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N Jacobsen

Publications and source records attributed to N Jacobsen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Reactions of beta-carotene with cigarette smoke oxidants. Identification of carotenoid oxidation products and evaluation of the prooxidant/antioxidant effect.

Recent intervention trials reported that smokers given dietary beta-carotene supplementation exhibited an increased risk of lung cancer and overall mortality. beta-Carotene has been hypothesized to promote lung carcinogenesis by acting as a prooxidant in the smoke-exposed lung. We have examined the interactions of cigarette smoke with beta-carotene in model systems. Both whole smoke and gas-phase smoke oxidized beta-carotene in toluene to several products, including carbonyl-containing polyene chain cleavage products and beta-carotene epoxides. A major product of the reaction was identified as 4-nitro-beta-carotene, which was formed by nitrogen oxides in smoke. Both cis and all-trans isomers of 4-nitro-beta-carotene were detected. The hypothesis that smoke-driven beta-carotene autoxidation exerts prooxidant effects was tested in a liposome system. Lipid peroxidation in dilinoleoylphosphatidylcholine liposomes exposed to gas-phase smoke was modestly inhibited by the incorporation of 0.1 mol % beta-carotene. Both the lipid soluble antioxidant alpha-tocopherol and the water soluble antioxidant ascorbate were oxidized more slowly by gas-phase smoke exposure in liposomes containing beta-carotene. These data indicate that beta-carotene exerts weak antioxidant effects against smoke-induced oxidative damage in vitro. It is unlikely that a prooxidant effect of beta-carotene occurs under biologically relevant conditions or is responsible for an increased incidence of lung cancer observed in smokers who consume beta-carotene supplements.

Animals↗
PubMed1999

Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease.

Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.

Calcium-Transporting ATPases↗
PubMed1999

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood.

Internal genitalia and uterine blood flow were assessed by ultrasound in 12 females 4.0-10.9 years after total body irradiation and allogeneic bone marrow transplantation for childhood leukaemia or lymphoma. Median age of the participants was 12.7 years (range 6.1-17.6) at bone marrow transplantation and 21.5 years (11.6-25.6) at the follow-up study. At follow-up all had entered puberty and 11/12 females had experienced the menarche. Eight females received sex steroid replacement therapy, three had spontaneous pubertal development and one woman experienced symptoms of estrogen deficiency. Median uterine and ovarian volumes were significantly reduced to -2.6 standard deviation scores (SDS) (-6.3 to -0.6), P = 0.002, and -2.6 SDS (-4.8 to -0.5), P = 0.002, respectively, compared with normal controls. Follicles were only detectable in two individuals. Uterine blood flow was impaired, as a systolic blood flow could be measured in 6/9 individuals, and a diastolic blood flow in 1/9 females. Our results indicate that the prescribed dosage of hormone replacement therapy, which was sufficient to induce bleeding and suppress other stigmata of premature menopause, was inadequate to generate normal uterine growth. In order to achieve uterine growth higher doses of hormone replacement therapy may be required. Our results confirm pelvic ultrasound as a reliable tool for investigation of internal female genitalia; however, in an infertility setting further tests are indicated.

Adolescent↗
PubMed1999

Single leukapheresis products collected from healthy donors after the administration of granulocyte colony-stimulating factor contain ten-fold higher numbers of long-term reconstituting hematopoietic progenitor cells than conventional bone marrow allografts.

Cytokine-mobilized peripheral blood progenitor cells (PBPCs) have been used successfully for hematopoietic reconstitution following allogeneic transplantation. The ease of harvest, the faster engraftment and the high yield of CD34+ cells have made this source of hematopoietic progenitor cells (HPCs) an attractive alternative to bone marrow (BM). In the present study we compared the engraftment potential of conventional BM allografts and single leukapheresis products (LPs) collected from healthy donors following the administration of granulocyte colony-stimulating factor (G-CSF). For this, lineage-committed and primitive HPCs were assessed by flow cytometry and by colony- and cobblestone area-forming cell (CFC, CAFC) assays. Mean numbers of CD34+ cells in LPs (n = 11) were similar to that of BM grafts (n = 12) (278+/-57 vs 227+/-34 x 10(6) CD34+ cells). The frequencies of CFCs, week 5 CAFCs and week 8 CAFCs were 1.6-, 8.4- and 10.3-fold higher in the CD34+ compartment of mobilized blood than that of marrow, resulting in significantly higher yields of clonogenic HPCs in LPs when compared to BM grafts. We conclude that G-CSF preferentially mobilizes clonogenic progenitors capable of short- and, in particular, longterm reconstitution, and that the engraftment potential of single LPs is superior to that of BM allografts. Hence, the use of PBPCs may be favorable for protocols that include graft manipulations with expected cell loss (eg T cell depletion, CD34+ selection). PBPCs may also be advantageous for gene therapy trials due to their high numbers of potential target cells (eg CAFCs).

Adolescent↗
PubMed1999

The graft versus leukemia effect after bone marrow transplantation: a case study using structural nested failure time models.

Over the last decade, J. M. Robins has developed a set of tools for assessing, from observational data, the causal effects of a time-dependent treatment or exposure in the presence of time-dependent covariates that may be simultaneously confounders and intermediate variables. This report concerns a case study of the application of one these techniques, G-estimation using structural nested failure time models, to the problem of assessing the effect of graft versus host disease on leukemia relapse after bone marrow transplantation.

Biometry↗
PubMed1999

A comparative study of CD34+ cells, CD34+ subsets, colony forming cells and cobblestone area forming cells in cord blood and bone marrow allografts.

Cord blood (CB) has become an alternative source of hematopoietic progenitor cells (HPCs) for allogeneic transplantation. We have developed a new efficient protocol for CB collection. Using this method an average of 17.7 x 10(8) [range (6.8-29.6) x 10(8), n = 13] total nucleated cells (TNCs) were harvested. Based on recent Eurocord data, which have shown safe engraftment using a threshold dose of 0.37 x 10(8) CB TNCs/kg body weight (BW), we calculated that six out of thirteen CB grafts collected by this method were sufficient to engraft adults. The CB derived CD34+ population contained two-fold higher numbers of committed HPCs (CFU-GM, BFU-E) and six-fold higher numbers of pluripotent HPCs [CD34+/CD38- cells, wk 5 and wk 8 cobblestone area forming cells (CAFCs)] than the CD34+ population of BM. Extrapolation revealed that BM grafts providing the threshold dose for allogeneic transplantation of 2 x 10(8) TNCs/kg BW contained nearly 3 times more pluripotent HPCs than CB grafts providing the Eurocord threshold dose. The assessment of CD34+/CD38(-) cell numbers in CB grafts was highly reproducible and correlated well with the in vitro performance of pluripotent HPCs, i.e. numbers of CAFCs. We conclude that CB grafts providing high numbers of TNCs have the potential to engraft adults and that the enumeration of pluripotent HPCs by flow cytometry may be a useful tool to define the ultimate threshold dose for CB transplantation.

ADP-ribosyl Cyclase↗
PubMed1999

Dental workplace exposure and effect on fertility.

OBJECTIVES: This study assessed occupational exposure in dental surgeries on the basis of the reported use of dental materials and techniques and applied waiting-time-to-pregnancy methodology to study fertility in relation to the occupational exposure. METHODS: Data were collected retrospectively using a self-administered postal questionnaire addressing the occupational and reproductive history of the participants. The study groups consisted of 558 female dental surgeons and 450 high school teachers that had given birth in Norway to at least 1 living child. The present study comprised data from a total of 1408 pregnancies. The effects of practicing dentistry and of the given workplace exposure on fertility were analyzed with the discrete proportional hazard regression method. RESULTS: Most of the female dental surgeons were using amalgam for fillings during the period they tried to conceive, and 1/3 placed more than 50 fillings a week. Tooth-colored fillings were in limited use. Prior to 75% of the pregnancies, the dental surgeons reported handling chloroform-based root canal sealers. Forty percent of the dental surgeons were daily exposed to disinfectants containing ethanol and benzene. No difference was found in fertility between the dental surgeons and the high school teachers. Exposure to mercury, chloroform, and benzene was not associated with decreased fertility, except for a possible effect of mercury in the last pregnancy of multiparous dental surgeons. CONCLUSIONS: Occupational exposures had no clear adverse effects on fertility among the female dental surgeons studied.

Dental Amalgam↗
PubMed1998

Signal transduction via the mitogen-activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor.

The putative role of tissue factor (TF) as a receptor involved in signal transduction is indicated by its sequence homology to cytokine receptors (Bazan, J. F. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 6934-6938). Signal transduction induced by binding of FVIIa to cells expressing TF was studied with baby hamster kidney (BHK) cells stably transfected with TF and with a reporter gene construct encoding a luciferase gene under transcriptional control of tandem cassettes of signal transducer and activator of transcription (STAT) elements and one serum response element (SRE). FVIIa induced a significant luciferase response in cells expressing TF, BHK(+TF), but not in cells without TF. The BHK(+TF) cells responded to the addition of FVIIa in a dose-dependent manner, whereas no response was observed with active site-inhibited FVIIa, which also worked as an antagonist to FVIIa-induced signaling. Activation of the p44/42 MAPK pathway upon binding of FVIIa to TF was demonstrated by suppression of signaling with the specific kinase inhibitor PD98059 and demonstration of a transient p44/42 MAPK phosphorylation. No stimulation of p44/42 MAPK phosphorylation was observed with catalytically inactive FVIIa derivatives suggesting that the catalytic activity of FVIIa was obligatory for activation of the MAPK pathway. Signal transduction caused by a putative generation of FXa activity was excluded by experiments showing that FVIIa/TF-induced signaling was not quenched by tick anticoagulant protein, just as addition of FXa could not induce phosphorylation of p44/42 MAPK in BHK(+TF) cells. These results suggest a specific mechanism by which binding of FVIIa to cell surface TF independent of coagulation can modulate cellular functions and possibly play a role in angiogenesis and tumor metastasis as indicated by several recent observations.

Animals↗
PubMed1998

Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

Allogeneic bone marrow transplantation (BMT) offers a potential cure for younger patients with myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (sAML). More than 600 patients from 50 European centers have now been reported to the European Group for Blood and Marrow Transplantation (EBMT). We retrospectively analyzed 131 patients reported to the Chronic Leukemia Working Party of the EBMT who underwent BMT from HLA-identical siblings without prior remission induction chemotherapy. At the time of BMT 46 patients had refractory anemia (RA) or RA with ringed sideroblasts, 67 patients had more advanced MDS subtypes and 18 patients had progressed to sAML. The 5-year disease-free (DFS) and overall survival (OS) for the entire group of patients was 34 and 41%, respectively. Fifty patients died from transplant-related complications, most commonly graft-versus-host disease and/or infections. Relapse occurred in 28 patients between 1 and 33 months after BMT, resulting in an actuarial probability of relapse of 39% at 5 years. DFS and OS were dependent on pretransplant bone marrow blast counts. Patients with RA/RARS, RAEB, RAEB/T and sAML had a 5-year DFS of 52, 34, 19 and 26%, respectively. The 5-year OS for the respective patient groups was 57, 42, 24 and 28%. In a multivariate analysis, younger age, shorter disease duration, and absence of excess of blasts were associated with improved outcome. From these data we conclude that patients with myelodysplasia who have appropriate marrow donors, especially those aged less than 40 years and those with low medullary blast cell count should be treated with BMT as the primary treatment early in the course of their disease. Transplantation early after establishing the diagnosis of MDS may improve prognosis due to a lower treatment-related mortality and a lower relapse risk.

Adolescent↗
PubMed1998

Influence of protective isolation on outcome of allogeneic bone marrow transplantation for leukemia.

Various isolation strategies are used to prevent infections during bone marrow transplantation; data on their efficacy are lacking. We studied whether use of high efficiency particulate air filtration (HEPA) and/or laminar airflow (LAF) units affect transplant-related mortality (TRM) or survival in the first year after allogeneic transplantation. 5065 patients with leukemia receiving bone marrow transplants from an HLA identical sibling (n = 3982) or alternative related or unrelated donors (n = 1083) between 1988 and 1992 were reported to the International Bone Marrow Transplant Registry by 222 teams. Two types of isolation were considered: (1) conventional protective isolation with single patient room and any combination of hand-washing, gloves, mask and gown; and (2) HEPA and/or LAF. Cox proportional hazards regression models were used to determine the relative risks (RRs) of transplant-related mortality (TRM) and of deaths from any cause in patients treated in HEPA/LAF units compared to patients treated in conventional isolation. HLA-identical sibling and alternative donor transplants were analyzed separately. Risks of TRM and overall mortality in the first 100 days post-transplant were significantly lower among patients treated in HEPA/LAF units than in those treated conventionally. RRs of TRM were 0.76 (P = 0.009) for recipients of HLA-identical sibling transplants and 0.65 (P = 0.003) for recipients of alternative donor transplants. Correspondingly RRs of overall mortality were 0.80 (P = 0.02) and 0.65 (P = 0.0006). Decreased risks of TRM and of death in the first 100 days post-transplant resulted in significantly higher 1-year survival rates in patients treated in HEPA/LAF rather than in conventional isolation units. Use of HEPA and/or LAF to prevent infections decreases TRM and increases survival after allogeneic bone marrow transplants for leukemia.

Adolescent↗
PubMed1998

Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: an EBMT survey. European Blood and Marrow Transplantation Group.

The Chronic Leukemia Working Party of the EBMT has collected data on 118 patients of median age 24 years (range 0.3 to 53 years) who underwent an allogeneic bone marrow transplantation from unrelated donors for treatment of MDS or secondary AML (RA/RARS, n = 24; RAEB, n = 26; RAEB-t, n = 34; CMML, n = 12; sAML, n = 22) between 1986 and 1996. The data were reported by 49 EBMT centers. Thirty-four of 118 patients are alive, relapse was the cause of death in 19 of 84 patients and the remaining patients died of transplant-related mortality. For the whole group the actuarial probability of survival at 2 years is 28%, disease-free survival 28%, relapse risk 35% and transplant-related mortality is 58%. The transplant-related mortality is significantly influenced by the age of the recipient (<18 years 40%, 18-35 years 61%, >35 years 81%). The relapse rate after BMT is influenced by FAB classification of the disease at BMT. Patients with a low blast count (RA, RAEB) have a lower probability of relapse (13%, 15%) compared to patients with RAEB-t or sAML (29%, 45%). Furthermore, we found evidence of a graft-versus-leukemia effect in MDS/sAML. Patients with acute GVHD, grade II-IV, had a probability of relapse of 26% vs 42% in patients with no acute GVHD or grade I only. Allogeneic transplantation with an HLA-matched, unrelated donor may be offered to younger patients (age <35 years) with poor risk myelodysplasia or secondary AML.

Adolescent↗
PubMed1998

Outcome of acute lymphoblastic leukaemia in Danish children after allogeneic bone marrow transplantation. Superior survival following transplantation with matched unrelated donor grafts.

Outcome of allogeneic BMT for childhood ALL performed at a national centre was evaluated for the period between 1985 and 1996. Sixty-seven patients representing all Danish children and adolescents (1-19 years) transplanted for ALL, were evaluated. Patients transplanted with a family donor (n = 51) had a 3-year probability of leukaemia-free survival (P-LFS) of 56% (95% confidence limits 41-69%) and patients receiving marrow from a matched unrelated donor (MUD) (n = 16) had a 3-year P-LFS of 67% (34-86%) (P = 0.38). Relapse was responsible for 48% of the deaths and occurred with increasing frequency among children transplanted with marrow from HLA-identical siblings. Patients transplanted with family donors from 1985-1989 had P-LFS of 72% (54-84%) compared to patients transplanted after 1990 who revealed a significantly reduced P-LFS of 28% (10-49%, P = 0.01). Furthermore, the risk of relapse was increased (65% (24-88%)) (P = 0.02) in the later period. In contrast, patients transplanted with marrow from a MUD (1990-1996) had a lower risk of relapse (11%, 5-20%) (P = 0.002) but a comparable risk of transplant-related mortality. Children who experience relapse after modern, intensive treatment for ALL may have an increased propensity for relapse even after BMT. Therefore, when performing BMT for childhood ALL, there may be a benefit in overall survival from the increased graft-versus-leukaemia effect that follows less intensive GVHD prophylaxis or transplantation with a MUD.

Adolescent↗
PubMed1998

Immunephenotyping of T lymphocytes from patients after allogeneic bone marrow transplantation.

The relative distribution of T cell subsets as defined by MABs was analyzed in PBMCs from 56 patients with various hematologic diseases. The percentage of PBMCs expressing the CD5 antigen revealed normal values shortly after transplantation. In most patients lymphocytes expressing CD8 were found in high proportion and CD4 in a low percentage. This resulted in a low CD4/CD8 ratio compared with that of lymphocytes from normal controls. In the course of time, a trend toward normalization was observed for all parameters investigated, however the kinetics of the recovery showed a marked heterogeneity. Nevertheless, we found a statistical correlation between the CD4+ cell count and the PHA transformation response. This could however, not be shown in ConA and PWM stimulated proliferation. No other correlation was found between any lymphocyte phenotype, as defined by MABs, and proliferative responses in vitro.

Bone Marrow Transplantation↗
PubMed1997

Results of transplanting bone marrow from genetically identical twins into patients with aplastic anemia.

BACKGROUND: Aplastic anemia is caused by several diverse factors, including a lack of or defective hematopoietic stem cells, immune abnormalities, and disorders of the bone marrow microenvironment. The outcome of transplanting bone marrow from genetically identical twins into patients with aplastic anemia may help define how frequently these factors play a role in this condition. OBJECTIVE: To determine the outcome of transplanting bone marrow from genetically identical twins into patients with aplastic anemia. DESIGN: Observational study. SETTING: 31 centers participating in the international Bone Marrow Transplant Registry. PATIENTS: 40 patients with aplastic anemia who received bone marrow transplants from their genetically identical twins between 1964 and 1992. INTERVENTION: 23 patients received their first bone marrow transplant without pretransplantation conditioning; 17 received it after pretransplantation conditioning with cyclophosphamide alone or combined with other drugs or radiation. Six patients received post-transplantation immunosuppressive therapy with methotrexate, cyclosporine, and corticosteroids, alone or in combination. MEASUREMENTS: Outcomes of transplantation, including hematologic recovery and survival. RESULTS: Seven of 23 patients who received their first transplant without receiving conditioning had sustained complete hematologic recovery. One of 16 patients who did not have complete recovery after the first transplantation recovered after a second transplantation, which was not preceded by conditioning. The other 15 patients had two to five transplantations that were preceded by conditioning; in 13 patients, sustained bone marrow function was recovered. Twelve of 17 patients whose first transplantation was preceded by conditioning had sustained complete hematologic recovery. The likelihood of hematologic recovery was greater in patients who had conditioning before the first transplantation (P = 0.033). The actuarial 10-year survival rate for the 40 patients was 78% (95% CI, 59% to 92%). The survival rate was higher in patients who did not have conditioning before the first transplantation (patients without conditioning, 87% [range, 65% to 99%]; patients with conditioning, 70% [range, 47% to 89%]; P = 0.037). CONCLUSIONS: Most patients with aplastic anemia recover bone marrow function after receiving a transplant from a genetically identical twin. Pretransplantation conditioning may increase the chance of bone marrow recovery but does not seem to improve survival.

Adolescent↗
PubMed1997

Donor search or autografting in patients with acute leukaemia who lack an HLA-identical sibling? A matched-pair analysis. Acute Leukaemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation (EBMT) and the International Marrow Unrelated Search and Transplant (IMUST) Study.

One hundred and ninety-one patients with acute leukaemia who received bone marrow from HLA-A, -B and -DR identical unrelated donors and were reported to EBMT and/or IMUST, were matched with 382 patients receiving autologous bone marrow for diagnosis, age, stage of disease and year of transplantation. Transplant-related mortality (TRM) was significantly higher in recipients of unrelated marrow compared to autograft recipients, 44 +/- 4% (+/- 95% confidence interval) and 15 +/- 3% at 2 years in the two groups, respectively (P < 10(-4)). In contrast, relapse probability was lower in recipients of unrelated marrow, being 32 +/- 5% at 2 years compared to 55 +/- 3% in recipients of autografts (P < 10(-4)). Two-year leukaemia-free survival (LFS) in patients with acute lymphoblastic leukaemia was 39 +/- 5% and 32 +/- 3% in the two groups, respectively. Among patients with acute myeloid leukaemia (AML), the corresponding figures were 36 +/- 6% and 46 +/- 5% in the two groups, respectively (P = NS). In AML in first remission (CR-1), the 2-year survival was 42 +/- 10% in recipients of unrelated bone marrow, compared to 69 +/- 8% in autograft recipients (P = 0.008). When all patients with acute leukaemia were included, the 2-year LFS was 38% in recipients of unrelated marrow, compared to 37% in autograft recipients (NS). In conclusion, this retrospective analysis supports the design of a prospective randomized study in patients with high-risk/advanced acute leukaemia who lack a suitable related bone marrow donor, to ascertain which of the two strategies, if any, should be favoured.

Acute Disease↗
PubMed1997

Haploidentical family member transplants for patients with chronic myeloid leukaemia: a report of the Chronic Leukaemia Working Party of off European Group for Blood and Marrow Transplantation (EBMT).

Within the registry of the chronic leukaemia working party of the European Group for Blood and Marrow Transplantation, data were available from 103 patients with chronic myeloid leukaemia who were treated by bone marrow transplantation from haploidentical family members. The patients of median age 30 years were transplanted between 1983 and 1994 in 25 European centres. The overall probabilities of survival and leukaemia-free survival (LFS) at 5 years were 32 and 25%, respectively. In univariate analysis, two factors were identified which affected survival and LFS, ie the state of disease at the time of transplant and the degree of HLA disparity. Fifty-nine patients were transplanted in first chronic phase and the probability of survival at 2 years was 47%. Forty-four patients received their transplants for advanced disease and their probability of survival at 2 years was 25% (P = 0.004). Donor bone marrow was HLA-mismatched for 0-1 antigens in 54 patients (group 1) and for 2-3 antigens in 49 patients (group 2). At 2 years, the probabilities of survival for groups 1 and 2 were 46 and 27% (P < 0.02) and the probabilities of LFS were 43 and 24% (P < 0.03), respectively. Multivariate analysis confirmed the prognostic importance of the disease stage and of the HLA disparity. Patients transplanted in first chronic phase from a donor mismatched for 0-1 HLA antigens had a probability of survival of 52% at 2 years compared with 19% for patients transplanted in advanced disease stage from donors mismatched for 2-3 HLA antigens.

Adolescent↗
PubMed1997

European results of matched unrelated donor bone marrow transplantation for chronic myeloid leukemia. Impact of HLA class II matching. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

We have retrospectively analyzed the impact of prognostic factors on the outcome of serologically HLA-matched unrelated donor (UD) BMT for CML. For this purpose, we have studied a cohort of 366 patients transplanted in Europe between January 1985 and December 1994. The median age of the 211 males and 155 females was 34 years; 238 patients were transplanted in first chronic phase and 116 in advanced phases. The median interval from diagnosis to BMT was 827 days. GVHD prophylaxis consisted of CsA and MTX in 202 patients or of ex vivo or in vivo T cell depletion (TCD) in 129. Recently, DNA-based methods of HLA-class II typing have been used to improve donor selection. We obtained complete data on 300 donor/recipient (D/R) pairs. Among them, we have identified three groups of patients, according to specific HLA-DRB1 D/R compatibility. Two hundred and ten patients received marrow from donors identical for HLA-DRB1 (group 1). Thirty-one patients received BMT from a donor who was HLA-DRB1 mismatched (group 2) and 59 from a donor in whom specific HLA-DRB1 typing was not performed (group 3). The overall survival was 37 +/- 3% at 2 years and leukemia-free survival (LFS) was 31 +/- 3%. In univariate analysis, five variables had a favorable effect on LFS: transplant in first chronic phase (P = 0.0001), time interval from diagnosis to BMT shorter than the median (P = 0.01), prophylaxis of GVHD without TCD (P + 0.001), acute GVHD < grade III (P = 0.0009) and HLA-DRB1 D/R matching (P = 0.0001). Transplant-related mortality (TRM) was 49 +/- 4% in group 1, 79 +/- 8% in group 2 and 80 +/- 6% in group 3 (P = 0.0001). Multivariate analysis confirmed that HLA-DRB1 matching was the most significant factor influencing survival (P = 0.04), LFS (P = 0.013) and TRM (P = 0.0049). From these results, we have defined a 'good risk' group, ie patients transplanted in first chronic phase, from an HLA-DRB1 matched donor, without TCD as prophylaxis against GVHD. The 2 year LFS, TRM and relapse incidence for this group were 51 +/- 5%, 47 +/- 5% and 2 +/- 2%, respectively. This suggests that the long-term outcome of patients with favorable prognostic features can approach that of patients transplanted from geno-identical siblings. In contrast, the TRM for patients transplanted for advanced disease from non HLA-DRB1-identical donors was 94%. Such a high TRM clearly indicates that UD BMT is not justifiable for these individuals.

Adolescent↗