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.     

Host-specific interleukin-2-secreting donor T-cell precursors as predictors of acute graft-versus-host disease in bone marrow transplantation between HLA-identical siblings.

BACKGROUND. Acute graft-versus-host disease (GVHD) is a serious complication of allogeneic bone marrow transplantation from an HLA-identical sibling. There is no practical test before transplantation that gives sufficient information to predict the degree of allogeneic reactivity between HLA-identical siblings. METHODS. We determined the frequency with which host-specific interleukin-2-secreting donor T-cell precursors occurred in 16 consecutive pairs of HLA-identical siblings before they underwent marrow grafting. The results were correlated with the development of acute GVHD after transplantation. RESULTS. High frequencies of host-specific T-cell precursors (> or = 1 per 100,000) were detectable before transplantation in eight donors whose siblings later had severe (grade II or III) acute GVHD. Among the donors to eight patients with mild (grade 0 or 1) acute GVHD, low frequencies (< 1 per 100,000) were found. CONCLUSIONS. Analysis of the frequency of such cells before transplantation may be a useful predictor of severe acute GVHD in allogeneic bone marrow transplantation between HLA-identical siblings. It is possible that the patients at risk for serious acute GVHD after marrow grafting may benefit from some alternative form of immunosuppressive therapy.     

Allogeneic peripheral blood stem cell rescue of late graft failure after bone marrow transplantation in patients with aplastic anemia

We investigated the effect and outcome of allogeneic peripheral blood stem cell (PBSC) rescue for aplastic anemia (AA) patients with graft failure after allogeneic bone marrow transplantation (BMT). Seven (28%) of 25 AA patients who received BMT from HLA-identical sibling donors developed late graft failure at a median of 7 months (range, 2.0-9.3 months) after transplantation. The patients with graft failure were treated with PBSC collected from the original donor after mobilization with granulocyte-colony stimulating factor (G-CSF). The median boost dose of peripheral blood mononuclear cells was 3.1 x 10(8)/kg (range, 1.4-11.9 x 10(8)/kg). Median times to reach an absolute neutrophil count greater than 0.5 x 10(9)/L and a platelet count greater than 50 x 10(9)/L were 7 days (range, 4-14 days) and 9 days (range, 3-41 days), respectively. There was sustained graft function in 6 of 7 patients, with a median follow-up duration of 3.3 yr (range, 1.0-6.2 yr). Grade-I acute graft-versus-host disease (GVHD) occurred in 2 patients, while extensive chronic GVHD developed in 3 patients. This report shows that G-CSF-mobilized allogeneic PBSC rescue is very effective in achieving complete and sustained engraftment in patients with AA after graft failure. However, more efficacious measures to prevent extensive chronic GVHD remain to be developed.     

HLA相合同胞异基因外周血造血干细胞移植治疗急性白血病

背景：HLA相合同胞间异基因外周血造血干细胞移植是治疗急性白血病的一种有效方法。 目的：评价HLA相合异基因外周血造血干细胞移植治疗急性白血病的临床疗效及并发症。 方法：25例急性白血病患者接受HLA相合同胞的异基因外周血造血干细胞移植,其中急性髓系白血病20例,急性淋巴细胞白血病5例。预处理方案为BU+CY方案或CY+TBI方案,移植物抗宿主病预防采用环孢素A+吗替麦考酚酯+短程甲氨蝶呤。 结果：最短随访2个月,最长随访80个月。患者均获造血重建,中性粒细胞≥0.5×10⁹ L^-1的时间为10~18 d,血小板≥20× 10⁹ L^-1的时间为10~37 d。主要并发症：感染败血症12例,巨细胞病毒感染9例,带状疱疹病毒感染3例,发生急性移植物抗宿主病10例,慢性移植物抗宿主病11例,出血性膀胱炎4例。至随访结束,17例无病生存,8例死亡。提示HLA相合同胞异基因外周血造血干细胞移植是治疗急性白血病安全有效的方法。     

Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma

We analyzed the relevance of HLA incompatibility to acute graft-versus-host disease, relapse, and survival in 281 patients with hematologic neoplasms who underwent bone marrow transplantation. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, -B, and -D antigens of the haplotype not shared; 29 were phenotypically identical, 119 were incompatible for one locus, 104 for two loci, and 29 for three loci. These 281 patients were compared with 967 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. Occurrence of severe acute graft-versus-host disease was evaluated in patients who achieved sustained engraftment. In recipients of haploidentical grafts occurrence of severe acute graft-versus-host disease was associated with (1) graft-versus-host disease prophylaxis containing the combination of methotrexate plus cyclosporine versus standard methotrexate, relative risk = 0.35; 95% confidence interval, 0.21-0.57, p less than 0.0001; and (2) the degree of recipient HLA incompatibility, relative risk = 1.95 for each locus incompatible; 95% confidence interval, 1.52-2.50, p less than 0.0001; (3) patient age, relative risk = 1.23 per decade; 95% confidence interval, 1.05-1.44, p = 0.0094. Acute graft-versus-host disease was associated with lower leukemic relapse after transplant in patients with acute lymphocytic leukemia, and chronic graft-versus-host disease was associated with lower relapse after transplant for acute nonlymphocytic leukemia in relapse or chronic myelogenous leukemia in blast crisis. After transplantation for acute nonlymphocytic leukemia in remission, the rate of leukemic relapse was 22% in 61 recipients of "one-locus" (A, B, or D)-incompatible grafts compared to 37% in 561 recipients of HLA-identical sibling grafts. Survival was decreased as the degree of HLA disparity increased. Survival of "one-locus"-incompatible transplant recipients, however, was equivalent to that of HLA-identical sibling transplant recipients.     

Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft

BACKGROUND: The treatment of chronic granulomatous disease with conventional allogeneic hematopoietic stem-cell transplantation carries a high risk of serious complications and death. We investigated the feasibility of stem-cell transplantation without ablation of the recipient's bone marrow. METHODS: Ten patients, five children and five adults, with chronic granulomatous disease underwent peripheral-blood stem-cell transplantation from an HLA-identical sibling. We used a nonmyeloablative conditioning regimen consisting of cyclophosphamide, fludarabine, and antithymocyte globulin. The allograft was depleted of T cells to reduce the risk of severe graft-versus-host disease. Donor lymphocytes were administered at intervals of 30 days or more after the transplantation to facilitate engraftment. RESULTS: After a median follow-up of 17 months (range, 8 to 26), the proportion of donor neutrophils in the circulation in 8 of the 10 patients was 33 to 100 percent, a level that can be expected to provide normal host defense; in 6 the proportion was 100 percent. In two patients, graft rejection occurred. Acute graft-versus-host disease (grade II, III, or IV) developed in three of the four adult patients with engraftment, one of whom subsequently had chronic graft-versus-host disease. None of the five children had grade II, III, or IV acute graft-versus-host disease. During the follow-up period, four serious infections occurred among the patients who had engraftment. Three of the 10 recipients died. Preexisting granulomatous lesions resolved in the patients in whom transplantation was successful. CONCLUSIONS: Nonmyeloablative conditioning followed by a T-cell-depleted hematopoietic stem-cell allograft is a feasible option for patients with chronic granulomatous disease, recurrent life-threatening infections, and an HLA-identical family donor.     

同胞与非血缘脐血移植治疗儿童恶性血液病的效果分析

背景:近年来,脐血逐渐成为亲缘及非血缘骨髓或外周血造血干细胞移植的一种极其关键的替代干细胞来源,被越来越多地用于儿童恶性血液病的治疗。目的:比较同胞与非血缘脐血移植治疗儿童恶性血液病的临床疗效。方法:回顾性分析1998-01-01/2018-12-31于郑州大学第一附属医院造血干细胞移植中心接受同胞脐血移植及非血缘脐血移植治疗儿童恶性血液病患者的临床资料,所有脐血移植患者均采用清髓性预处理方案,同时应用环孢素A±吗替麦考酚酯方案预防移植物抗宿主病。结果与结论:①2例同胞脐血移植患者及3例非血缘脐血移植患者造血植入失败继发感染死亡,其他全部脐血移植患者均顺利达到造血植入;同胞脐血移植组、非血缘脐血移植组中性粒细胞与血小板中位植入时间分别为[17 d(11-43 d),18 d(12-45 d),P=0.307]与[20.5 d(15-50 d),27 d(18-56 d),P=0.773],差异均无显著性意义;②同胞脐血移植组、非血缘脐血移植组急性移植物抗宿主病与慢性移植物抗宿主病的发生率分别为(36%vs.43%,P=0.737)与(15%vs.33%,P=0.412),差异均无显著性意义;同胞脐血移植组与非血缘脐血移植组移植后感染的发生率为56%,71%,差异无显著性意义(P=0.343);③同胞脐血移植组、非血缘脐血移植组2年总体生存率与2年无复发生存率分别为(61%vs.36%,P=0.301)与(56%vs.33%,P=0.151),差异均无显著性意义;同胞脐血移植组、非血缘脐血移植组5年总体生存率和5年无复发生存率分别为(54%vs.24%,P=0.044)与(50%vs.20%,P=0.039),两组在长期生存方面差异有显著性意义;④结果显示同胞与非血缘脐血移植均是治疗儿童恶性血液病安全有效可行的移植方式,尤其在儿童血液病患者替代供者移植的长期生存方面明显受益。     

Comparable outcomes of matched-related and alternative donor stem cell transplantation for pediatric severe aplastic anemia.

Matched sibling donor (MSD) bone marrow transplantation is the treatment of choice for pediatric patients with severe aplastic anemia (SAA); however, only about 33% of patients will have an HLA-identical sibling. Alternative donor (AD) transplants may be an option for these patients, but such therapies have been associated with greater incidence of graft failure and graft-versus-host disease (GVHD). We retrospectively analyzed 36 pediatric patients who received 38 bone marrow or peripheral blood stem cell transplants (15 MSD and 23 AD) for SAA at our institution from April 1997 to October 2005. Nineteen AD recipients received reduced intensity conditioning with cyclophosphamide, low-dose total body irradiation, and antithymocyte globulin (ATG) or Campath. The 4-year overall survival for MSD recipients was 93% versus 89% for AD recipients treated with reduced intensity conditioning regimens at a median follow-up of 52 months (range, 6-99 months). No patient receiving Campath, compared with 3 of 9 patients receiving ATG, developed extensive, chronic GVHD. We conclude that, for children with SAA, AD transplantation is as effective as MSD transplantation. Further, compared with ATG, preparatory regimens containing Campath may be associated with a lower incidence of extensive, chronic GHVD.     

HLA单倍体相合与全相合外周血造血干细胞移植后的急性移植物抗宿主病

背景：异基因外周血造血干细胞移植成为造血干细胞移植的主要方式,近年来HLA单倍体相合造血干细胞移植因供者来源广泛在临床应用较多,急性移植物抗宿主病仍是影响移植成功率的主要因素。 目的：观察亲缘HLA单倍体相合与全相合异基因外周血造血干细胞移植后急性移植物抗宿主病的发生特点,探讨降低急性移植物抗宿主病发生率的方法及单倍体造血干细胞移植应用于临床的意义。 方法：行异基因外周血造血干细胞移植的患者52例,其中HLA全相合组31例,单倍体组21例。HLA单倍体组采用改良马利兰/环磷酰胺+兔抗人胸腺T细胞免疫球蛋白预处理方案,HLA全相合组采用改良马利兰/环磷酰胺预处理方案。移植物抗宿主病的预防采用短程甲氨蝶呤+环孢素A+吗替麦考酚酯的方案。 结果与结论：52例患者均获得完全持久干细胞植入。其中,急性移植物抗宿主病发病率为48%(25/52),Ⅲ-Ⅳ度急性移植物抗宿主病发病率为23%(12/52);全相合组及单倍体组急性移植物抗宿主病累积发病率分别为39%(12/31)和62%(13/21)(P > 0.05);全相合组及单倍体组Ⅲ-Ⅳ度急性移植物抗宿主病累积发病率分别为10%(3/31)和43%(9/21)(P < 0.05);发生于移植后+30 d、+31 d-+60 d、+61 d-+100 d的急性移植物抗宿主病类型分布差异无显著性意义(P > 0.05);发生在移植后+30 d内的急性移植物抗宿主病发生率高于移植后   +31 d-+60 d和+61 d-+100 d;发生急性移植物抗宿主病组和无急性移植物抗宿主病组复发率、2年无病生存率差异无显著性意义(P > 0.05),全相合组与单倍体组相比复发率差异无显著性意义(P > 0.05),2年无病生存率前者高于后者(P < 0.05)。说明采用上述移植方案,单倍体组安全性与疗效接近全相合组;在缺乏HLA相合供者时,单倍体造血干细胞移植是治疗恶性血液病的重要方法。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：     

Allogeneic hematopoietic cell transplantation following reduced intensity conditioning for treatment of myelofibrosis.

This report describes our experience with reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using matched sibling and unrelated donors (MUDs) for treatment of myelofibrosis (MF). Nine patients with MF (median age, 54 years) were treated with RIC allogeneic HCT using MUDs for 7 of the 9 patients and sibling donors for 2 patients. By the Lille classification, 4 patients were characterized as having high risk, 4 as having intermediate risk, and 1 as having low risk. The RIC regimen consisted of fludarabine and a single dose of total body irradiation for the first patient and fludarabine/melphalan for the remaining 8 patients. Granulocyte colony-stimulating factor-primed peripheral blood stem cells (PBSCs) were used for all but 1 patient who received a total of 3 products because of graft failure, of which 2 were bone marrow cells and the third was PBSCs. Prophylaxis against graft-versus-host disease consisted of cyclosporin/mycophenolate with or without methotrexate. Seven patients were successfully engrafted with white blood cells, with an absolute neutrophil count > or =500 by a median of day +15 (range, 10-21 days). At the time of final fluorescence in situ hybridization and/or short tandem repeat analysis, 8 of 9 patients were chimeric, with 96%-100% donor cells and/or DNA. Five of the 9 patients were alive at the time of final contact, with a median follow-up of 32.2 months for the living patients. Overall survival probability at 1 year was 55.6% (95% confidence interval, 31.3%-77.4%). These results suggest that RIC MUD HCT using PBSCs can be an effective treatment for older patients with MF.     

Conditioning with Purine Analogs Leads to Good Engraftment Rates of Immunodepleted Grafts for Aplastic Anemia

Immunodepletion with alemtuzumab is an effective strategy for preventing graft-versus-host disease after allogeneic stem cell transplantation (SCT), but it may be associated with graft failure. We tested the effectiveness of a purine analog-based reduced-intensity conditioning combination in patients undergoing allogeneic SCT for bone marrow aplasia. Patients with severe marrow aplasia who had a tissue-compatible sibling donor were conditioned with fludarabine 30 mg/m² for 5 days and cyclophosphamide 120 mg/kg. Stem cells from HLA-identical sibling donors were mobilized with filgrastim, and the harvested blood concentrates were incubated ex vivo with alemtuzumab. After graft infusion, patients received therapeutic doses of cyclosporine up to day 90. The primary objective of this study was to examine the proportion of patients who achieved engraftment and overall survival. Secondary objectives were the rates of graft-versus-host disease, posttransplantation infections, and graft failure. The study group comprised 30 patients who received a total of 31 cytokine-mobilized blood stem cell transplantations. The median CD34⁺ cell dose infused was 4.99 × 10⁶/kg. All patients engrafted at a median of 12 days post-SCT. Two patients exhibited delayed graft failure, at 3 months and 7 months post-SCT, and required retransplantation or donor lymphocyte infusion to reestablish full-donor chimerism. At a median of 1,560 days post-SCT, all patients survived and were transfusion-free. We confirm that the combination of purine analog and cyclophosphamide is adequate for engraftment of grafts immunodepleted with alemtuzumab. This strategy is associated with excellent outcomes.     

ABO blood group barrier in allogeneic bone marrow transplantation revisited.

Reports have shown a worse outcome for donor-recipient pairs mismatched for ABO blood groups in bone marrow transplantation (BMT). These studies, however, included small and heterogeneous study populations, and not all considered bidirectional ABO incompatibility separately. Because the issue remains controversial, we analyzed the effect of ABO mismatch on the overall survival, transplant-related mortality, and occurrence of acute and chronic graft-versus-host disease (GVHD) in a large homogenous group of patients undergoing allogeneic BMT. A total of 3103 patients with early-stage leukemia who underwent transplantation between 1990 and 1998 with bone marrow from an HLA-identical sibling and who were reported to the Center for International Blood and Marrow Transplant Research were studied. The median follow-up was 54 months. A total of 2108 (67.9%) donor-recipient pairs were ABO identical, 451 (14.5%) had a minor mismatch, 430 (13.9%) had a major mismatch, and 114 (3.7%) had a bidirectional ABO mismatch. The groups did not differ significantly in patient or donor characteristics except for more female-to-male sex mismatch in the bidirectional ABO mismatch group (P = .017). In multivariate models of overall survival, transplant-related mortality, and grade II to IV acute GVHD, there were no significant differences among the 4 groups. Bidirectional ABO mismatch was associated with a significantly higher risk of grade III or IV acute GVHD (hazard ratio, 1.869; 95% confidence interval, 1.192-2.93; P = .006). Patients with major ABO mismatch received red blood cell transfusions (P = .001) for a longer timer after transplantation and had a slightly slower neutrophil recovery (P < .001). There was no evidence of a substantial effect of ABO blood group incompatibility on the outcome of conventional BMT among patients with leukemia.     

Partial T Cell-Depleted Peripheral Blood Stem Cell Transplantation from HLA-Identical Sibling Donors for Patients with Severe Aplastic Anemia

We analyzed the outcomes of 26 consecutive patients with acquired severe aplastic anemia (SAA) undergoing peripheral blood stem cell transplantation (PBSCT) with partial ex vivo T cell depletion with a targeted T cell dose from HLA-identical sibling donors. The median patient age was 37 years (range, 3 to 63 years). Four patients with uncontrolled pneumonia at the time of transplantation died, on days +1, +2, +21, and +26. All evaluable patients engrafted, with a median time to neutrophil recovery of 11 days (range, 10 to 14 days) and a median time to platelet recovery of 19 days (range, 8 to 53 days). Two patients had transient grade I acute graft-versus-host disease (GVHD) with skin involvement, but no patients developed grade II-IV acute GVHD. Two patients had mild skin chronic GVHD, and 1 patient had moderate chronic GVHD with ocular involvement. No relapse was observed after a median follow-up of 114 months (range, 4 to 233 months). The overall cumulative incidence of TRM at 10 years was 19%, whereas it was 5% for those with a Karnofsky Performance Status (KPS) score >60 at the time of transplantation. Disease-free survival, overall survival, and GVHD and relapse-free survival at 10 years were 81%, 81%, and 80%, respectively, for all patients and 95%, 95%, and 90%, respectively, for patients with a KPS score >60 at transplantation. Our data indicate that PBSCT with partial ex vivo T cell-depleted targeted cell dose grafts from an HLA-identical sibling donor is a feasible, safe, and effective approach to reduce GVHD and cure patients with SAA.     

Prevention of infection and graft-versus-host disease by suppression of intestinal microflora in children treated with allogeneic bone marrow transplantation

The effect of suppression with antimicrobial agents of the intestinal microflora of paediatric bone marrow graft recipients on severe bacterial and fungal infections and on moderate to severe acute graft-versus-host disease was studied retrospectively. Data on 65 cases of bone marrow transplantation for either severe bone marrow failure or leukaemia, performed in a strict protective environment with either complete or selective gastrointestinal decontamination, were evaluated. All bone marrow grafts were from HLA-identical siblings and were not depleted of T-lymphocytes. Twenty percent of the recipients had one or more episodes of septicaemia during the granulocytopenic period after transplantation, mostly due to gram-positive bacteria. Only five children died due to infection, in each case caused by a microorganism originating from the endogenous flora. Complete gastrointestinal decontamination was superior to selective gastrointestinal decontamination in preventing infectious complications (p<0.001). The same was the case for the prevention of acute graft-versus-host disease of grade II or higher, which was observed in 7 of 40 (17.5 %) completely decontaminated children versus 9 of 18 (50 %) selectively decontaminated children evaluable for graft-versus-host disease (p<0.01). It is concluded that complete gastrointestinal decontamination in a strict protective environment is a feasible and very effective method for preventing severe infections and acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents; it resulted in a low transplantation-related mortality of 26 % and a good quality of survival in 69 % of the graft recipients.     

Filgrastim following HLA-Identical Allogeneic Bone Marrow Transplantation: Long-Term Outcomes of a Randomized Trial

Human recombinant granulocyte colony stimulating factor reduces the duration of neutropenia following HLA-identical allogeneic bone marrow transplantation. However, its use remains controversial due to the risk of increasing the incidence of acute graft-versus-host disease (GVHD) and slower platelet recovery. To clarify these risks, we conducted a prospective randomized placebo-controlled trial of filgrastim 5 µg/kg/day i.v. from day 7 post-transplant until neutrophil recovery in 145 consecutive adults undergoing HLA-identical allogeneic bone marrow transplantation, with cyclosporine and methotrexate as GVHD prophylaxis. The primary endpoint was the incidence of acute GVHD; hematological recovery, nonrelapse mortality, and post-transplant complications were secondary endpoints. Filgrastim had no significant effect on the incidence of acute GVHD, platelet recovery, platelet transfusion requirements, chronic GVHD, or survival. Filgrastim accelerated granulocyte recovery significantly (with absolute neutrophil counts >.5?×?10⁹/L achieved after a median of 16 days versus 23 days for placebo; P < .0001), and reduced both early nonrelapse mortality (2.9% versus 10.5%; P = .042) and the duration of i.v. antibiotic therapy (18 days versus 26 days; P = .001) and hospitalization (27 versus 34 days; P = .017). In conclusion, in this setting, filgrastim reduced significantly the duration of neutropenia, i.v. antibiotic therapy, hospitalization, and early nonrelapse mortality, without increasing the risk of acute and chronic GVHD or relapse, or delaying platelet recovery.     

The Effect of Granulocyte Colony-Stimulating Factor Use on Hospital Length of Stay after Allogeneic Hematopoietic Cell Transplantation: A Retrospective Multicenter Cohort Study

Granulocyte colony-stimulating factor (G-CSF) is administered after allogeneic hematopoietic cell transplantation (HCT) to aid neutrophil recovery. We compared the effect of empiric G-CSF administration on the duration of index inpatient hospitalization stay after HCT for patients aged ≥18 years with a hematologic malignancy. G-CSF was considered empiric if administered between day -3 and day +6 in relation to graft infusion. We studied 3562 HCTs (1487 HLA-matched sibling donor HCTs and 2075 HLA-matched unrelated donor HCTs) between 2007 and 2016. Three hundred and thirteen (21%) recipients of HLA-matched sibling donor HCT and 417 (20%) recipients of HLA-matched unrelated donor HCT received empiric G-CSF therapy. The effect of G-CSF therapy on the index hospitalization stay was examined in generalized linear models (GLMs) with adjustment for other patient, disease, and transplantation characteristics and acute graft-versus-host disease and infection post-transplantation. The duration of index hospitalization by treatment group did not differ for HLA-matched sibling donor HCT but was shorter with G-CSF for HLA-matched unrelated donor HCT (15 days versus 19 days; P < .001). Our GLMs confirmed shorter hospitalization with the use of G-CSF therapy for HLA-matched unrelated donor HCT (P = .01). G-CSF therapy was not associated with early survival for either donor type, and there was no benefit or disadvantage of giving G-CSF to promote neutrophil recovery.     

Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms

The occurrence of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation for leukemia is thought to decrease the probability of recurrence. To study this effect (called adoptive immunotherapy) we modified the prophylaxis of GVHD in patients with advanced hematologic neoplasms (mostly leukemia) who received bone marrow transplants. Patients under 30 years of age were randomly assigned to one of three regimens of post-transplantation immunosuppression: Group I (n = 44) received a standard course of methotrexate for 102 days after transplantation, Group II (n = 40) received an abbreviated (11-day) course of methotrexate, and Group III (n = 25) received the standard course of methotrexate plus viable buffy-coat cells from the marrow donors. All 109 patients received cyclophosphamide (60 mg per kilogram of body weight on each of two days), total-body irradiation (2.25 Gy daily for seven days), and unmodified marrow from HLA-identical sibling donors. The frequency of GVHD of Grades II through IV was 25 percent in Group I, 59 percent in Group II, and 82 percent in Group III (P = 0.0001). The incidence of chronic GVHD, however, did not differ significantly among the groups (33, 51, and 44 percent, respectively), nor did the five-year probability of recurrence of disease (38, 45, and 33 percent, respectively). However, mortality from causes other than cancer was 34 percent in Group I, 45 percent in Group II, and 64 percent in Group III (I vs. III, P = 0.024); the deaths were due primarily to infections complicating the course of GVHD. With a median follow-up of 5.1 years (range, 3.9 to 7.4), disease-free survival was 41 percent in Group I, 30 percent in Group II, and 24 percent in Group III (the differences were not statistically significant). We conclude that abbreviating methotrexate prophylaxis or infusing donor buffy-coat cells increased the incidence of acute GVHD and related mortality without altering the incidence of chronic GVHD or the recurrence of malignant disease.     

Comparable long-term survival after bone marrow versus peripheral blood progenitor cell transplantation from matched unrelated donors in children with hematologic malignancies.

Despite the increasing use of peripheral blood progenitor cells (PBPC) instead of bone marrow (BM) for allogeneic hematopoietic stem cell transplantation (allo HSCT) from human leukocyte antigen (HLA)-matched unrelated donors in children, the relative benefits and risks of both stem cell sources in the pediatric setting remain largely unknown. Recently, the only larger study comparing the value of the 2 stem cell sources in a young patient group was confined to transplantation from HLA-identical sibling donors in older children and adolescents with acute leukemia. Based on the paucity of data in pediatric HLA-matched unrelated donor transplantation, we analyzed the outcome of 23 BM and 38 PBPC transplantations performed at our center. Neutrophil and platelet engraftment were achieved significantly faster in PBPC compared to BM recipients (18 versus 22 days and 26 versus 33 days; P < .001 and P = .03) whereas the risk for grade II-IV acute graft-versus-host disease (aGVHD) (62% versus 55%; P = .53) and chronic GVHD (cGVHD 65% versus 59%; P = .54) was comparable. As overall survival (OS; PBPC versus BM: 47.5% +/- 8.6% versus 51.8% +/- 10.5%; P = .88) and relapse-free survival (43.3% +/- 8.3% versus 51.8% +/- 10.5%; P = .60) are without detectable difference, PBPC and BM appear both as a valid stem cell source for HLA-matched unrelated donor transplantation in children with hematologic malignancies.     

Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers

BACKGROUND: In recipients of allogeneic hematopoietic-cell transplants, peripheral-blood cells mobilized with the use of filgrastim (recombinant granulocyte colony-stimulating factor) engraft more rapidly than bone marrow. However, the relative effects of these techniques on the rates of acute and chronic graft-versus-host disease, overall survival, and disease-free survival have not been determined in randomized studies. METHODS: Between March 1996 and July 1999, 172 patients (12 to 55 years of age) with hematologic cancer were randomly assigned to receive either bone marrow or filgrastim-mobilized peripheral-blood cells from HLA-identical relatives for hematopoietic rescue after the treatment of hematologic cancer with high doses of chemotherapy, with or without radiation. RESULTS: The recovery of both neutrophils and platelets was faster with peripheral-blood cells than with marrow (P<0.001 for both comparisons). The cumulative incidence of grade II, III, or IV acute graft-versus-host disease at 100 days was 64 percent with peripheral-blood cells and 57 percent with marrow (hazard ratio, 1.21; 95 percent confidence interval, 0.81 to 1.81; P=0.35). The cumulative incidence of chronic graft-versus-host disease was 46 percent with peripheral-blood cells and 35 percent with marrow (hazard ratio, 1.16; 95 percent confidence interval, 0.71 to 1.90; P=0.54). The estimated overall probability of survival at two years was 66 percent with peripheral-blood cells and 54 percent with marrow (hazard ratio for death, 0.62; 95 percent confidence interval, 0.38 to 1.02; P=0.06). The rate of disease-free survival at two years was 65 percent with peripheral-blood cells and 45 percent with marrow (hazard ratio for relapse or death, 0.60; 95 percent confidence interval, 0.38 to 0.95; P=0.03). CONCLUSIONS: In patients given high-dose chemotherapy, with or without radiation, for the treatment of hematologic cancer, allogeneic peripheral-blood cells used for hematopoietic rescue restore blood counts faster than allogeneic bone marrow, without increasing the risk of graft-versus-host disease.     

Effects of race on survival after stem cell transplantation.

Effects of race or ethnicity on survival after high-dose chemoradiation followed by stem cell transplantation (SCT) have not been thoroughly evaluated. We analyzed survival according to racial/ethnic categories for 3587 consecutive patients who had SCT at a single US institution between July 1992 and December 2000. Among 1366 patients who received autologous SCT, race or ethnicity was not significantly associated with survival. In contrast, among 2221 patients who received allogeneic SCT from HLA-matched unrelated or sibling donors, blacks had a significantly greater mortality than whites (unadjusted hazard ratio, 1.65; 95% confidence interval, 1.21-2.25). Mortality among other racial or ethnic groups was not significantly different from that among whites. The greater mortality hazard among blacks persisted after controlling for donor type, pretransplantation risk category, patient age, donor/patient sex, and cytomegalovirus exposure (hazard ratio, 1.71; 95% confidence interval, 1.25-2.34). SCT from both HLA-matched unrelated and HLA-identical sibling donors was associated with more severe acute graft-versus-host disease and higher nonrelapse mortality among blacks compared with whites. Furthermore, blacks who received SCT for chronic myeloid leukemia had longer diagnosis-to-transplantation intervals than whites. A matched-cohort analysis showed that the higher mortality among blacks could not be explained by obvious socioeconomic differences. The higher incidence of severe graft-versus-host disease among blacks compared with whites, both with HLA-identical sibling donors, might be related to yet-unidentified "immune-enhancing" genetic polymorphisms. We cannot exclude the possibility that the increased mortality risk among blacks after discharge from the transplant center might in part be related to unidentified sociocultural differences that influence medical care.