high-risk' patients. After engraftment, CsA was discontinued, and weekly MTX was reinstituted and given until 3 months post-bone marrow transplant. Conditioning consisted of busulfan (BU) + cyclophosphamide (CY) (n = 35) or CY + total body irradiation (TBI) (n = 38). Retrospective controls were given CY + TBI and MTX + CsA (n = 39). The median observation time was 5 yr 11 months. Chronic GVHD increased to 53% in the individual BU + CY group and 46% in the individual CY + TBI group, compared to 25% in the control group (p = 0.05). This increase was restricted to the limited form. The actuarial relapse incidence decreased to 20% in the individual BU + CY group, compared to 52% in the control group, p = 0.03. In the individual CY + TBI group, the relapse incidence was 44% (n.s. versus controls, p = 0.04 versus individual BU + CY). The 5-yr relapse-free survival (RFS) in the individual BU + CY group was 66%, in the control group, 41% (p = 0.07), and in the individual CY + TBI group, 45% (p = 0.1 versus individual BU + CY). Patients with early leukemia in the individual BU + CY group had a RFS of 83%, compared to 44% in the control group (p = 0.02) and 42% in the individual CY + TBI group (p = 0.01). In the multivariate analysis, advanced leukemia beyond first complete remission and first chronic phase and conditioning with CY + TBI were correlated to poor RFS. In summary, the individualized prophylaxis itself did not reduce the relapse incidence. However, in patients with early leukemia conditioning with BU + CY, our method of individualizing the GVHD prophylaxis might be of value, since this group had the best RFS in this study.     

Tacrolimus and methotrexate for the prophylaxis of graft-versus-host disease after unrelated donor cord blood transplantation for adult patients with hematologic malignancies

Eighteen patients with hematologic malignancies underwent cord blood transplantation (CBT) from unrelated donors after being conditioned with myeloablative or reduced-intensity regimens, and received tacrolimus and methotrexate (15 mg/m(2) on day 1, 10 mg/m(2) on days 3 and 6) as graft-versus-host disease (GVHD) prophylaxis. The median number of nucleated cells in infused cord blood was 2.66 x 10(7)/kg (range 1.90 to 4.15 x 10(7)/kg). Engraftment was achieved in 16 of 18 patients. The median time to absolute neutrophil count >0.5 x 10(9)/L was 21.5 days (range 17 to 32), and the median time to platelet count >2.0 x 10(9)/L was 36 days (range 26 to 57). Of the 16 evaluable patients, five and eight had grades I and II acute GVHD, respectively, and none had grades III/IV acute GVHD. The cumulative incidence of grade II acute GVHD was 44.4%. Chronic GVHD occurred in 7 of 15 evaluable patients: limited type in three patients, extensive type in four patients. Of the 18 patients, 14 were alive and disease-free between 173 and 1514 days after CBT (median 746 days). The probability of disease-free survival at 2 years was 79.1%. These results, although in a retrospective study, suggested that tacrolimus and short-term methotrexate effectively prevented the occurrence of severe acute GVHD after unrelated CBT, and may contribute to a high survival rate.     

Low‐dose methotrexate may preserve a stronger antileukemic effect than that of cyclosporine after modified donor lymphocyte infusion in unmanipulated haploidentical HSCT

To compare the impacts of low‐dose methotrexate (MTX) with cyclosporine (CSA) on graft‐versus‐host disease (GVHD) and graft‐versus‐leukemia (GVL) effect after haploidentical modified donor lymphocyte infusion (DLI). Fifty‐five consecutive patients who had relapsed acute leukemia after haploidentical hematopoietic stem cell transplantation (HSCT) and received modified DLI were retrospectively studied. Forty‐one patients received CSA and 14 received low‐dose MTX after DLI to prevent DLI‐associated GVHD. The incidence of acute GVHD and grade 2–4 acute GVHD in MTX group showed a trend toward being higher than in CSA group (61.0% vs. 37.3%, p = 0.198 and 61.0% vs. 35.5%, p = 0.155). However, no significant difference in the incidence of grade 3–4 acute GVHD between two groups (p = 0.982) was observed. Moreover, compared with CSA, patients treated with MTX had lower re‐relapse rate (38.1% vs. 80.8%, p = 0.029), better disease‐free survival (DFS) (51.9% vs. 15.6%, p = 0.06), and higher absolute lymphocyte counts at 30, 45, 60, and 90 d after modified DLI (p < 0.05). This study suggested that after haploidentical modified DLI, low‐dose MTX is at least as effective as CSA in the prevention of DLI‐associated GVHD and probably allowed stronger GVL effect than CSA. This phenomenon was probably due to a direct antitumor effect and a better reconstitution of lymphocytes after modified DLI induced by low‐dose MTX.     

异基因造血干细胞移植治疗重型β珠蛋白生成障碍性贫血

目的 探讨异基因造血干细胞移植(allo-HSCT)治疗重型β珠蛋白生成障碍性贫血的临床疗效.方法 PesaroⅡ-Ⅲ度重型β珠蛋白生成障碍性贫血患者24例接受allo-HSCT治疗,其中男性18例,女性6例,患者年龄中位数为4岁(2～15岁).24例中,同胞供者23例,母亲供者1例;HLA 6个抗原全相合23例,5个抗原相合1例;骨髓混合外周血干细胞移植15例,脐带血移植9例.采用白消安+环磷酰胺+氟达拉滨的预处理方案.环孢素A(CsA)+甲氨蝶呤(MTX)+抗胸腺细胞球蛋白(ATG)+吗替麦考酚酯(MMF)联用预防移植物抗宿主病(GVHD).中位随访时间13个月(3～69个月).结果 移植后22例患者造血功能顺利恢复.至随访结束,无病存活21例;移植相关死亡1例(4.2%);移植物排斥反应2例(8.3%).21例的3年无病存活率为87.5%,3年总体存活率为91.7%.Ⅱ-Ⅳ度急性GVHD的累积发生率为16.7%,慢性GVHD的累积发生率为20.3%,广泛性慢性GVHD的发生率为5.0%.结论 异基因骨髓混合外周血干细胞移植治疗珠蛋白生成障碍性贫血可获得确切疗效,同时脐带血是珠蛋白生成障碍性贫血移植的重要干细胞来源.CsA+MTX+ATG+小剂量、短疗程MMF的方案可以有效地减少严重急性GVHD的发生,提高移植疗效.

Abstract：

Objective To investigate the effect of allgeneic hematopoietic stem cell transplantation (allo-HSCT) for β-thalassemia major. Methods Twenty-four β-thalassemia major patients with median age of 4 years (range: 2～15 years), 18 boys and 6 girls, received allo-HSCT.They were classified into class Ⅱ-Ⅲ according to Pesaro thalassemia classification. Twenty-three transplantations were from sibling donor and 1 was from mother, either HLA-identical (n = 23) or HLA-mismatched (5/6) (n = 1). Fifteen patients received bone marrow transplantation (BMT) plus peripheral blood stem cell transplantation (PBSCT), and 9 were subjected to umbilical cord blood transplantation (UCBT). The conditioning regimen consisted of busalphan, cyclophosphamide,fludarabine, plus hydroxyurea before transplantation. Graft-versus-host disease (GVHD) prophylaxis included CsA, methotrexate, antilymphpcute globulin, and mycophenolate mofetil. The median follow-up period was 13 months (range: 3～69). Results Of 24 patients, there were 21 cases (87. 5 %) of disease-free survival, 1 (4. 2 %) transplantation-related death, and 2 cases (8. 3 %) of rejection. Three-year overall survival and disease-free survival rate was 91.7 % and 87. 5 %respectively. The cumulative incidence of grade Ⅱ -Ⅳ acute GVHD and chronic GVHD was 16. 7 %and 20. 3 %, particularly cumulative extensive chronic GVHD was 5. 0 %. Conclusion The sibling donor BMT plus PBSCT is an effective and safe way to treat β-thalassemia major. Cord blood is an important source of hematopoietic stem cells for HSCT. The protocol GVHD prophylaxis of CsA,MTX, ATG with a low-dose and short course of MMF can effectively reduce the incidence of severe acute GVHD, improve the outcome of thalassemia transplantation.     

ABO compatibility and acute graft-versus-host disease following allogeneic bone marrow transplantation

If ABO antigens/antibodies play any role in the pathogenesis of acute graft-versus-host disease (GVHD), one would expect the highest incidence of GVHD in recipients of minor ABO-mismatched grafts, followed by ABO-matched grafts, and the lowest incidence in major ABO-mismatched transplants. To test this hypothesis 174 patients receiving an HLA-identical allogeneic bone marrow transplant (BMT) for aplastic anemia (n = 32) or leukemia (n = 142) were analyzed for factors associated with acute GVHD. Variables analyzed included diagnosis, sex, age, blood group of donor and recipient, ABO compatibility, Rhesus compatibility, sex compatibility, number of bone marrow cells given at BMT, year of transplant, day of engraftment, and GVHD prophylaxis. We first carried out an exploratory contingency table analysis: minor ABO incompatibility was associated with a significantly higher risk of severe acute GVHD when compared with ABO-matched and major-ABO mismatched pairs (P = 0.003): 14/9, 57/67, and 5/22 patients developed, respectively, 0-I/II-IV acute GVHD in ABO major-mismatched, matched, and minor-mismatched pairs. Donors of group 0, (P = 0.06), older recipient's age (P = 0.08), fast engraftment (P = 0.03), and older donor's age (0.08) were also associated with a higher risk of GVHD. Recipient's ABO group, diagnosis, year of transplant, Rhesus group of donor or recipient, Rhesus compatibility, sex of donor or recipient, sex compatibility, and type of GVHD prophylaxis were not predictive of GVHD. A Cox multifactorial proportional hazards analysis confirmed that ABO matching was the single most significant factor associated with GVHD (P = 0.006). The cumulative incidence of GVHD grade II+ was 39%, 54%, and 82% for ABO major-mismatched, matched, and minor-mismatched pairs (P = 0.01). This study suggests that ABO antigens may play a role in the development of acute GVHD.     

First-Line Unrelated Double-Unit Umbilical Cord Blood Transplantation for Acquired Severe Aplastic Anemia

We analyzed the outcomes of 14 patients with severe aplastic anemia (SAA) who received first-line double-unit cord blood transplantation (dUCBT). Patients’ median age was 24.5 years (range, 10-44 years). The median numbers of infused nucleated and CD34⁺ cells were 5.48 × 10⁷/kg (range, 3.33-7.96 × 10⁷/kg) and 2.30 × 10⁵/kg (range, 0.86-3.97 × 10⁵/kg), respectively. One patient died 5 days after transplantation. Three of the 13 patients acquired autologous myeloid recovery. Neutrophil engraftment was observed in 10 patients (76.29%), and the median time of neutrophil recovery was 19 days (range, 15-40 days). Platelet engraftment was observed in 7 cases (53.8%), and 3 patients experienced platelet graft failure. The median time of platelet recovery was 32 days (range, 22-80 days). The cumulative incidence of grade II-IV acute graft-vs-host disease (GVHD) was 38.5%. One patient demonstrated mild chronic GVHD. After a median follow-up of 61 months (range, 18-102 months), 6 patients were alive. The predicted 5-year overall survival and GVHD-free, failure-free survival rates were 42.9% ± 13.2% and 14.3% ± 9.4%, respectively. The first-line dUCBT for SAA is still primarily evaluated through multicenter prospective clinical trials by an optimal conditioning regimen, cell dose, and other graft and transplantation-related factors.     

Transplant in Aplastic Anemia Using Combined Granulocyte Colony-Stimulating Factor Primed Blood and Bone Marrow Stem Cells: A Retrospective Analysis

IntroductionAplastic anemia (AA) is characterized by diminished hematopoietic precursors in the bone marrow, most often due to injury to the pluripotent stem cell. In Pakistan, AA is not uncommon, and allogeneic hematopoietic stem cell transplant remains the only curative option for these patients.ObjectiveThe objective of this study was to determine the transplant outcome of combined granulocyte colony-stimulating factor (G-CSF) primed blood and bone marrow grafts in adult and pediatric patients with AA.MethodsWe retrospectively collected the data of all transplant procedures performed from 2004 to 2019 at Aga Khan University in Karachi, Pakistan. Variables analyzed included age, sex, type of stem cells used, conditioning regimens, and overall survival for patients undergoing transplant in AA.ResultsA total of 351 transplants were performed during the study period. Out of these, 239 were allogeneic transplants, whereas 112 were autologous procedures. We performed 70 transplants for AA during the study period, of which 52 were male patients and 18 were female patients. The median age ± standard deviation (SD) was 17.5 ± 9.4 years (range, 2-43 years). Cyclophosphamide/antithymocyte globulin (ATG) was used as a conditioning regimen in 65 patients, while ATG/cyclophosphamide/fludarabine was used in 5 patients. In 60 patients, a combination of G-CSF primed blood and bone marrow stem cells were used. The mean CD34 count was 5.2 × 10⁶/kg. Graft-vs-host disease (GVHD) prophylaxis was done with cyclosporine and methotrexate. All patients received standard infection prophylaxis. Engraftment was achieved in 86% of patients. The median day of myeloid engraftment was 15 (range, 10-22 days). Chronic GVHD was present in 3 patients while 4 had acute GVHD. The overall survival was 71.2% (median duration of 80 months). The main cause of mortality was gram-negative sepsis.ConclusionA combination of blood and bone marrow stem cells results in early engraftment with decreased frequency of GVHD in AA. The overall survival was comparable to international literature.     

Post-transplant cyclophosphamide and early mixed donor Chimerism in myeloid malignancies; a single-center experience

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for high-risk myeloid malignancies. Post-transplant cyclophosphamide (PT-Cy) has proven to be effective for graft versus host disease (GVHD) prophylaxis. Given that graft-versus-tumor (GVT) effect plays a major role in reducing the risk of disease relapse, the application of PT-Cy must balance the risk of relapse. Mixed chimerism (MC) refers to a state of concurrent presence of recipient and donor cells post allo-HSCT which may precede relapse disease.ObjectiveWe investigated the impact of PT-Cy on early MC (EMC) and disease relapse in patients with a myeloid malignancy post allo-HSCT.Study designThis retrospective single-center study included patients that underwent allo-HSCT between 2015 and 2021. Patient and disease characteristics were collected from the electronic health records. EMC was defined as <95% donor cells at day 90–120 post allo-HSCT.ResultsA total of 144 patient that received an allo-HSCT were included in the study. One hundred and eight (75%) patients received PT-Cy as part of the GVHD prophylaxis regimen. The majority underwent allo-HSCT for acute myeloid leukemia (62%) or myelodysplastic syndrome (31%). Sixty-five percent received allo-HSCT from a matched unrelated donor transplant and 65% received a myeloablative conditioning regimen. A lower rate of chronic GVHD (p = 0.03) and a higher rate of EMC (p = 0.04) were observed in patients that received PT-Cy. PT-Cy was not associated with overall survival (OS) and relapse-free survival (RFS). Multivariable analysis identified measurable residual disease status (p = 0.003), hematopoietic cell transplantation-specific comorbidity index (p = 0.012) and chronic GVHD (p = 0.006) as independent prognostic variables for OS. AML-adverse risk (p = 0.004) and EMC (p = 0.018) were independently prognostic for RFS. While EMC overall was not significantly associated with higher risk of relapse, EMC was associated with shorter RFS within adverse-risk AML patients.ConclusionOur study shows that PT-Cy was associated with an increased risk of EMC. The predictive value of EMC for relapse remains unclear and may depend on the underlying disease, which should be validated in a larger cohort.     

非清髓性外周血干细胞移植后白血病复发的防治

目的探讨非清髓性造血干细胞移植后白血病复发的防治。方法7例合并有其它系统疾病的白血病患者接受非清髓性外周血干细胞移植,移植后采用环孢素A及短程甲氨蝶呤预防移植物抗宿主病(GVHD),造血细胞植入后,动态检测骨髓单个核细胞嵌合体的变化,根据嵌合体状态,采用供者淋巴细胞输注(DLI),并配合环孢素A用量的调整来防治白血病复发。结果7例患者移植后造血功能得到恢复,3例移植前合并的疾病有所加重,经处理缓解,移植早期相关并发症少而轻。移植后有3例嵌合体由混合嵌合体(MC)转为完全供者型嵌合体(CC),再转为MC,伴Ph染色体阳性,DLI5~6次后Ph染色体转为阴性,嵌合体状态又转为CC,其中2例发生广泛皮肤慢性GVHD;3例的嵌合体持续为CC,无复发,其中2例接受了1次DLI,此2例在环孢素A减量过程中发生GVHD;1例的嵌合体持续为MC,虽经3次DLI,但无效,患者死于白血病复发。结论非清髓性造血干细胞移植后应动态监测嵌合体状态,采用供者淋巴细胞输注,并配合环孢素A用量的调整,对白血病的复发有一定的效果。     

Tacrolimus as prophylaxis for acute graft-versus-host disease in reduced intensity cord blood transplantation for adult patients with advanced hematologic diseases

BACKGROUND: Myeloablative cord blood transplantation (CBT) for adult patients offers a 90% chance of engraftment with a 50% rate of transplant-related mortality, mostly attributable to infection. We have demonstrated the feasibility of reduced-intensity CBT (RI-CBT) for adult patients, in which cyclosporine was used for acute graft-versus-host disease (GVHD) prophylaxis. Transplantation-related mortality (TRM) was 27% within 100 days. Therefore our objective was to evaluate the feasibility of RI-CBT with tacrolimus as GVHD prophylaxis for adult patients with hematologic malignancies. METHODS: Thirty-four patients with a median age of 56.5 years (range; 22-68) with hematologic diseases underwent RI-CBT at Toranomon Hospital between November 2003 and September 2004. Preparative regimen comprised fludarabine 25 mg/m2 on days -7 to -3, melphalan 80 mg/m2 on day -2, and 4 Gy total body irradiation on day -1. GVHD prophylaxis was continuous intravenous infusion of tacrolimus 0.03 mg/kg, starting on day -1. RESULTS: Thirty-one patients achieved neutrophil engraftment at a median of day 20. Median infused total cell dose was 2.4 x 10E7/kg (range; 1.6-4.8). Thirty-two patients achieved complete donor chimerism at day 60. Grade II-IV acute GVHD occurred in 45% of patients, with a median onset of day 26. Primary disease recurred in five patients, and TRM within 100 days was 12%. Estimated 1-year overall survival was 70%. CONCLUSION: This study demonstrated the possible improvement in transplant-related mortality by tacrolimus as GVHD prophylaxis in adult RI-CBT recipients.     

Graft-versus-host disease prevention in allogeneic bone marrow transplantation from histocompatible siblings. A pilot study using immunotoxins for T cell depletion of donor bone marrow

Seventeen patients, ages 7-53 years were transplanted with histocompatible bone marrow that had been depleted of T lymphocytes by ex vivo immunotoxin (IT) treatment. Twelve patients had high-risk acute leukemias, and five had chronic myelogenous leukemia. No other graft-vs.-host disease (GVHD) prophylaxis was used. A mixture of three anti-T-cell monoclonal antibodies conjugated to ricin were used in this study: TA-1, UCHT-1 (anti-CD3), and T101 (anti-CD5). The mean number of bone marrow cells infused was 1.5 X 10(8) mononuclear cells/kg recipient weight. Thirteen of the 17 patients demonstrated complete and sustained engraftment. Four patients experienced autologous marrow recovery and/or graft rejection. Compared with an historical group of leukemic patients who received GVHD prophylaxis with methotrexate alone or combinations of methotrexate, and prednisone plus antithymocyte globulin, (ATG) or OKT3, the IT patients with stable engraftment demonstrated shorter time to recovery of leukocytes greater than or equal to 1000mm3 for three consecutive days (median, 20 days vs. 26 days, P = .03). The recovery of total lymphocytes, B and T cell subsets, and T cell function by day 28 was highly variable, but similar, for patients in both the IT-treated group and historical controls. Four patients (ages 13, 18, 21, and 38) developed grade II skin GVHD, but none had severe GVHD. Eight of the 13 patients with durable engraftment have had posttransplant leukemic relapse. Currently only four patients remain alive; two have not relapsed posttransplant, while the other two achieved remission following posttransplant relapse. We conclude that severe GVHD was not observed in this small series with ex vivo T cell depletion for GVHD prophylaxis, and that favorable recovery of hematologic and lymphocytic function was demonstrated for cases where primary engraftment was sustained. A larger randomized controlled study will be needed to establish whether T cell depletion of donor bone marrow with IT can significantly reduce GVHD, and/or improve disease-free survival.     

HLA单倍体相合与全相合外周血造血干细胞移植治疗恶性血液病的疗效比较

目的 观察和比较亲属间人类白细胞抗原(HLA)单倍体相合与全相合外周血造血干细胞移植(PBSCT)治疗恶性血液病的临床疗效.方法 2004年5月至2009年2月,共111例恶性血液病患者进行了异基因PBSCT(allo-PBSCT),其中单倍体相合移植受者51例(单倍体组),同期全相合移植受者60例(全相合组).两组的预处理方案均为清髓性;两组预防移植物抗宿主病(GVHD)均以经典环孢素A加短程甲氨蝶呤作为基础方案,HLA 1个抗原不合时,加用吗替麦考酚酯,HLA 2～3个抗原不合时,再加用抗胸腺细胞球蛋白(ATG)及抗CD25单克隆抗体.移植物为经粒细胞集落刺激因子动员的、未进行体外去除T淋巴细胞的外周血造血干细胞(PBSC).结果 111例受者均获得完全、持久供者干细胞植入.单倍体组和全相合组受者中性粒细胞≥0.5×10~9/L的中位时间分别为14 d和12 d,血小板≥20×10~9/L的中位时间分别为15 d和13 d.单倍体组有25例受者发生急性GVHD(aGVHD),其中Ⅰ度20例,Ⅱ度5例;有33例发生慢性GVHD(cGVHD),其中局限型30例,广泛型3例;4年累积发病率为70.4%;无白血病存活40例,3年预期总无白血病存活率(LFS)为74.5%,其中标危型77.3%,高危型68.2%.全相合组有14例发生aGVHD,其中Ⅰ度10例,Ⅱ度2例,Ⅲ度2例;有37例发生cGVHD,其中局限型32例,广泛型5例;4年累积发病率为58.1%.无白血病存活46例,3年预期总LFS为72.1%,其中标危型77.6%,高危型52.7%.单倍体组受者移植后aGVHD发生率高于全相合组,差异有统计学意义(P<0.05);但cGVHD、原发病复发率和LFS差异均无统计学意义(P>0.05).结论 应用清髓性预处理联合多种免疫抑制剂进行非体外去T淋巴细胞的、亲属间HLA单倍体相合与全相合PBSCT均为治疗恶性血液病安全有效的方案.     

Combination of tacrolimus,methotrexate, and methylprednisolone prevents acute but not chronic graft-versus-host disease in unrelated bone marrow transplantation

BACKGROUND: Graft-versus-host disease (GVHD) is still a major problem in allogeneic bone marrow transplantation (BMT). Prophylactic regimens used against GVHD in unrelated BMT, including cyclosporine (CsA)-plus-methotrexate (MTX), CsA-plus-MTX-plus-prednisone, and tacrolimus (FK506)-plus-MTX, are still unsatisfactory (34-70% occurrence of grades II-IV GVHD). To address this problem, we examined the efficacy of FK506-plus-MTX-plus-methylprednisolone (mPSL) in 20 patients who underwent BMT from unrelated donors. METHODS: All patients received FK506 beginning the day before transplantation at a dose of 0.03 mg/kg per day by continuous intravenous (IV) infusion. MTX was administered at a dose of 10 mg/m(2) IV on day 1, and 7 mg/m(2) on days 3, 6, and 11. Intravenous administration of mPSL was started at a dose of 2 mg/kg per day on day 1. In the absence of acute GVHD, mPSL was gradually tapered from day 29. RESULTS: Development of acute GVHD was almost completely suppressed (one patient with grade I, none with grades II-IV). However, the incidence and severity of chronic GVHD did not decrease. Eight of 12 patients with extensive chronic GVHD died of thrombotic microangiopathy or infection. A vigorous fluctuation (>100 U/mL per 10 days) of the soluble interleukin 2 receptor level in the serum after engraftment was highly related to the occurrence of chronic GVHD. CONCLUSIONS: An FK506-plus(+)-MTX-plus(+)-mPSL prophylactic regimen could almost completely suppress acute GVHD but not chronic GVHD in unrelated BMT. In this GVHD prophylactic system, the extent of the change of soluble interleukin 2 receptor level may be a good predictor of development of chronic GVHD.     

Haploidentical Stem Cell Transplantation for Acute Leukemia Patients Who Experienced Early Relapse Within One Year After the First Transplantation

To assess the safety and efficacy of allogeneic stem cell transplantation from haploidentical related donors (haplo-SCT) as 2nd transplantation for patients with early relapsed disease, we retrospectively evaluated 7 consecutive patients (median age, 42 years; range, 29–63 years) who experienced relapse within 1 year of the 1st transplantation and received haplo-SCT as a 2nd transplantation. Among the 7 patients who received haplo-SCT, 2 who were in morphologically complete remission (CR) at transplantation were conditioned with a reduced-intensity regimen, and the 5 non-CR patients were conditioned with a myeloablative regimen. Both conditioning regimens included antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone. Sustained neutrophil engraftment was achieved in all 7 patients. One patient developed severe acute GVHD. Notably, only 1 patient experienced relapse, and each patient achieved longer CR duration than after the 1st transplantation. Three of the 7 patients died from treatment-related causes: acute GVHD, post-transplantation lymphoproliferative disorder, and bacterial pneumonia. At the time of analysis, the 2-year overall survival rate of these 7 patients was 42.9%. This suggests that use of haploidentical related donors is a viable alternative for 2nd transplantation and should be confirmed in larger cohorts.