Showing papers by "Eliane Gluckman published in 2001"
TL;DR: The use of UCBT, as a source of hematopoietic stem cells, is a reasonable option for children with AL lacking an acceptably matched unrelated marrow donor.
745 citations
TL;DR: In addition to previously described clinical risk factors, genetic risk factors are independently associated with the risk of developing graft-versus-host disease and may, thus, be considered for the selection of the donor.
Abstract: BACKGROUND Graft-versus-host disease is the main complication of hematopoietic stem cell transplantation. Recently, pro- and anti-inflammatory cytokines and mismatches of minor histocompatibility antigens between HLA-identical sibling donor/recipient pairs have been implicated in the development of acute graft-versus-host disease. It is not known, however, whether these factors are independent of other clinically recognized risk factors such as age and disease stage. METHODS In this study, we searched for risk factors of acute graft-versus-host disease using multivariate Cox regression analysis in 100 consecutive patients who underwent allogeneic stem cell transplantation from an HLA-identical sibling donor. Eight polymorphisms from five different cytokine genes were studied (tumor necrosis factor alpha, tumor necrosis factor beta, interleukin (IL) 6, IL-10, and interferon gamma). Mismatches for the minor histocompatibility antigen HA-1 were searched in HLA-A*0201 individuals. In addition to these new risk factors, patient, donor, disease, and transplant risk factors were analyzed by multivariate analysis using the Cox proportional hazards model. RESULTS Acute graft-versus-host disease was independently associated with IL-10 gene polymorphisms both from the recipient (relative risk=7.9, P<0.0001) and the donor (relative risk=3.5, P=0.02), a donor's positive serology for cytomegalovirus, and HA-1 mismatches in HLA-A*0201 individuals (relative risk=2.8, P=0.05). Chronic graft-versus-host disease was independently associated with IL-6 gene polymorphism from the recipient (relative risk=4.2, P=0.02), older age (relative risk=2.5, P=0.0009), and previous acute graft-versus-host disease (relative risk=9.7, P=0.003). CONCLUSION In addition to previously described clinical risk factors, genetic risk factors are independently associated with the risk of developing graft-versus-host disease and may, thus, be considered for the selection of the donor.
163 citations
TL;DR: It is found that, more than 1 year post SCT, cellular and humoral immunity was still altered in a significant number of patients, and human leucocyte antigen disparity between donor and recipient and chronic graft‐versus‐host disease were the leading causes affecting immune reconstitution.
Abstract: To evaluate the long-term immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), we prospectively screened standard immune parameters in a series of 105 patients, at a median time of 15 months after SCT. Analysing lymphoid phenotypes, in vitro immune functions and immunoglobulin levels, we found that, more than 1 year post SCT, cellular and humoral immunity was still altered in a significant number of patients. CD4+ T cells were < 200/microl in one third of patients, and the CD4/CD8 ratio was still reversed in 78% of patients. Almost all patients showed positive T-cell responses against mitogens, but antigen-specific proliferation assays identified 20% to 80% of non-responders. B-cell counts were reconstituted in 61% of the patients, but levels of total immunoglobulins were still low in 59%. In multivariate analyses, human leucocyte antigen (HLA) disparity between donor and recipient and chronic graft-versus-host disease were the leading causes affecting immune reconstitution. Interestingly, cytomegalovirus (CMV) infections were strongly associated with normal CD8+ T-cell counts. Studying the impact of impaired immune reconstitution on the rate of infections occurring in the 6 years following screening, we identified three parameters (low B-cell count, inverted CD4/CD8 ratio, and negative response to tetanus toxin) as significant risk factors for developing such late infections.
151 citations
TL;DR: Transplantation of umbilical-cord blood was successfully performed for the first time in 1988 to treat a boy with Fanconi's anemia; the donor, the boy's newborn sister, was a perfect HLA match for her brother.
Abstract: Transplantation of umbilical-cord blood was successfully performed for the first time in 1988 to treat a boy with Fanconi's anemia; the donor, the boy's newborn sister, was a perfect HLA match for her brother.1 Since then, the advantages of cord blood as a source of hematopoietic stem cells for transplantation have become clear. First, the proliferative capacity of hematopoietic stem cells in cord blood is superior to that of cells in marrow or blood from adults. A 100-ml unit of cord blood contains 1/10 the number of nucleated cells and progenitor cells (CD34+ cells) present in 1000 ml of marrow, . . .
135 citations
TL;DR: In children with sustained myeloid engraftment the concern that lymphocyte recovery after CBT could be delayed does not appear to be substantiated by the results.
Abstract: Immune recovery after cord blood transplantation (CBT) is of concern owing to the low number of lymphocytes transferred with the graft and their immaturity. Risk factors influencing lymphocyte subset reconstitution related to disease, patient, donor and transplant were studied in 63 children (< 16 years), given either related (n = 14) or unrelated (n = 49) CBT for malignant (n = 33) or non-malignant diseases (n = 30). Only children with sustained myeloid engraftment were analysed. Absolute numbers of T (CD3+, CD4+, CD8+), B and natural killer (NK) cells were reported 2–3, 6, 9, 12 and 12–24 months after CBT. Median patient age was 4·0 years (0–15) and median follow-up was 23 months (1·7–61·0). Twenty-six patients received human leucocyte antigen (HLA)-matched CBT and 37 received HLA-mismatched CBT. The median number of nucleated cells (NCs) collected/recipient weight was 6·1 × 107/kg. In this selected population, the estimate 2 year survival was 85%. Lymphocyte reconstitution (defined as the median time to reach the normal value of age-matched healthy children) was 3, 6 and 8 months for NK, B and CD8+ cells, while it was 11·7 months for both CD3+ and CD4+ lymphocytes. In the multivariate analysis, factors favouring T-cell recovery were: related donor (P = 0·002); higher NCs/kg (P = 0·005) and recipient cytomegalovirus (CMV)-positive serology (P = 0·04). Presence of acute graft-versus-host disease (GVHD) delayed T-cell recovery (P = 0·04). To summarize, in children with sustained myeloid engraftment the concern that lymphocyte recovery after CBT could be delayed does not appear to be substantiated by our results.
125 citations
TL;DR: The molecular and genealogical evidence is consistent with transmission of the major mutation to Western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa.
Abstract: Fanconi anemia (FA) is a rare, genetically heterogeneous autosomal recessive disorder associated with progressive aplastic anemia, congenital abnormalities, and cancer. FA has a very high incidence in the Afrikaner population of South Africa, possibly due to a founder effect. Previously we observed allelic association between polymorphic markers flanking the FA group A gene (FANCA) and disease chromosomes in Afrikaners. We genotyped 26 FA families with microsatellite and single nucleotide polymorphic markers and detected five FANCA haplotypes. Mutation scanning of the FANCA gene revealed association of these haplotypes with four different mutations. The most common was an intragenic deletion of exons 12-31, accounting for 60% of FA chromosomes in 46 unrelated Afrikaner FA patients, while two other mutations accounted for an additional 20%. Screening for these mutations in the European populations ancestral to the Afrikaners detected one patient from the Western Ruhr region of Germany who was heterozygous for the major deletion. The mutation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogical investigation of 12 Afrikaner families with FA revealed that all were descended from a French Huguenot couple who arrived at the Cape on June 5, 1688, whereas mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular and genealogical evidence is consistent with transmission of the major mutation to Western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa.
121 citations
TL;DR: This large registry study confirms the potential benefit of using umbilical cord blood hematopoietic stem cells for allogeneic transplants.
Abstract: The number of umbilical cord blood transplants (UCBT) is increasing worldwide, and the purpose of Eurocord is to evaluate the results and compare the outcome of UCBT with allogeneic bone marrow transplants (BMT). Data have been reported to Eurocord by many transplant centers. Close links have been established with cord blood banks through Netcord. BMT data have been provided by transplant centers and also by the European Blood and Marrow Transplant (EBMT) and International Bone Marrow Transplant Registries (IBMTR). Eurocord has analyzed the outcome of unrelated UCBT from 121 transplant centers and 29 countries. The results have shown that survival with unrelated mismatched UCBT was comparable to that with unrelated BMT. Engraftment with cord blood was delayed, resulting in an increased incidence of early transplant complications. The incidence of acute and chronic graft-versus-host-disease (GVHD) was reduced with cord blood grafts even in HLA mismatched transplants and in adults. In patients with leukemia, the rate of relapse was similar to that after BMT. The overall event-free survival with UCBT was not statistically different when compared to BMT. In conclusion, this large registry study confirms the potential benefit of using umbilical cord blood hematopoietic stem cells for allogeneic transplants.
97 citations
TL;DR: In 1992, the results of the first randomized trial comparing the combination of cyclophosphamide (CY) (120 mg/kg) and total body irradiation (TBI) versus CY and busulfan (BU) (BUCY) as preparation for an allogeneic bone marrow transplantation (BMT) for adult patients with acute leukemia was reported.
82 citations
TL;DR: The results showed that survival with unrelated mismatched umbilical cord blood transplants was comparable to that with unrelated bone marrow transplants, which confirms the potential benefit of using umbilicals cord blood hematopoietic stem cells for allogeneic transplants.
Abstract: The number of umbilical cord blood transplants is increasing worldwide. The purpose of Eurocord is to evaluate the results and to compare the outcome of umbilical cord blood transplants with allogeneic bone marrow transplants. Data have been reported to Eurocord by multiple transplant centers. Close links have been established with the cord blood banks through Netcord. Bone marrow transplant data have been provided by transplant centers and also through the European Group for Blood and Marrow Transplantation (EBMT) and International Bone Marrow Transplant Registries (IBMTR). Eurocord has analyzed the outcome of unrelated umbilical cord blood transplants from 121 transplant centers and 29 countries. The results showed that survival with unrelated mismatched umbilical cord blood transplants was comparable to that with unrelated bone marrow transplants. Engraftment with cord blood was delayed, resulting in an increased incidence of early transplant complications. The incidence of acute and chronic graft-vs.-host disease was reduced with cord blood grafts even in human leukocyte antigen (HLA)-mismatched transplants and in adults. In patients with leukemia, the rate of relapse was similar to the rate of relapse after bone marrow transplant. The overall event-free survival with umbilical cord blood transplantation was not statistically different when compared to bone marrow transplants. This large registry study confirms the potential benefit of using umbilical cord blood hematopoietic stem cells for allogeneic transplants.
70 citations
TL;DR: Routine tests in adult patients were able to detect significant numbers of‐non‐symptomatic complications enabling early treatment, and risk factors for altered pulmonary function tests included previous smoking habits, irradiation and chronic GvHD.
Abstract: Increasing numbers of patients are surviving after allogeneic haematopoietic stem cell transplantation (SCT). Among these patients, a number of late complications have been described but few data on the risk factors of these long-term effects of SCT are available. We report the analysis on 105 adult patients, surviving free of haematological disease at a median time of 15 months after SCT. At the time of screening, 52% had returned to work, general health status was normal in 67% and 47% were sexually active. Female patient gender odds ratio (OR) 2.9 (P = 0.01) and age > 25 years (OR = 3.2, P = 0.02) were associated with non-return to work. Decreased general status was associated with chronic graft-versus-host disease (GvHD) (OR = 3.2, P = 0.009) and irradiation (OR = 3.6, P = 0.004). Sexual inactivity was associated with younger age (OR = 7.0, P = 0.0002) and chronic GvHD (OR = 3.3, P = 0.006). Risk factors for altered pulmonary function tests included previous smoking habits, irradiation and chronic GvHD. Obstructive lung disease was associated with a previous history of asthma. Sicca syndrome and conjunctivitis were increased in patients with previous acute GvHD and cataracts were less frequent in patients with aplastic anaemia. Persistent impaired hair re-growth was less frequent in patients who received irradiation (OR = 0.18, P = 0.002) but increased in patients with previous acute GvHD (OR = 5.3, P = 0.007). Microalbuminuria was more frequent in irradiated patients (OR = 9.4, P = 0.05). Raised cholesterol was associated with age (OR = 20.8, P < 0.001), previous acute GvHD (OR = 4.7, P = 0.03), steroid use (OR = 6.3, P = 0.001) and familial hypercholesterolaemia (OR = 4.4, P = 0.04). Decreased bone density was associated with chronic GvHD (OR = 3.9, P = 0.001). Thus, using routine tests in adult patients we were able to detect significant numbers of-non-symptomatic complications enabling early treatment.
53 citations
TL;DR: In order to study the influence of bone marrow CD34+ cell dose on the outcome of allogeneic bone marrow transplantation (BMT), the results of BMT from HLA-identical siblings donors in 50 patients with chronic myeloid leukaemia were analysed.
Abstract: In order to study the influence of bone marrow CD34(+) cell dose on the outcome of allogeneic bone marrow transplantation (BMT), we analysed the results of BMT from HLA-identical siblings donors in 50 patients with chronic myeloid leukaemia (CML). The median numbers of nucleated cells (NC) and CD34(+) cells infused were 2.18 x 10(8)/kg (0.05-4.14 x 10(8)/kg) and 3.12 x 10(6)/kg (0.35-8.52 x 10(6)/kg), respectively. All patients engrafted. In univariate analysis, there was no correlation between the number of CD34(+) cells infused and the time to neutrophil recovery (P = 0.17). The Kaplan-Meier estimate of grade II-IV acute graft-versus-host disease (GVHD) at day 100 was 53 +/- 14% and 2-year survival was 46 +/- 15%. A number of CD34(+) cells infused greater than the median was the main factor increasing survival (P = 0.0006) and decreasing 100 day transplant-related mortality (P = 0.009). Patient-, disease- and transplant-related characteristics were not statistically different among patients receiving more or less than the median number of CD34(+) cells. The rate of infectious deaths was significantly higher in patients receiving less than 3.12 x 10(6) CD34/kg (48% vs 16%, P = 0.01). In a multivariable analysis, two factors associated with increased risk of death were advanced disease status at transplant (HR: 2.5 (95% CI: 1.09-5.75), P = 0.03) and a lower number of marrow CD34(+) cells infused/kg (HR: 4.55 (95% CI: 1.87-10.90), P = 0.0008).
TL;DR: Findings suggest a common genetic origin of Fanconi's anemia, which can be associated with growth retardation, and biologic growth hormone deficiency, isolated or associated with thyrotropin abnormality, and pituitary stalk interruption syndrome on magnetic resonance imaging of 5 patients with Fanconi't anemia.
TL;DR: A high cell dose of CD3/CD8 is associated with faster neutrophil recovery, whereas a high cell doses of CD4+ cells increases the incidence of acute GVHD, and a high number of nucleated cells and CD34+ cells infused was associated with decreased risk of chronic GV HD and improved survival.
TL;DR: A 52-yr-old woman with refractory T-PLL underwent a nonmyeloablative regimen followed by allogeneic peripheral blood stem cell transplantation (a “minitransplant”) from her HLA-matched sibling and, on day 84 after transplantation, had a relapse in the central nervous system.
Abstract: Aim: T-prolymphocytic leukemia (T-PLL) is a rare disease of the elderly characterized by a high white blood cell count and organomegaly, and is currently incurable. Our aim was to elicit graft-versus-leukemia reactions in a patient with T-PLL. Methods: A 52-yr-old woman with refractory T-PLL underwent a nonmyeloablative regimen followed by allogeneic peripheral blood stem cell transplantation (a “minitransplant”) from her HLA-matched sibling. Results: There was no treatment related toxicity other than neutropenia. Engraftment was successful. The patient experienced no graft-versus-host disease (GVHD) at any time but, on day 84 after transplantation, had a relapse in the central nervous system. Despite infusion of donor lymphocytes and intralumbar chemotherapy, she died on day 157 of systemic disease. Conclusion: The reasons why treatment may have failed are discussed (nature of disease, disease progression, treatment schedule).
TL;DR: As in solid organ transplant recipients, anogenital condyloma may develop after allogeneic bone marrow transplantation, because the oncoprotein of HPV is able to bind and to degrade p53, it may lead to genetic instability, and subsequently to malignant transformation.
Abstract: Background Secondary malignant diseases are late complications after allogeneic bone marrow transplantation (BMT) Anogenital lesions associated with human papillomavirus (HPV) infection have been described in renal transplant recipients but not after BMT HPV types 16 and 18 are strongly linked to the malignant transformation Methods In a series of 238 patients with allogeneic BMT, three had anogenital lesions We looked for HPV in DNA extracted from embedded tissue to study HPV genotypes, p53 expression, and ploidy Results In two patients, HPV sequences were detected One of them, with giant condyloma, had HPV type 18 and two aneuploid clones, but p53 expression was not found Conclusion As in solid organ transplant recipients, anogenital condyloma may develop after BMT Because the oncoprotein of HPV is able to bind and to degrade p53, it may lead to genetic instability, and subsequently to malignant transformation
TL;DR: Three patients in whom toxoplasmic pneumonitis developed, leading to fatal acute respiratory distress syndrome (ARDS), are reported, in whom the possible role of an immunopathologic response to T gondii in the lungs in triggering ARDS is discussed.
Abstract: Toxoplasmosis is a rare but severe complication of bone marrow transplantation. Here, we report three patients in whom toxoplasmic pneumonitis developed, leading to fatal acute respiratory distress syndrome (ARDS). All patients had positive pretransplantation tests for Toxoplasma gondii and were therefore at risk to develop toxoplasmosis reactivation. They all recovered from aplasia, but soon after they died from brutal and severe ARDS. The possible role of an immunopathologic response to T gondii in the lungs in triggering ARDS is discussed.Early screening of parasitemia using highly sensitive polymerase chain reaction methods in seropositive patients with unexplained fever may be needed.
TL;DR: In a retrospective analysis of hemorrhagic cystitis subsequent to allogeneic bone marrow transplantation, patients who underwent subtotal cystectomy with ileocystoplasty were focused on because stepwise use of conservative treatments had failed.
TL;DR: Cytomegalovirus infection remains associated with increased mortality in immunocompromised populations, particularly in allogeneic hematopoietic stem cell transplant (HSCT) recipients.
TL;DR: It is concluded that cytogenetic analysis is necessary at diagnosis of AA or after recovery of blood counts, and the literature arguments about considering some cases of AA as preleukaemic disorders are discussed.
Abstract: We report three cases of typical aplastic anaemia (AA) associated with a Philadelphia chromosome. This translocation was detected at the time of diagnosis of AA (one patient) and when overt leukaemia was diagnosed (two patients: one chronic myeloid leukaemia and one acute lymphoblastic leukaemia) after AA therapy and recovery of blood counts. We discuss the literature arguments about considering some cases of AA as preleukaemic disorders and suggest that our cases illustrate the association of AA with a clonal malignant disorder. We conclude that cytogenetic analysis is necessary at diagnosis of AA or after recovery of blood counts.
TL;DR: It was revealed that CB NK cells induced a dose‐dependent inhibition of T lymphocyte proliferation as evidenced by decreased 3H‐thymidine incorporation in MLC.
Abstract: We tested the immunosuppressive effect of cord blood (CB) natural killer (NK) cells using highly purified CB NK cells in mixed lymphocyte cultures (MLC) containing autologous CB T cells as responders. Control cultures were done without NK cells. Our findings revealed that CB NK cells induced a dose-dependent inhibition of T lymphocyte proliferation as evidenced by decreased 3H-thymidine incorporation in MLC. The T cell alloproliferation was significantly decreased in the presence of an NK cell to responder cell ratio of 0.1, 0.2 or 0.4 compared with control cultures done without NK cells (p=0.02, 0.003 and 0.0002, respectively). T lymphocyte inhibition was also achieved using irradiated CB NK cells and still demonstrable on addition of disparate CB NK and T cells to the MLC. In agreement with previous reports, adult blood NK cells inhibited the alloreactive T cells in the MLC using adult T lymphocytes as responders. Compared to control cultures done without NK cells, statistically significant inhibition of 3H-thymidine incorporation in MLC was observed at a ratio of NK cells to responder cells ratio of 0.2 or 0.4 (p=0.02). To investigate the mechanism whereby CB NK cells can interfere with the development of alloreactive T cells in MLC, we measured the tumour necrosis factor-alpha (TNF-alpha) concentrations in MLC supernatants using NK cell-depleted or unseparated CB mononuclear cells (MNC) as responders. The results revealed significantly high levels of TNF-alpha in the absence of NK cells (p=0.007). We conclude that CB NK cells suppress alloreactive T lymphocytes as do their counterparts in adult blood. However, the high NK to T cell ratio in CB could contribute to a more marked suppressive potential compared to that in adult blood. The mechanism of NK-mediated inhibition is likely related to disruption of the TNF-alpha pathway of T-lymphocyte activation.
TL;DR: AFP values were significantly higher in FA than in non-FA patients, but the diagnostic precision and optimal cutoff values varied, and new methods must be evaluated before use in differential diagnosis of aplastic patients.
Abstract: Background: The significantly higher serum α-fetoprotein (AFP) in patients with Fanconi anemia (FA) than in non-FA aplastic patients has potential diagnostic utility, but the increase is method-dependent. The aim of this study was to compare five AFP assays on FA and non-FA samples and to investigate possible explanations for FA-specific discrepancies.
Methods: Two methods available in our laboratory (Kryptor and IMx) were compared on 59 FA and 27 non-FA patient samples. Kryptor, Immulite, Elecsys, Immuno-I, and Elsa-2 methods were then compared on 14 FA and 14 non-FA patient samples. The AFP glycosylation profile was analyzed by electrophoretic separation in a lectin-containing gel.
Results: With all six methods, AFP values were significantly higher in FA than in non-FA patients, but the diagnostic precision and optimal cutoff values varied. Indeed, two methods reached 100% sensitivity and specificity, but in other methods, one or both of these parameters were significantly <100%. Neither heterophilic antibodies nor a specific glycosylation profile was detected in FA samples.
Conclusions: AFP results are method-dependent in FA. New methods must be evaluated before use in differential diagnosis of aplastic patients.
TL;DR: Farge et al. as mentioned in this paper designed a national, non-randomised, open, phase I-II trial to determine the feasibility, tolerance and efficacy of autologous HSC transplantation with CD34+ selection in severe scleroderma (Sc) and myositis (M).
Abstract: Background Autologous bone marrow transplant is a new treatment for autoimmune diseases (AD). Objectives To determine the feasibility, tolerance and efficacy of autologous HSC transplantation with CD34+ selection in severe scleroderma (Sc) and myositis (M). Methods We designed a national, non randomised, open, phase I-II trial.1Mobilisation of HSC used cyclophosphamide (CYCLO) (4 g/m2)+ G-CSF (5 microg/kg day) or G-CSF alone (10 microg/kg day) if left ventricular ejection fraction (LVEF) was Results 12 Sc + 3 M, age 36 yrs, were included in 2 years, meanwhile 10 candidates died from their disease. HSC mobilisation was successful in 14 patients, but in 2 cases did not yield enough HSC to allow CD34+ selection. After 2 (1–4) aphereses, the total number of CD34+ collected for each patient was 10.9 × 106/kg (3.9?34.3). Purity was 99.2% (92–99.8). CD34+ cells yield was 60.7% (46.4–80). Intensive immunosuppression was performed in 13 patients with low toxicity. Number of reinfused cells was 5.8 × 106 CD34+/kg (3.3–10.2). Duration of aplasia was 2.9 weeks (2.5–3) with low toxicity. No mortality was associated with the procedure. Early clinical evolution (18 mths) showed improved functional status (PS, SHAQ) and fall in skin score in 8/12 Sc and no clinical benefit in M. Conclusion Autologous HSC transplantation is feasible in Sc and M, with a lower risk compared to spontaneous evolution of AD and early clinical benefit in Sc. These results call for phase III studies to compare cyclophosphamide alone versus autologous transplantation in Sc and for more myositis in phase I–II studies. Reference Farge D, Gluckman E, Tyndall A. Treatment of severe autoimmune diseases by immunoablative chemotherapy and autologous bone marrow transplantation. EJIM 1999;10:88–96