Comparison of long-term outcomes after allogeneic hematopoietic stem cell transplantation from matched sibling and unrelated donors

Long-term survivors of hematopoietic stem cell transplants remain at risk of potentially fatal complications that detract from life quality. Long-term morbidity and mortality were compared between matched recipient cohorts surviving 2 or more years and defined by donor type, HLA matched sibling donor (MSD) or volunteer unrelated donor (URD). Patients were previously entered into the prospective multicenter International Unrelated Search and Transplant Study. Thirty-nine centers provided data on 108 URD and 355 MSD recipients surviving more than 2 years. Long-term survival, performance status, chronic GvHD (c-GvHD), secondary malignancy, endocrine dysfunction, cataracts, bone necrosis and dental pathology were compared between cohorts. Twelve year survival was 77+/-5% for the MSD and 67+/-11% for the URD cohort (P=0.1). Late death occurred in 105 of 463 recipients alive at 2 years, 73 after 355 (21%) MSD and 32 after 108 (30%) URD transplants, P=0.10. Of 105 deaths, the cause was relapse in 60 and unrelated to relapse in 45 cases. Cumulative incidence of extensive c-GvHD (P=0.002), cataracts (P=0.02) and bone necrosis (P=0.02) was higher after URD transplants. No long-term difference in endocrine dysfunction, secondary malignancy and major dental pathology was detected. This landmark study will assist physicians counseling patients pre-transplant and with their long-term care post transplant.     

Varicella zoster virus meningoencephalitis after allogeneic hematopoietic stem cell transplantation

Although the reactivation of varicella zoster virus (VZV) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), VZV meningoencephalitis is a rare life‐threatening infectious disease after HSCT. We describe here a patient who developed VZV meningoencephalitis 2 years after human leukocyte antigen‐matched unrelated HSCT for acute myeloblastic leukemia. She developed chronic graft‐versus‐host disease, and cyclosporine (CSA) was continued until 17 months after HSCT. Low‐dose acyclovir (ACV) at 200 mg/day was administered to prevent the reactivation of VZV from day ?7 to the termination of CSA. At 22 months, she suddenly developed fever, loss of consciousness, and seizure, with generalized skin rash. A high level of VZV DNA was detected in her cerebrospinal fluid (CSF). She was diagnosed to have VZV meningoencephalitis. Intravenous ACV at 30 mg/kg/day was given for 2 months. Although loss of consciousness was quickly resolved, some neurologic symptoms persisted. She did not have any known risk factors for VZV reactivation. Therefore, we should keep in mind that any HSCT recipient may develop VZV meningoencephalitis, and examination of CSF for VZV infection with an empiric administration of ACV may be recommended for HSCT recipients with central nervous system symptoms, even in the absence of skin manifestations.     

Plasma antioxidants in subjects before hematopoietic stem cell transplantation

Chemo-irradiation induced oxidative damage to vascular endothelium may contribute to pulmonary complications of hematopoietic stem cell transplantation (HSCT). We measured antioxidants, markers of oxidative stress and plasma antioxidant capacity in plasma or serum from 24 subjects at day 7 before HSCT and 20 control subjects. The plasma concentration of extracellular glutathione peroxidase (GPX-3) was significantly reduced in the HSCT subjects compared with controls (HSCT: 98+/-42 microg/ml, control: 169+/-56 microg/ml, P<0.0001). The concentration of gamma-tocopherol was significantly higher in the HSCT subjects compared with controls (HSCT: 207+/-103 microg/dl; Control: 98+/-52 microg/dl; P=0.0002). The plasma concentrations of protein carbonyl, nitrotyrosine, malondialdehyde, alpha-tocopherol, vitamin A, homocysteine, cysteine and cysteinylglycine did not differ between HSCT and control subjects. Plasma from HSCT subjects was as effective as control plasma in quenching menadione-induced intracellular reactive oxygen species production in human microvascular endothelial cells. In summary, subjects before HSCT have significantly reduced plasma concentrations of GPX-3, elevated plasma gamma-tocopherol yet retains the ability to quench an acute oxidative stress. These changes may play a role in chronic oxidative stress in the HSCT population.     

Availability of unrelated donors for hematopoietic stem cell transplantation for hemoglobinopathies

Hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with hemoglobinopathies. However, fewer than 30% of individuals will have an HLA-identical sibling. Improvement in outcomes after HSCT using unrelated donors (URD), and the development of novel nontoxic preparative regimens may make URD HSCT an option for hemoglobinopathy patients who do not have an HLA-identical sibling donor. The National Marrow Donor Program (NMDP) maintains a Registry of 4 million volunteer donors, and facilitates URD HSCT for patients with life-threatening blood diseases. In light of the increased representation of minorities in the NMDP registry, donor searches were run in April 2001 for a cohort of 272 thalassemia patients and 77 sickle cell disease (SCD) patients for whom searches had been submitted between 1989 and 2001 in order to determine the current likelihood of finding a potential donor of hematopoietic stem cells for hemoglobinopathy patients. About 59.7% SCD patients 80.2% thalassemia patients will find at least one potential 6/6 HLA matched donor or umbilical cord blood (UCB) unit. All patients will find at least one donor or UCB that is a potential 5/6 HLA match. In conclusion the majority of hemoglobinopathy patients will find at least one potential HLA matched unrelated bone marrow donor or UCB.     

Outcomes of 138 myelodysplastic syndrome patients with HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation

正Objective To evaluate the outcomes of myelodysplastic syndromes (MDS) patients who received HLAmatched sibling donor allogeneic peripheral blood stemcell transplantation (MSD-PBSCT).Methods The clinical data of 138 MDS patients received MSD-PBSCT from Sep.2005 to Dec.2017 were retrospectively analyzed,and the overall survival (OS) rate,disease-free survival(DFS) rate,relapse rate (RR),non-relapse mortality     

Cardiac systolic function before and after hematopoietic stem cell transplantation

In order to examine the effect of hematopoietic stem cell transplantation (HSCT) on cardiac systolic function, we measured left ventricular ejection fraction (LVEF) by radioventriculography (RVG) before and after the transplantation procedure. One hundred and forty-eight patients were examined, 96 undergoing allogeneic grafting and 52 autologous. Fifty patients had CML, 48 AML, 21 ALL, 18 multiple myeloma and 11 breast cancer. The second RVG examination was performed 22 to 227 days (median 60 days) after HSCT. The mean LVEF value in the whole patient group was 60.2% (range 39-81%) before and 61.1% (35-86%) after transplantation. Patients with CML had significantly higher LVEF before transplantation than patients with acute leukemia (P = 0.007) and multiple myeloma (P = 0.005). No significant changes in mean LVEF between the pre- and post-transplant measurements were seen in any of the diagnostic subgroups or in allogeneic or autologous recipients. None of the 148 patients in the study has shown any signs of clinical heart failure at 2, 5 to 10 years follow-up. Patients who had received anthracyclines in the previous treatment had significantly lower LVEF before transplantation but showed no increased risk of decline in cardiac function. In conclusion, the HSCT procedure does not seem to affect myocardial function 1-7 months after transplantation.     

Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors

Killer immunoglobulin-like receptor (KIR) ligand incompatibility in the graft-versus-host direction was demonstrated to be associated with improved outcome in patients given haploidentical, T-cell-depleted hematopoietic stem cell transplants (HSCTs). The goal of this study was to evaluate whether that observation could be generalized for patients receiving unmanipulated HSCTs from unrelated donors (URD). One hundred thirty patients with hematologic malignancies entered the study. Graft-versus-host disease (GVHD) prophylaxis was uniform and consisted of cyclosporin, short-term methotrexate, and pretransplantation antithymocyte globulin (ATG). Patients were divided into those with (n = 20) and those without (n = 110) KIR ligand incompatibility with respect to their donors. At 4.5 years patients with KIR ligand incompatibility had higher probability of overall survival (87% versus 48%, P =.006) and disease-free survival (87% versus 39%, P =.0007) compared with those without KIR ligand incompatibility. Transplant-related mortality for the 2 groups equaled 6% and 40% (P =.01), respectively. Relapse rates for patients receiving transplants from a donor with or without KIR ligand incompatibility were 6% and 21%, respectively (P =.07). All patients with myeloid malignancies receiving transplants from KIR ligand-disparate donors (n = 13) are alive and disease free. These data indicate that natural killer (NK) cell alloreactivity is associated with better outcome after URD-HSC transplantation when ATG is used as part of GVHD prophylaxis.     

Prognostic value of pretransplantation host thymic function in HLA-identical sibling hematopoietic stem cell transplantation

Thymic function is critical for immune reconstitution after hematopoietic stem cell transplantation (HSCT). We evaluated recipient thymic function before HSCT by quantifying T-cell receptor excision circles (TRECs) in pretransplantation peripheral blood lymphocytes from 102 patients who received HSCs from an HLA-identical sibling for malignant (n = 87) or nonmalignant diseases (n = 15). Median TREC value before transplantation was 257 TRECs per 150,000 CD3+ cells (range, 0-42,746). We assessed 172 TRECs per 150,000 CD3+ cells as the most discriminating TREC value for survival in a first cohort of patients (n = 62). This cut-off was validated in a second independent prospective group of 40 patients. In the 102 patients, a TREC value greater than or equal to 172 was associated with a better survival (P < .000 01), a decreased incidence of grade II-IV acute graft-versus-host disease (GVHD; P = .017), chronic GVHD (P = .023), and bacterial (P = .003) and cytomegalovirus (CMV) infection (P = .024). In a multivariate analysis, low pretransplantation TREC values were associated with a higher incidence of CMV infection (hazard ratio [HR] = 2.0, P = .06) and severe bacterial infections (HR = 2.8, P = .036). Finally, high TREC values (HR = 6.6, P = .002) and ABO compatibility (HR = 2.7, P = .02) were associated with a better survival. Therefore, recipient host thymic function assessment could be helpful in predicting HSCT outcome and identifying patients who require a close immunologic monitoring.     

Non-TBI stem cell transplantation protocol for Fanconi anaemia using HLA-compatible sibling and unrelated donors

Allogeneic haemopoietic stem cell transplantation (SCT) is the only curative option for severe bone marrow (BM) failure in patients with Fanconi anaemia (FA). We have developed a non total body irradiation (TBI) conditioning protocol consisting of fludarabine (120-150 mg/m(2)), low dose of cyclophosphamide (40 mg/kg) and antilymphocyte globulin (45 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin alone for sibling allografts but also included Campath-1 H (days 1-5 post SCT) for the unrelated allografts. We have performed two sibling and two unrelated BM transplants with a follow-up of 11-51 months. All patients experienced minimal toxicity and were discharged from hospital 28-32 days post SCT. Neutrophil and platelet engraftment occurred from days 11 to 19 and 15 to 34, respectively. All patients achieved stable full donor haemopoiesis with normalisation of the peripheral blood count despite one of them having myelodysplasia (MDS) with 8% blasts prior to the SCT. The only site of acute GVHD was in the skin (grade I-II) and only one patient progressed to limited chronic GVHD. This protocol is associated with reduced toxicity and prompt engraftment in FA patients with AA and/or MDS undergoing SCT using sibling or unrelated donors.     

Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes

In this multicenter retrospective study, the outcomes of 836 patients with myelodysplastic syndrome (MDS) who underwent transplantation with a human leukocyte antigen (HLA)-identical sibling donor were analyzed according to 2 types of conditioning: reduced-intensity conditioning (RIC) in 215 patients, and standard myeloablative (or high-dose) conditioning (SMC) in 621 patients. In multivariate analysis, the 3-year relapse rate was significantly increased after RIC (hazard ratio [HR], 1.64; 95% confidence interval [95% CI], 1.2-2.2; P = .001), but the 3-year nonrelapse mortality (NRM) rate was decreased in the RIC group (HR, 0.61; 95% CI, 0.41-0.91; P = .015). The 3-year probabilities of progression-free and overall survivals were similar in both groups (39% after SMC vs 33% in RIC; multivariate P = .9; and 45% vs 41%, respectively; P = .8). In conclusion, the lower 3-year NRM after RIC is encouraging, since these patients were older (age > 50 years in 73% RIC vs 28% in SMC, P < .001) and had more adverse pretransplantation variables. However, based on the higher risk of relapse, patients with no contraindications for SMC should not receive RIC outside of prospective randomized trials, which are needed to establish the position of RIC-based transplantation in the treatment of patients with MDS.     

Allogeneic hematopoietic stem cell transplantation

More than 30 years have passed since the first clinical application of allogeneic bone marrow transplantation to treat hematological diseases. In recent years, the availability of peripheral blood and cord blood as additional sources of stem cells other than bone marrow has expanded the applicability of hematopoietic stem cell transplantation. In addition to differences in stem cell content, immune cells in the grafts from the three sources are different in quality and quantity. As a consequence, transplants from different sources have different kinetics of hematological recovery. Stem cell sources also influence risks for developing graft-versus-host disease. In this paper, we review recently reported results of thus diversified allogeneic hematopoietic, stem cell transplantation.     

Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study

Objective

Acyl-CoA oxidase (ACOX1) deficiency is a rare disorder of peroxisomal very-long chain fatty acid oxidation. No reports detailing attempted treatment, longitudinal imaging, or neuropathology exist. We describe the natural history of clinical symptoms and brain imaging in two siblings with ACOX1 deficiency, including the younger sibling’s response to allogeneic unrelated donor hematopoietic stem cell transplantation (HSCT).

Methods

We conducted retrospective chart review to obtain clinical history, neuro-imaging, and neuropathology data. ACOX1 genotyping were performed to confirm the disease. In vitro fibroblast and neural stem cell fatty acid oxidation assays were also performed.

Results

Both patients experienced a fatal neurodegenerative course, with late-stage cerebellar and cerebral gray matter atrophy. Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter. The successfully engrafted younger sibling had less brain inflammation, cortical atrophy, and neuronal loss on neuro-imaging and neuropathology compared to the untreated older sister. Fibroblasts and stem cells demonstrated deficient very long chain fatty acid oxidation.

Interpretation

Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain. Demyelination continued because of ongoing neuronal loss, which may be due to inability of transplant to prevent progression of gray matter disease, adverse effects of chronic corticosteroid use to control graft-versus-host disease, or intervention occurring beyond a critical point for therapeutic efficacy.     

CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors

CTLA-4 is an inhibitory molecule that down-regulates T-cell activation. Although polymorphisms at CTLA-4 have been correlated with autoimmune diseases their association with clinical outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has yet to be explored. A total of 5 CTLA-4 single-nucleotide polymorphisms were genotyped on 536 HLA-identical sibling donors of allo-HSC transplants. Genotypes were tested for an association with patients' posttransplantation outcomes. The effect of the polymorphisms on cytotoxic T-lymphocyte antigen 4 (CTLA-4) mRNA and protein production were determined in 60 healthy control participants. We observed a reduction in the mRNA expression of the soluble CTLA-4 isoform in the presence of a G allele at CT60 and +49. Patients receiving stem cells from a donor with at least 1 G allele in position CT60 had worse overall survival (56.2% vs 69.8% at 5 years; P = .001; hazard ratio [HR], 3.80; 95% confidence interval [CI], 1.75-8.22), due to a higher risk of relapse (P = .049; HR, 1.71; 95% CI, 1.00-2.93). Acute graft-versus-host disease (aGVHD) was more frequent in patients receiving CT60 AA stem cells (P = .033; HR, 1.54; 95% CI, 1.03-2.29). This is the first study to report an association between polymorphisms at CTLA-4 and clinical outcome after allo-HSCT. The CT60 genotype influences relapse and aGVHD, probably due to its action on CTLA-4 alternative splicing.