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A Gratwohl

Publications and source records attributed to A Gratwohl.

At least 91 records · Page 5Linked to original sources
PubMed2000

Myeloproliferative disorders: complications, survival and causes of death.

This retrospective single-center study compared thromboembolic and hemorrhagic complications, survival and causes of death in a cohort of 102 consecutive patients with myeloproliferative disorders (MPD). We included 17 patients with essential thrombocythemia (ET), 59 with polycythemia vera (PV), and 26 with osteomyelofibrosis (OMF). The median follow-up was 3.7 years. Estimated 8-year probability of complications for the entire cohort was 80 +/- 11% (95% confidence interval), without significant differences among MPD subgroups. The rate of thromboembolic complications, expressed as the number of events per 100 patient years, was 16.7 for patients with PV, 13.8 for OMF, and 7.5 for ET. Fifty-four percent of thromboembolic events in PV involved cerebral or limb arteries. The rate of bleeding complications was highest in patients with OMF (31.8 per 100 patient years), followed by ET and PV (11.8). Ninety percent of bleeding episodes affected the skin. mucosal membranes, and the gastrointestinal tract. Eight-year survival was highest in ET with 91 +/- 17%, followed by PV (66 +/- 18%) and OMF (40 +/- 31%) (P< 0.01). Twenty-four patients died during the observation period, and fatal thrombosis (in five patients) represented the leading cause of death. Only two patients with MPD died from fatal hemorrhage and one from acute leukemia. We conclude that survival is highest in ET and lowest in OMF. Both thromboembolic and hemorrhagic complications are frequent. However, thrombosis appears to be more often fatal than bleeding complications. Prophylaxis of thromboembolic events remains a key issue in the management of MPD.

Adolescent↗
PubMed2000

Treatment of solid tumors following allogeneic bone marrow transplantation.

Second solid tumors are well known late complications after bone marrow transplantation. Treatment strategies are ill defined. We retrospectively evaluated treatment and outcome in a single institution. From August 1974 to July 1996, six solid tumors were observed in five of 387 patients 2 to 13 years after BMT, corresponding to a probability of developing a second solid tumor of 9% (1-17%, 95 CI) at 15 years: these comprised endometrial carcinoma, carcinoma of the thyroid gland, cervical carcinoma, sarcoma of the small intestine, osteosarcoma of the tibia and ovarian carcinoma. All five patients were treated as intensively as they would be without a history of BMT. At last follow-up four of the five patients were alive and without signs of tumor. We postulate that second solid tumors after BMT should be treated as de novo tumors. Early detection based on consequent clinical follow-up of the transplant patients might explain the relatively good outcome.

Adenocarcinoma↗
PubMed2000

Bone marrow transplantation with unrelated donors: what is the probability of identifying an HLA-A/B/Cw/DRB1/B3/B5/DQB1-matched donor?

Patients transplanted with marrow from an HLA-ABDR serologically matched unrelated donor suffer from more post-transplant complications than those who are transplanted with marrow from an HLA-identical sibling. This is most likely due to either HLA-ABDR incompatibilities not resolved by standard techniques and/or HLA polymorphisms not tested for by routine tissue typing (HLA-Cw,-DQ). By resolving these incompatibilities by molecular techniques combined with the in vitro cytotoxic T lymphocyte precursor frequency (CTLpf) test, we have shown that a high degree of HLA compatibility is associated with increased patient survival. However, higher requirements for HLA matching decrease the number of available donors. We have estimated the probability of finding an HLA-A/B/Cw/DRB1/DRB3/DRB5/DQB1 compatible donor based on 104 consecutive unrelated bone marrow donor searches initiated between January 1995 and December 1997, with December 1998 as the endpoint. For 96 patients (92.3%), one or more ABDR-identical donors were listed in the Bone Marrow Donor Worldwide Registry (BMDW). After contacting the registries, we obtained at least one (mean, 5.36; range, 1-20; total, 461) blood sample for 86 patients. A highly compatible donor was identified for 33/86 patients (38.4%), after testing an average number of 4.5 donors/patients (range, 1-13). However, by accepting an HLA-DRB3 or -DQB1 or -Cw incompatibility, this number would be as high as 68.6%. Approximately half of the patients (n = 40) for whom a search had been initiated have been transplanted: 22 patients with a perfectly matched donor, 15 patients with an HLA-DRB3 or -DQB1 or -Cw mismatch and three with other mismatches. The average time needed to identify the most compatible donor was 4 months. Extremely long searches seemed to be less useful, because after testing the first seven, a more compatible donor was seldom found. These results show that even when requirements for compatibility are high, the chances of finding a donor remain considerably low.

Bone Marrow Transplantation↗
PubMed2000

Increased stem cell dose, as obtained using currently available technology, may not be sufficient for engraftment of haploidentical stem cell transplants.

The best strategies for haploidentical stem cell transplants are not known. We used a standard myeloablative pretransplant conditioning regimen (30 mg/kg VP-16, 120 mg/kg cyclophosphamide, and 12 Gy of TBI in six fractions), an increased peripheral stem cell dose of > 10 x 10(6) CD34+ cells/kg, T cell depletion (with CD34+ cell selection and CD4/CD8 depletion steps) to < 1 x 10(5) CD3+ cells/kg and cyclosporine post transplant. Ten patients (7M/3F, median age 11 (3-33) years) with high-risk leukemia (AML in 4, MDS in 2, CML in 1 and T-ALL in 3) received a hemopoietic stem cell transplant (HSCT) from a haploidentical father or sibling. The median number of CD34+ cells was 12.9 (9.5-45.7) x 10(6) cells/kg; median number of CD3+ cells was 0.41 (0.09-1.89) x 10(5) CD3+ cells/kg. All patients initially achieved 0.5 x 10(9)/l neutrophils at a median 12 (10-21) days. Graft failure in two consecutive patients out of four on the original protocol led to a modification adding ATG pretransplant and OKT3 post transplant. Graft failure was observed in one out of six subsequent patients. Acute GVHD > or = grade II was observed in three patients. Three of 10 patients are alive in CR at > 24 and >3 (2) months after transplant. Seven patients died: four of transplant related complications and three of relapse. Increased stem cell dose (> or = 10 x 10(6) CD34+ cells/kg) as obtained using currently available technology may not be sufficient to ensure stable engraftment in patients with high-risk leukemia using standard myeloablative conditioning regimens.

Graft vs Host Disease↗
PubMed2000

HLA-DR4 is associated with a diminished risk of the development of chronic myeloid leukemia (CML). Chronic Leukemia Working Party of the European Blood and Marrow Transplant Registry.

CML is characterized by the chromosomal translocation t(9;22) (q34;q11) resulting in the chimeric bcr-abl oncogene that encodes P210 fusion proteins with novel amino acid sequences in the breakpoint region. If these peptides derived from P210 are presented by HLA molecules on the cell membrane of leukemic cells an immunological response may occur. Recent studies using synthetic peptides identical to the bcr-abl fusion region revealed that some peptides are capable of binding to the class I molecules HLA-A2,-A3,-A11 and -B8 and the class II molecules HLA-DR1, -DR2, -DR3, -DR4 and -DR11. Moreover T cell responses have been induced against bcr-abl-derived synthetic peptides bound to some of these HLA molecules. For HLA class I, we have previously shown that individuals expressing HLA-A3 and -B8 have a diminished risk of development of CML. To assess a similar protective effect of class II molecules we performed a large multi-center study. This study compared the frequencies of HLA-DR1, -DR2, -DR3, -DR4 and -DR11 of patients with CML from the database of the EBMT (n = 1462) with unaffected individuals from the registry of Bone Marrow Donors Worldwide (n = 500 596). Patients and controls were matched per country. This analysis yielded significantly lower odds ratios (ORs) of 0.86 (95% CI 0.75-0.98) for HLA-DR3 and of 0.80 (95% CI 0.71-0.89) for HLA-DR4. The OR was 0.91 (95% CI 0.80-1.04) for HLA-DR1, 1.05 (95% CI 0.94-1.18) for HLA-DR2 and 0.87 (95% CI 0.74-1.01) for HLA-DR11. To assess a possible effect of the linkage disequilibrium between HLA-B8 and HLA-DR3 we found that coexpression of HLA-B8 and HLA-DR3 gave an OR of 0.84 (95% CI 0.72-0.98), whereas HLA-DR3 positive/HLA-B8 negative individuals showed an OR of 1.02 (95% CI 0.84-1.24). This means that the protective effect of HLA-DR3 of the development of CML was probably caused by its linkage disequilibrium with HLA-B8. In contrast, as there is no linkage disequilibrium of HLA-DR4 with HLA-A3 or HLA-B8, the results indicate that HLA-DR4 expression itself is associated with a diminished incidence of CML possibly by the presentation of bcr-abl breakpoint peptides in these HLA molecules on the membrane of the leukemic cells.

Bone Marrow Transplantation↗
PubMed2000

Hematopoietic stem cell transplantation in Europe 1998.

INTRODUCTION: Transplantation of hematopoietic stem cells from blood or bone marrow has become accepted therapy for many diseases. Numbers of transplants have increased significantly and stem cell source, donor type and indications have changed during this decade. Information on these changes is essential for interpretation of current data, patient counseling and health care planning. PATIENTS AND METHODS: Since 1990, members of the European Group for Blood and Marrow Transplantation and teams known to perform blood or marrow transplants have been invited annually to report their transplant numbers by indication, donor type and stem cell source. Data from these surveys have been used to present data for 1998, to assess current status and to give numbers of transplants per participating country, coefficients of variation between countries for individual indications and changes in indication, stem cell source and donor type over the past decade. RESULTS: In 1998, a total of 20 892 transplants were performed by 528 teams in 31 European countries. Of these transplants 18 400 were first transplants, 5308 (29%) were allogenic, and 13 092 (71%) were autologous. Of the autologous transplants, 809 (6%) were bone marrow derived, and 12 283 (94%) were from peripheral blood stems cells. Of the allogeneic transplants, 3372 (64%) were bone marrow derived, and 1936 (36%) were peripheral blood stem cell transplants. In 1990, the respective figures were 2137 allogeneic (50%) and 2097 (50%) autologous transplants, all exclusively bone marrow derived. Main indications in 1998 were leukemias with 6015 transplants (33%), 68% thereof allogeneic transplants; lymphomas with 7492 transplants (41%), 94% thereof autologous transplants; solid tumors with 4025 transplants (22%), 99% thereof autologous transplants; non-malignant disorders with 868 transplants (5%), 80% thereof allogeneic transplants. Absolute numbers of transplants per year did increase from 4234 in 1990 to 20 892 in 1998. Increase is higher for autologous, than for allogeneic transplants. There were differences in absolute or relative increase over time for individual indications. Transplant rates per number of inhabitants varied between countries, ranging from 0 to >500 total transplants per 10 million inhabitants with a clear correlation between number of teams and transplants per 10 million inhabitants (r=0.61, P<0.001). The least variation between countries was observed for acute leukemias, chronic myeloid leukemia and severe aplastic anemia in allogeneic transplants, for Hodgkin's disease and non-Hodgkin's lymphoma in autologous transplants. CONCLUSION: These data reflect the current status of blood and marrow transplantation in Europe. They show the continuing increase in utilization, highlight the change from bone marrow to blood as stem cell source and give an objective assessment on presence or absence of trends.

Anemia, Aplastic↗
PubMed2000

Dose-finding study of valspodar (PSC 833) with daunorubicin and cytarabine to reverse multidrug resistance in elderly patients with previously untreated acute myeloid leukemia.

INTRODUCTION: This trial was designed to determine the maximum tolerated dose of intravenous daunorubicin (DNR) in combination with valspodar and to test the feasibility of P-glycoprotein modulation using valspodar in elderly patients with previously untreated acute myelogenous leukemia receiving standard induction chemotherapy. METHODS: Patients > or =60 years of age with previously untreated AML received valspodar (10 mg/kg/24 h by continuous intravenous infusion [CIV] on days 1-4 with a 2-mg/kg loading dose on day 1) in conjunction with two cycles of induction chemotherapy consisting of cytarabine (200 mg/m(2) CIV on days 1-7), and DNR (35 mg/m(2) [cohort 1] or 45 mg/m(2) [cohort 2] on days 1-3, intravenous bolus). Patients were assessed for dose-limiting toxicities (DLT), response rate, event-free and overall survival, and pharmacokinetics of valspodar and DNR. RESULTS: Valspodar was well tolerated at the lower DNR dose level (ie, 35 mg/m(2)) resulting in a 21% rate of DLT and only three toxic deaths. Treatment-related mortality was unacceptably high at the 45 mg/m(2) DNR dose level. The complete response rate was 49% overall and similar in both cohorts. The median overall survival of patients was 333 days in cohort 1 compared to 98 days in cohort 2. At baseline, 70% of assessable patients were P-glycoprotein positive. CONCLUSION: Substantial inhibition of P-glycoprotein activity can be achieved in this patient population at clinically tolerable doses of valspodar and DNR. The maximum tolerated dose of DNR was established as 35 mg/m(2). This regimen is being further evaluated in phase III trials.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Natural killer-type receptors for HLA class I antigens are clonally expressed in lymphoproliferative disorders of natural killer and T-cell type.

In recent years, natural killer (NK) cells, as well as subpopulations of T cells, have been found to express diverse NK receptors (NKRs) for HLA class I molecules. We have characterized NKR phenotypes in lymphoproliferative disorders of NK or T-cell type. Peripheral blood of patients with lymphoproliferative disorders (n = 9) was analysed by multiparametric immunofluorescence flow cytometry with eight different antibodies against NKRs. Abnormal neoplastic cell populations from different types of NK or T-cell lymphoproliferative disorders lacked diversity in their NKR repertoires, i.e. all or none of the abnormal cells expressed individual NKRs and this expression occurred at single levels of intensity. This pattern of expression was specific for lymphoproliferative disorders as these resticted NKR repertoires were not found either in healthy donors (n = 9) or in patients with viral or autoimmune disease (n = 5). We conclude that NKRs are clonally expressed in lymphoproliferative disorders of NK or T-cell origin. NKR repertoires may represent a novel tool in diagnosing clonal disorders of NK and T-cell type.

CD3 Complex↗
PubMed2000

Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

Allogeneic stem cell transplantation from an HLA-identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors. Alternative stem cell sources have been used more recently, such as unrelated donors, non-identical family members or autologous transplants. This analysis of 1378 transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) addresses the outcome of the varying procedures according to the known risk factors. The estimated disease-free survival (DFS) and estimated relapse risk at 3 years were both 36% for 885 patients transplanted with stem cells from matched siblings. In the multivariate analysis, age and stage of disease had independent prognostic significance for DFS, survival and treatment-related mortality. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for the 198 patients with voluntary unrelated donors, 28% for the 91 patients with alternative family donors and 33% for the 126 patients autografted in first complete remission. The non-relapse mortality was 58% for patients with unrelated donors, 66% for patients with non-identical family donors and 25% for autografted patients. The relapse rate of 18% was relatively low for patients with non-identical family donors, 41% for patients with unrelated donors and 55% for patients treated with autologous stem cell transplantation. Both allogeneic and autologous stem cell transplantation have emerged as treatment options for patients with myelodysplastic syndromes. Transplantation with an HLA-identical sibling donor is the preferred treatment option. Patients without an HLA-identical sibling donor may be treated with either autologous stem cell transplantation or an alternative donor transplantation. Patients younger than 20 years may be treated with an unrelated donor transplantation. Patients older than 40 years, and probably also patients between 20 and 40 years, may benefit most from an autologous stem cell transplantation.

Actuarial Analysis↗
PubMed2000

Preterm birth and the availability of cord blood for HPC transplantation.

BACKGROUND: Cord blood from deliveries at term can be used for HPC transplantation. The objective of this study was to determine the amounts of cord blood nucleated cells (NCs) and HPCs that were collectable from preterm deliveries. STUDY DESIGN AND METHODS: Cord blood collected from preterm deliveries between 22 and 36 weeks of gestation was compared with regard to volume, NC count (/mL), CD34+ cell count (/mL), and the NC and CD34+ cell counts per cord blood sample and at different gestational ages. RESULTS: A correlation was found between gestational age and NC count (r = 0.52, p<0.001), and an inverse relation was found between gestational age and CD34+ cell count (r = - 0.68, p<0.001). The CD34+ cell count per cord blood sample was independent of gestational age (r = - 0.13, p = NS), and no significant difference between early (22-32 week) and late (33-36 week) preterm deliveries was found (p = 0.870). Comparison with published data from cord blood transplantations revealed that up to one-third of preterm samples contained at least as many NCs (or CD34+ cells) as the median cell dose transplanted (calculated for the median recipient weight) in the respective study. Furthermore, 77 percent of all preterm samples contained at least 1 x 10(7) NCs (and 42% at least 1 x 10(5) CD34+ cells) per kg for transplantation in a recipient of 20-kg body weight, which corresponds to the lower threshold of cells per kg in the graft recommended by Eurocord. CONCLUSION: Preterm delivery should not be a reason to exclude cord blood collection if allogeneic cord blood transplantation in a sibling is planned.

Blood Donors↗
PubMed2000

Umbilical cord blood collection before placental delivery during cesarean delivery increases cord blood volume and nucleated cell number available for transplantation.

OBJECTIVE: We sought to determine whether umbilical cord blood collection during cesarean delivery can be improved by collecting cord blood before delivery of the placenta. STUDY DESIGN: Patients undergoing cesarean delivery were randomly assigned to cord blood collection before or after placental delivery. Closed sterile collection systems were used for blood sampling. Cord blood characteristics and maternal outcome parameters were compared between the 2 groups. RESULTS: A total number of 40 patients were available for analysis. No differences in maternal and neonatal characteristics were found. A larger amount of cord blood volume (mean +/- SEM, 93 +/- 7.5 vs 66 +/- 6.6 mL; P =.013) and total nucleated cell number (11.1 +/- 1.2 vs 7.4 +/- 0.8 x 10(8) cells; P =.026) was obtained in the samples collected before compared with those collected after placental delivery. Similarly, there was a trend toward higher total CD34(+) cell number in samples collected in situ (30.0 +/- 6.0 vs 17.4 +/- 2.4 x 10(5) cells; P =.076). Estimated intraoperative blood loss, difference between prepartum and postpartum hemoglobin values, operating time, and puerperal infection rates were similar in both groups. CONCLUSION: If a cesarean delivery is performed, cord blood sampling is more efficacious if performed before delivery of the placenta. This collection method seems beneficial and safe and might therefore be preferably used for related, as well as unrelated, cord blood stem cell banking and transplantation.

Antigens, CD34↗
PubMed2000

C-reactive protein and fever in neutropenic patients.

The predictive value of daily C-reactive protein (CRP) monitoring to distinguish causes of fever in neutropenic patients was studied retrospectively. A total of 143 fever episodes during 113 consecutive hospitalizations were studied in 71 patients who had been referred for chemotherapy or haemopoietic stem cell transplantation (HSCT). There were, on average, 1.3 fever episodes per hospital stay, attributed to: infection (55, 27 invasive bacterial, 5 fungal, 3 viral and 20 probable infections); acute graft vs host disease (GvHD) (20); drugs (22); transfusions (7); and not attributable (39). 130 (91%) fever episodes were accompanied by a rise in CRP, 6 (4%) episodes were fatal. Maximal CRP levels (CRPmax) and maximal temperature (Tmax) were higher in invasive bacterial infections than in aGvHD and higher in aGvHD than in drug- or transfusion-related fever (p < 0.0001). Temperature and CRP rose in parallel. A total of 16 patients developed grade II-IV aGvHD by day 11 (9-21) (median, range) after allogeneic HSCT. Acute GvHD was preceded by fever for 3 d (1-7), and by CRP increase for 5 d (0-15) (p < 0.0001). CRP monitoring may be useful to distinguish between causes of fever. Very high CRP levels tend to be associated with invasive bacterial infections. CRP is not an early warning sign. An increase in CRP and fever may precede other clinical manifestations of aGvHD.

Adolescent↗
PubMed1999

Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure.

The influence of interferon-alpha (IFN) pretreatment on the outcome after allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) is controversial. One goal of the German randomized CML Studies I and II, which compare IFN +/- chemotherapy versus chemotherapy alone, was the analysis of whether treatment with IFN as compared to chemotherapy had an influence on the outcome after BMT. One hundred ninety-seven (23%) of 856 Ph/bcr-abl-positive CML patients were transplanted. One hundred fifty-two patients transplanted in first chronic phase were analyzed: 86 had received IFN, 46 hydroxyurea, and 20 busulfan. Forty-eight patients (32%) had received transplants from unrelated donors. Median observation time after BMT was 4.7 (0.7 to 13.5) years. IFN and chemotherapy cohorts were compared with regard to transplantation risks, duration of treatments, interval from discontinuation of pretransplant treatment to BMT, conditioning therapy, graft-versus-host disease prophylaxis and risk profiles at diagnosis and transplantation, and IFN cohorts also with regard to performance and resistance to IFN. Outcome of patients receiving related or unrelated transplants pretreated with IFN, hydroxyurea, or busulfan was not significantly different. Five-year survival after transplantation was 58% for all patients (57% for IFN, 60% for hydroxyurea and busulfan patients). The outcome within the IFN group was not different by duration of prior IFN therapy more or less than 5 months, 1 year, or 2 years. In contrast, a different impact was observed in IFN-pretreated patients depending on the time of discontinuation of IFN before transplantation. Five-year survival was 46% for the 50 patients who received IFN within the last 90 days before BMT and 71% for the 36 patients who did not (P =.0057). Total IFN dosage had no impact on survival after BMT. We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN.

Adolescent↗
PubMed1999

HLA-B8 and HLA-A3 coexpressed with HLA-B8 are associated with a reduced risk of the development of chronic myeloid leukemia. The Chronic Leukemia Working Party of the EBMT.

Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation t(9;22) resulting in the chimeric bcr-abl oncogene that encodes the P210 fusion protein, which contains a unique amino acid sequence. If peptides derived from the leukemia-specific part of P210 are expressed in HLA molecules on the cell membrane of leukemic cells, an immunological response may occur. Recent studies using synthetic peptides identical to the bcr-abl fusion region showed that some peptides are capable of binding to HLA-A3, -A11, and -B8 molecules. Cytotoxic T-cell responses have been induced against bcr-abl-derived synthetic peptides bound to HLA-A3 and -B8. We hypothesized that if antigen processing of the P210 fusion protein leads to presentation of peptides from the fusion region by major histocompatibility complex (MHC) molecules in vivo, this may be reflected in a diminished incidence of CML in individuals expressing HLA-A3, -A11, or -B8. Consequently, lower frequencies of these antigens would be expected in patients with CML compared with unaffected individuals. A case-control study and a meta-analysis were performed to test this hypothesis. The multicenter case-control study compared patients with CML from the data base of the European Group for Blood and Marrow Transplantation (EBMT) with unaffected individuals from the registry of Bone Marrow Donors Worldwide. Patients and controls were matched per country. The meta-analysis consisted of five studies reported in the literature. The multicenter case-control study consisting of 1,899 patients and 512, 363 bone marrow donors as controls yielded odds ratios (ORs) of 0.90 (95% confidence interval [CI], 0.80 to 1.00) for HLA-A3, 1.16 (95% CI, 1.02 to 1.33) for HLA-A11, and an OR of 0.73 (95% CI, 0.65 to 0. 82) for HLA-B8. Coexpression of HLA-A3 and HLA-B8 gave an OR of 0.51 (95% CI, 0.40 to 0.67). This can be translated in a protective effect of 27% for HLA-B8, 10% for HLA-A3, and 49% protection for the combination of HLA-A3 and HLA-B8. The meta-analysis comprising 463 CML patients and 4,912 controls showed a 29% risk reduction for individuals expressing HLA-B8 (OR of 0.71; 95% CI, 0.52 to 0.97), but an OR of 1.19 (95% CI, 0.90 to 1.56) for HLA-A3 and an OR of 1. 09 (95% CI, 0.80 to 1.50) for HLA-A11. In conclusion, these results indicate that HLA-B8 expression, in particular when HLA-A3 is coexpressed, is associated with a diminished incidence of CML. A biological mechanism may be that presentation of bcr-abl breakpoint peptides in these HLA molecules can induce a protective immune response.

Case-Control Studies↗
PubMed1999

Sequencing of two HLA-A blank alleles: implications in unrelated bone marrow donor matching.

BACKGROUND: DNA-based methods can type for HLA antigens with no or very low cell surface expression. The role of such serological blank antigens in bone marrow donor selection is unknown. METHODS: HLA-A serological blank antigens detected in two leukemic patients were cloned and sequenced from genomic DNA. mRNA expression and exon 3 splicing were determined by reverse transcriptase-polymerase chain reaction (PCR). RESULTS: Two patients typed A2/x and A3/x by serology were revealed to be A*01/A*0201 and A*03/A*24 by DNA typing. The HLA-A*O1 blank antigen was identified as the A*0104N allele with a C insertion in exon 4, which results in a stop codon. The HLA-A*24 blank antigen was identified as the A*2402102L allele characterized by a mutation in intron 2 leading to impaired splicing of mainly exon 3. As a consequence, functional A24 mRNA was reduced to less than 5% compared with the other HLA-A allele. For both patients, a search for an unrelated donor was initiated on the basis of the functional absence of the serologically blank allele. The second patient with the A*24 blank antigen could undergo transplantation with marrow from a "fully A/B/C/DRB1/DRB5/DQB1-compatible" donor, homozygous for the A antigen. Donor T cells did not react against the patient in a pretransplantation cytotoxic T lymphocyte precursor frequency test known to detect all class I incompatibilities. However, despite this functional pretransplantation compatibility, the patient died 44 days after bone marrow transplantation, suffering from graft-versus-host disease grade IV. The presence of potentially functional A*2402 mRNA could be demonstrated by reverse transcriptase-PCR and sequencing: 50% of the A24 mRNA molecules were estimated to contain exon 3 with a correct splice site. CONCLUSIONS: These findings show that serological blank antigens with low mRNA expression might still be recognized after bone marrow transplantation. The determination of such alleles by molecular methods and the assessment of mRNA expression should therefore be included in the unrelated bone marrow donor search protocol.

Alleles↗