Severe Aplastic Anemia and a Healthy Pregnancy Immediately Following Syngeneic Transplantation: An Extremely Rare Case Report.

Aplastic anemia is potentially fatal, particularly if the disease does not respond to immunotherapy and progresses to severe pancytopenia. Allogeneic hematopoietic stem cell transplant from an HLA-matched sibling donor, the first-line treatment in patients younger than 40 years, is used as a curative treatment option in severe aplastic anemia. The availability of an identical twin donor is infrequent, and there is limited experience in this context. Additionally, the choices for a conditioning regimen for a syngeneic transplant to prevent engraftment failure and the necessity of graft-vs-host disease prophylaxis are controversial. Although long-term survival gradually increases after an allogeneic hematopoietic stem cell transplant, hypogonadism and infertility are the main problems that significantly affect patients' quality of life. We present a patient diagnosed with severe aplastic anemia who has had a healthy pregnancy immediately after a syngeneic transplant.

Survival and Functional Immune Reconstitution After Haploidentical Stem Cell Transplantation in Atm-Deficient Mice.

Hematopoietic stem cell transplantation (HSCT) has been proposed as a promising therapeutic opportunity to improve immunity and prevent hematologic malignancies in Ataxia-telangiectasia (A-T). However, experience in the transplantation strategy for A-T patients is still scarce. The aim of this study was to investigate whether different approaches of HSCT are feasible in regard to graft versus host response and sufficient concerning functional immune reconstitution. Atm-deficient mice were treated with a clinically relevant non-myeloablative host-conditioning regimen and transplanted with CD90.2-depleted, green fluorescent protein (GFP)-expressing, and ataxia telangiectasia mutated (ATM)-competent bone marrow donor cells in a syngeneic, haploidentical or allogeneic setting. Like syngeneic HSCT, haploidentical HSCT, but not allogeneic HSCT extended the lifespan of Atm-deficient mice through the reduction of thymic tumors and normalized T-cell numbers. Donor-derived splenocytes isolated from transplanted Atm-deficient mice filled the gap of cell loss in the naïve T-cell population and raised CD4 cell functionality up to wild-type level. Interestingly, HSCT using heterozygous donor cells let to a significantly improved survival of Atm-deficient mice and increased CD4 cell numbers as well as CD4 cell functionality equivalent to HSCT using with wild-type donor cells. Our data provided evidence that haploidentical HSCT could be a feasible strategy for A-T, possibly even if the donor is heterozygous for ATM. However, this basic research cannot substitute any research in humans.

Evaluating full-thickness skin grafts in intraperitoneal onlay mesh position versus onlay position in mice.

BACKGROUND: Importance: Hernia surgery requires reinforcement material with few side effects when used in the intraperitoneal position. Autologous skin grafting may meet this requirement, but animal experiments are obligatory before being applied in humans. OBJECTIVE: To compare survival and effects of isogeneic full-thickness skin grafts in the intraperitoneal onlay mesh (IPOM) position in mice, with a control group using the onlay position. Primary end point was graft survival and secondary end point adhesion formation and inflammation through NF-κB activity. METHODS: Design: Intervention study with 8-week follow-up in accordance with ARRIVE criteria, performed between 2015 and 2016. SETTING: Animal laboratory. PARTICIPANTS: Transgenic C57BL/6 mice with isogeneic background were used. Recipients were female wild-type phenotype mice >3 mo (n = 24). Donors were male or female mice >7 mo, with phenotype-positive for the luciferase gene (n = 20) or positive for NF-κB-luciferase gene (n = 4). INTERVENTION: Full-thickness skin was grafted in the IPOM position and compared with grafts in the onlay position as controls. Survival was evaluated by regular longitudinal postoperative luminescence imaging over 8 wk. Adherence formation was evaluated macroscopically after sacrifice. Inflammation of full-thickness skin grafts in IPOM position of NF-κB mice was evaluated in four additional mice. Main outcome and measure: Survival of grafts, evaluated by luminescence. RESULTS: Ten animals received grafts in the IPOM position, and 10 in the onlay position as controls. Graft survival after 8 wk was 100% (20/20). Average luminescence at the end of the 8-week period was 999,597 flux (min 162,800, max 2,521,530) in the IPOM group (n = 10) and 769,708 flux (min 76,590, max 2,164,080) in the onlay control group (n = 10). No adhesions requiring sharp dissection (Jenkins' scale >2) were seen. Four animals with grafts in the IPOM position showed peak inflammation (NF-κB activity) 5 d after surgery subsiding toward the end of follow-up. CONCLUSIONS: Full-thickness skin survives as well in the IPOM position as in the onlay control position, and few adherences develop. Further studies are required to fully characterize the tissue remodeling and repair processes associated with IPOM skin grafting. The result is relevant in the search for alternative reinforcement materials to be used in complex hernia surgery in humans.

Highly Angiogenic, Nonthrombogenic Bone Marrow Mononuclear Cell-Derived Spheroids in Intraportal Islet Transplantation.

Highly angiogenic bone marrow mononuclear cell-derived spheroids (BM-spheroids), formed by selective proliferation of the CD31+CD14+CD34+ monocyte subset via three-dimensional (3D) culture, have had robust angiogenetic capacity in rodent syngeneic renal subcapsular islet transplantation. We wondered whether the efficacy of BM-spheroids could be demonstrated in clinically relevant intraportal islet transplantation models without increasing the risk of portal thrombosis. The thrombogenic potential of intraportally infused BM-spheroids was compared with that of mesenchymal stem cells (MSCs) and MSC-derived spheroids (MSC-spheroids). The angiogenic efficacy and persistence in portal sinusoids of BM-spheroids were examined in rodent syngeneic and primate allogeneic intraportal islet transplantation models. In contrast to MSCs and MSC-spheroids, intraportal infusion of BM-spheroids did not evoke portal thrombosis. BM-spheroids had robust angiogenetic capacity in both the rodent and primate intraportal islet transplantation models and improved posttransplant glycemic outcomes. MRI and intravital microscopy findings revealed the persistence of intraportally infused BM-spheroids in portal sinusoids. Intraportal cotransplantation of allogeneic islets with autologous BM-spheroids in nonhuman primates further confirmed the clinical feasibility of this approach. In conclusion, cotransplantation of BM-spheroids enhances intraportal islet transplantation outcome without portal thrombosis in mice and nonhuman primates. Generating BM-spheroids by 3D culture prevented the rapid migration and disappearance of intraportally infused therapeutic cells.

Multiple transmissions of chromosomally integrated human herpesvirus-6 in one family.

Chromosomally integrated human herpesvirus-6 (ciHHV-6) can be transmitted from parent to child or via allogeneic hematopoietic cell transplantation (HCT). We report a case of ciHHV-6 transmitted via syngeneic HCT, and vertically across 3 generations. ciHHV-6 was transmitted from a parent to the patient and her identical twin, and from the patient to her son. The patient underwent syngeneic HCT as rescue from chemotherapy-induced aplasia during which ciHHV-6 was re-transmitted to her, this time from her identical twin. This is the first report, to our knowledge, of a patient acquiring ciHHV-6 once via germline from a parent and again via syngeneic HCT from an identical twin.

Effect of liver histopathology on islet cell engraftment in the model mimicking autologous islet cell transplantation.

BACKGROUND: The inflammatory milieu in the liver as determined by histopathology is different in individual patients undergoing autologous islet cell transplantation. We hypothesized that inflammation related to fatty-liver adversely impacts islet survival. To test this hypothesis, we used a mouse model of fatty-liver to determine the outcome of syngeneic islet transplantation after chemical pancreatectomy. METHODS: Mice (C57BL/6) were fed a high-fat-diet from 6 weeks of age until attaining a weight of ≥28 grams (6-8 weeks) to produce a fatty liver (histologically > 30% fat);steatosis was confirmed with lipidomic profile of liver tissue. Islets were infused via the intra-portal route in fatty-liver and control mice after streptozotocin induction of diabetes. Outcomes were assessed by the rate of euglycemia, liver histopathology, evaluation of liver inflammation by measuring tissue cytokines IL-1ß and TNF-α by RT-PCR and CD31 expression by immunohistochemistry. RESULTS: The difference in the euglycemic fraction between the normal liver group (90%, 9/10) and the fatty-liver group (37.5%, 3/8) was statistically significant at the 18th day post- transplant and was maintained to the end of the study (day 28) (p = 0.019, X2 = 5.51). Levels of TNF-α and IL-1ß were elevated in fatty-liver mice (p = 0.042, p = 0.037). Compared to controls cytokine levels were elevated after islet cell transplantation and in transplanted fatty-liver mice as compared to either fatty- or islet transplant group alone (p = NS). A difference in the histochemical pattern of CD31 could not be determined. CONCLUSION: Fatty-liver creates an inflammatory state which adversely affects the outcome of autologous islet cell transplantation.

Fibrosis in small syngeneic rat liver grafts because of damaged bone marrow stem cells from chronic alcohol consumption.

A patient with liver failure due to chronic and acute alcohol abuse under consideration for an urgent liver transplant shortly after stopping alcohol may have residual abnormalities that threaten transplant success, particularly for a small graft. To address this, we studied a model in which reduced-size (50%) Lewis rat livers are transplanted into green fluorescence protein transgenic Lewis recipients after they are fed alcohol or a control diet for 5 weeks. Here we show that normal small Lewis grafts transplanted to alcohol-fed Lewis hosts developed fibrosis, whereas no fibrosis was observed in control-fed recipients. Host-derived CD133 + 8-hydroxy-2'-deoxyguanosine (8-OHdG) cells were significantly increased in livers recovered from both alcohol-fed and control recipients, but only alcohol-fed recipients demonstrated co-staining (a marker of oxidative DNA damage). α smooth muscle actin (α-SMA) staining, a marker for myofibroblasts, also co-localized with CD133 + cells only in the livers of alcohol-fed recipients. Immunostaining and polymerase chain reaction analysis confirmed that chronic alcohol consumption decreased the proportion of bone marrow stem cells (BMSCs) expressing CD133, c-Kit, and chemokine (C-X-C motif) receptor 4 markers and caused oxidative mitochondria DNA (mtDNA) damage. Culture of CD133 + cells from normal rats with medium containing 3% ethanol for 48 hours resulted in elevated mitochondrial 8-OHdG and mtDNA deletion, and ethanol exposure diminished CD133 expression but dramatically increased α-SMA expression. In conclusion, oxidative mtDNA damage and deletions occur in BMSCs of chronic alcohol-fed recipients, and these damaged cells mobilize to the small liver grafts and become myofibroblasts where they play a key role in the subsequent development of fibrosis. Liver Transplantation 23 1564-1576 2017 AASLD.

MHC Class I Expression by Donor Hematopoietic Stem Cells Is Required to Prevent NK Cell Attack in Allogeneic, but Not Syngeneic Recipient Mice.

NK cells resist engraftment of syngeneic and allogeneic bone marrow (BM) cells lacking major histocompatibility (MHC) class I molecules, suggesting a critical role for donor MHC class I molecules in preventing NK cell attack against donor hematopoietic stem and progenitor cells (HSPCs), and their derivatives. However, using high-resolution in vivo imaging, we demonstrated here that syngeneic MHC class I knockout (KO) donor HSPCs persist with the same survival frequencies as wild-type donor HSPCs. In contrast, syngeneic MHC class I KO differentiated hematopoietic cells and allogeneic MHC class I KO HSPCs were rejected in a manner that was significantly inhibited by NK cell depletion. In vivo time-lapse imaging demonstrated that mice receiving allogeneic MHC class I KO HSPCs showed a significant increase in NK cell motility and proliferation as well as frequencies of NK cell contact with and killing of HSPCs as compared to mice receiving wild-type HSPCs. The data indicate that donor MHC class I molecules are required to prevent NK cell-mediated rejection of syngeneic differentiated cells and allogeneic HSPCs, but not of syngeneic HSPCs.

Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease.

The murine model of cyclosporine A (CsA)-induced syngeneic graft-versus-host disease (SGVHD) is a bone marrow (BM) transplantation model that develops chronic colon inflammation identical to other murine models of CD4(+) T cell-mediated colitis. Interestingly, SGVHD animals develop chronic liver lesions that are similar to the early peribiliary inflammatory stages of clinical chronic liver disease, which is frequently associated with inflammatory bowel disease (IBD). Therefore, studies were initiated to investigate the chronic liver inflammation that develops in the SGVHD model. To induce SGVHD, mice were lethally irradiated, reconstituted with syngeneic BM, and treated with CsA. All of the SGVHD animals that developed colitis also develop chronic liver inflammation. Liver samples from control and SGVHD animals were monitored for tissue pathology, RNA for inflammatory mediators, and phenotypic analysis and in vitro reactivity of the inflammatory infiltrate. Diseased animals developed lesions of intrahepatic and extrahepatic bile ducts. Elevated levels of mRNA for molecules associated with chronic liver inflammation, including mucosal cellular adhesion molecule -1, the chemokines CCL25, CCL28, CCR9, and T(H)1- and T(H)17-associated cytokines were observed in livers of SGVHD mice. CD4(+) T cells were localized to the peribiliary region of the livers of diseased animals, and an enhanced proliferative response of liver-associated mononuclear cells against colonic bacterial antigens was observed. The murine model of SGVHD colitis may be a valuable tool to study the entero-hepatic linkage between chronic colon inflammation and inflammatory liver disease.

Inhibition of complement component C3 reduces vein graft atherosclerosis in apolipoprotein E3-Leiden transgenic mice.

BACKGROUND: Venous bypass grafts may fail because of development of intimal hyperplasia and accelerated atherosclerosis. Inflammation plays a major role in these processes. Complement is an important part of the immune system and participates in the regulation of inflammation. The exact role of complement in the process of accelerated atherosclerosis of vein grafts has not yet been explored, however. METHODS AND RESULTS: To assess the role of complement in the development of vein graft atherosclerosis, a mouse model, in which a venous interposition was placed in the common carotid artery, was used. In this model, vein graft thickening appeared within 4 weeks. The expression of complement components was studied with the use of immunohistochemistry on sections of the thickened vein graft. C1q, C3, C9, and the regulatory proteins CD59 and complement receptor-related gene y could be detected in the lesions 4 weeks after surgery. Quantitative mRNA analysis for C1q, C3, CD59, and complement receptor-related gene y revealed expression of these molecules in the thickened vein graft, whereas C9 did not show local mRNA expression. Furthermore, interference with C3 activation with complement receptor-related gene y-Ig was associated with reduced vein graft thickening, reduced C3 and C9 deposition, and reduced inflammation as assessed by analysis of influx of inflammatory cells, such as leukocytes, T cells, and monocytes. In addition, changes in apoptosis and proliferation were observed. When C3 was inhibited by cobra venom factor, a similar reduction in vein graft thickening was observed. CONCLUSIONS: The complement cascade is involved in vein graft thickening and may be a target for therapy in vein graft failure disease.

Transplantation of preconditioned intestinal grafts is associated with lower inflammatory activation and remote organ injury in rats.

Reperfused grafts--particularly the intestine--release free radicals and cytokines into the systemic circulation. The type of discharge, which is greatly dependent on the local injury, may also induce inflammatory activation in distant organs and leading to multiple system and organ failure. It has been suggested that intestinal grafts from tacrolimus (TRL)-pretreated donors show improved morphology and microcirculation. We studied whether transplantation of intestines from TRL-pretreated donors influenced inflammatory response and remote organ injury posttransplantation. Donor Sprague Dawley rats received TRL or saline (controls) intravenously at 6 hours prior to graft harvest. The intestinal grafts were preserved in saline for 3 hours before transplantation. At 6 and 12 hours postreperfusion hepatic and renal cortical microcirculation were assessed using laser-Doppler flowmetry (n = 8-12 per group). Blood pressure was measured; liver, kidney, and serum samples were obtained. We analyzed hepatic and renal ICAM-1 expression and caspase-3-like activity as well as plasma content of tumor necrosis factor-alpha and interleukin-6. Pretreated graft recipients had higher mean arterial pressure (82 +/- 10 vs 51 +/- 17 mm Hg, P < .05) and renal perfusion at 6 hours whereas liver perfusion was similar at both 6 and 12 hours. Liver and renal functions were also superior among recipients of pretreated grafts. Both caspase-3-like activity and ICAM-1 expression in liver and kidney were lower in pretreated graft recipients. Plasma IL-6 levels were lower in animals receiving pretreated grafts. Transplantation of intestines from TRL-pretreated donors was followed by a lower systemic inflammatory response, improved organ function and decreased remote injury early posttransplantation compared with animals receiving grafts from untreated donors.

Role for tumor necrosis factor alpha in murine cytomegalovirus transcriptional reactivation in latently infected lungs.

Interstitial pneumonia is a major clinical manifestation of primary or recurrent cytomegalovirus (CMV) infection in immunocompromised recipients of a bone marrow transplant. In a murine model, lungs were identified as a prominent site of CMV latency and recurrence. Pulmonary latency of murine CMV is characterized by high viral genome burden and a low incidence of variegated immediate-early (IE) gene expression, reflecting a sporadic activity of the major IE promoters (MIEPs) and enhancer. The enhancer-flanking promoters MIEP1/3 and MIEP2 are switched on and off during latency in a ratio of approximately 2:1. MIEP1/3 latency-associated activity generates the IE1 transcript of the ie1/3 transcription unit but not the alternative splicing product IE3 that encodes the essential transactivator of early gene expression. Splicing thus appeared to be an important checkpoint for maintenance of latency. In accordance with previous work of others, we show here that signaling by the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) activates IE1/3 transcription in vivo. As an addition to current knowledge, Poisson distribution analysis revealed an increased incidence of IE1/3 transcriptional events as well as a higher amount of transcripts per event. Notably, TNF-alpha promoted the splicing to IE3 transcripts, but transcription did not proceed to the M55/gB early gene. Moreover, the activated transcriptional state induced by TNF-alpha did not predispose latently infected mice to a higher incidence of virus recurrence after hematoablative treatment. In conclusion, TNF-alpha is an important inductor of IE gene transcriptional reactivation, whereas early genes downstream in the viral replicative cycle appear to be the rate-limiting checkpoint(s) for virus recurrence.

Syngeneic graft-versus-host disease: a report of two cases and literature review.

Rappeport et al first reported the clinical syndrome of graft-versus-host disease (GVHD) in syngeneic bone marrow transplant patients. Recently, there have been more reports of a GVHD-like syndrome in syngeneic bone marrow transplant patients (SGVHD) that may result in significant clinical morbidity. A total of 17 cases of SGVHD in syngeneic bone marrow transplant patients have been reported to date in the medical literature. The current report reviews these cases and presents two additional cases of severe SGVHD that have occurred at our institution.

Unexpected T-cell diversity in syngeneic graft-versus-host disease revealed by interaction with peptide-loaded soluble MHC class II molecules.

BACKGROUND: Administration of cyclosporine after syngeneic bone marrow transplantation elicits a systemic autoaggression syndrome termed syngeneic graft-versus-host disease (SGVHD). The effector T cells recognize a peptide from the invariant chain termed CLIP (MHC class II invariant chain peptide) presented on MHC class II molecules. Moreover, the N-terminal flanking region of CLIP interacts with the T-cell receptor (TcR) beta chain. METHODS: The current study uses a novel approach to isolate and examine the responding T cells ex vivo. A soluble MHC class II molecule using immunoglobulin (Ig)G (MHC class II-Ig) as a scaffold was constructed. The MHC class II-Ig molecule loaded with different peptide variants of CLIP (lacking the N-terminal or C-terminal flanking regions of CLIP) was used to isolate antigen-specific T cells from animals with SGVHD by panning or by flow cytometric sorting. RESULTS: Two subsets of antigen specific T cells restricted by the N- and C-terminal flanking regions of CLIP can be isolated during acute SGVHD that express the Vbeta8.5 TcR determinant but secrete different cytokines (interferon [IFN]-gamma, interleukin [IL]-10) as detected by real-time quantitative polymerase chain reaction (PCR). Spectratyping of the complementarity-determining region 3 regions reveals that the N-terminal CLIP reactive population has greater diversity in both the CDR3 and J regions than the C-terminal CLIP reactive subset. Interestingly, the N-terminal CLIP reactive cells can be preferentially detected in the target tissues during acute SGVHD. However, only IFN-gamma messenger (m)RNA was detected in the tissues. CONCLUSION: The ability to isolate and examine antigen specific T cells ex vivo has revealed unexpected differences in TcR diversity and cytokine production in SGVHD.

Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia.

Graft-versus-host disease in its acute (aGvHD) or chronic form (cGvHD) remains the most important posttransplantation factor influencing outcome after allogeneic hematopoietic stem cell transplantation (HSCT). It increases transplantation-related mortality (TRM) but reduces risk of relapse. The net effect of these 2 discordant effects determines survival. In view of current interests to exploit graft-versus-leukemia (GVL) effects, we analyzed 4174 HLA-identical sibling transplantations for chronic myeloid leukemia in first chronic phase, depending on the presence or absence and severity of GvHD with a landmark analysis. During the first 100 days, only aGvHD grades III and IV had an impact on TRM. During the time period day 100 to 3 years increasing severity of aGvHD is associated with increased TRM and decreased relapse incidence (RI) with hazard ratios (HRs) for TRM as follows: grade 0, HR = 1.0; grade I, HR = 1.52 (1.19-1.96); grade II, HR = 2.48 (1.95-3.14); grade III, HR = 5.76 (4.44-7.48); grade IV, HR = 14.7 (10.9-19.9) and likewise for RI: grade I versus 0, HR = 0.94 (0.76-1.16); grade II, HR = 0.60 (0.46-0.77); grade III, HR = 0.48 (0.29-0.81); grade IV, HR = 0.14 (0.02-0.99). Beyond 3 years, TRM and RI are determined by cGvHD. Limited cGvHD reduces RI to the same extent as extensive cGvHD but has no impact on TRM and, hence, results in best survival with an HR = 0.48 (0.32-0.71). aGvHD grade I has the highest likelihood of subsequent limited cGvHD, which results in cumulative incidence estimates of survival at 10 years being best for patients with initial aGvHD grade I: survival at 10 years grade 0 = 59%, I = 63%, II = 56%, III = 26%, IV = not applicable. These data clarify the role of GvHD in posttransplantation outcome. Considerations for long-term outcome are essential when short-term data of interventions on GvHD are analyzed.

Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation.

We made the hypothesis that donor and recipient gene polymorphisms that drive the host response to microorganisms could be associated with infections after bone marrow transplantation (BMT). HLA-identical BMT was performed for patients with acute (n = 39) or chronic leukemia (n = 68). Genotyping was performed in 107 D/R DNA pairs for gene polymorphisms of cytokines (tumor necrosis factor-alpha [TNF-alpha] and TNF-beta, interleukin-1 receptor antagonist [IL-1Ra], IL-6, and IL-10), adhesion molecules (CD31 and CD54), Fcgammareceptors (FcgammaRIIa, IIIa, IIIb), mannose-binding lectin (MBL), and myeloperoxidase (MPO). First infection (overall) and first episodes of bacterial, viral, or invasive fungal infection were studied retrospectively for 180 days after BMT. Univariate and multivariate analyses, using death as a competing event, were performed to study risk factors. In multivariate analysis, first overall infections were increased in patients with the FcgammaRIIa R-131 genotype (hazard ratio [HR] = 1.92; P =.04), and severe bacterial infections were increased when the MPO donor genotype was AG or AA (HR = 2.16; P =.03). Viral and invasive fungal infections were not influenced by any genetic factor studied. Interestingly, we also found that (1) time to neutrophil recovery was shorter when donors were FcgammaRIIIb HNA-1a/HNA-1b (HR = 1.77; P =.002); (2) donor IL-1Ra (absence of IL-1RN*2) increased the risk for acute graft-versus-host disease (GVHD) (II-IV) (HR = 2.17; P =.017); and (3) recipient IL-10 (GG) and IL-1Ra genotypes increased the risk for chronic GVHD (P =.03 and P =.03, respectively). Finally, 180-day transplantation-related mortality rates were increased when donors were FcgammaRIIIb HNA-1a/HNA-1a or HNA-1b/HNA-1b (HR = 2.57; P =.05) and donor MPO genotype was AA (HR = 5.14; P =.004). In conclusion, donor and recipient gene polymorphisms are informative genetic risk factors for selecting donor/recipient pairs and could help in the understanding of mechanisms involved in host defenses of BM transplant recipients.

Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia.

Allogeneic hematopoietic stem cell transplantation is the only curative therapy for myelodysplasia (MDS). To identify factors influencing transplantation outcome, we studied 452 recipients of HLA-identical sibling transplants for MDS from 1989 to 1997, reported to the International Bone Marrow Transplant Registry. Patients with treatment-related MDS or unclassified MDS were excluded. Median age was 38 years (range, 2-64 years). Sixty percent had refractory anemia with excess blasts (n = 136) or with excess blasts in transformation (n = 136). Conditioning regimens included total body irradiation in 199 (44%) cases. Marrow was T-cell depleted for 58 (13%) transplants. Cumulative incidences of neutrophil engraftment, grades II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were 91% (95% confidence interval [CI], 88%-93%), 36% (95% CI, 31%-40%), and 39% (95% CI, 33%-44%), respectively. Three-year transplantation-related mortality (TRM), relapse, disease-free survival, and overall survival rates were 37% (95% CI, 32%-42%), 23% (95% CI, 19%-27%), 40% (95% CI, 36%-45%), and 42% (95% CI, 37%-47%), respectively. Multivariate analyses showed that young age and platelet counts higher than 100 x 10(9)/L at transplantation were associated with lower TRM and higher disease-free and overall survival rates. Relapse incidence was higher in patients with high percentages of blasts in the marrow at transplantation or presentation, with high International Prognostic Scoring System scores at diagnosis, and with T-cell-depleted transplants. These findings indicate that transplantation from an HLA-identical sibling offers the possibility of long-term, disease-free survival to patients with MDS. Best candidates are younger patients with a low percentage of blasts and preserved platelet counts.

Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes.

We report the results of a prospective study of a reduced-intensity conditioning (RIC) regimen followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling in 37 patients with acute myeloid leukemia (AML; n = 17) or myelodysplastic syndrome (MDS; n = 20). The median age was 57 years, and 22 (59%) were beyond the early phase of their disease. The incidence of grade II to IV acute graft-versus-host disease (GVHD) was 19% (5% grade III-IV), and the 1-year incidence of chronic extensive GVHD was 46%. With a median follow-up of 297 days (355 days in 24 survivors), the 1-year probability of transplant-related mortality was 5%, and the 1-year progression-free survival was 66%. The 1-year incidence of disease progression in patients with and without GVHD was 13% (95% CI, 4%-34%) and 58% (95% CI, 36%-96%), respectively (P =.008). These results suggest that a graft-versus-leukemia effect plays a crucial role in reducing the risk of relapse after a RIC allograft in AML and MDS.

Risk factors for acute graft-versus-host disease in patients undergoing transplantation with CD34+ selected blood cells from HLA-identical siblings.

A study on 315 patients undergoing transplantation with CD34+ selected blood cells from HLA-identical siblings was performed to determine risk factors for acute GVHD (aGVHD). Recipients of a dose of CD34+ cells (x 10(6)/kg) of 2 or less, more than 2 to 4, and more than 4 had a cumulative incidence of aGVHD grades I-IV of 21%, 35%, and 43%, respectively (log-rank P =.01); similarly, recipients of a dose of CD3+ cells (x 10(6)/kg) of 0.05 or less, more than 0.05 to 0.1, and more than 0.1 had a cumulative incidence of aGVHD grades I-IV of 18%, 35%, and 44%, respectively (log-rank P =.007). Using a Cox regression model, 4 independent factors for aGVHD I-IV were identified: increased CD34+ cell dose (P =.02), increased CD3+ cell dose (P =.02), female patients (P =.01), and higher patient age (> 42 years) (P =.007). This study shows, for the first time in T-cell-depleted transplantations, a positive correlation between the number of CD34+ cells and aGVHD and, also, that the number of CD3+ cells necessary to initiate aGVHD is lower than previously reported.