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ABSTRACT: We describe the rare occurrence of a granulomatous pneumonitis seen in a patient following allogeneic bone marrow transplantation. Interestingly sarcoidosis was diagnosed in the marrow donor less than a year after donating his bone marrow.
Bone Marrow Transplantation 10/2001; 28(6):627-30. · 3.75 Impact Factor
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H J Deeg,
I D Amylon,
R E Harris,
R Collins, P G Beatty,
S Feig,
N Ramsay,
M Territo,
S P Khan,
D Pamphilon,
J F Leis,
S Burdach,
C Anasetti,
R Hackman,
B Storer,
B Mueller
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ABSTRACT: Patients with aplastic anemia who do not have suitably HLA-matched, related donors generally receive immunosuppressive treatment as first-line therapy and are considered for transplantation from an unrelated donor only if they fail to respond to immunosuppressive treatment. In this setting, rates of transplantation-related morbidity and mortality have been high. We conducted a prospective study to determine the minimal dose of total body irradiation (TBI) sufficient to achieve sustained engraftment when it is used in combination with 3 cycles of 30 mg/kg of antithymocyte globulin (ATG) and 4 cycles of 50 mg/kg of cyclophosphamide (CY). We also wanted to determine the tolerability and toxicity of the regimen. The starting dosage of TBI was 3 x 200 cGy given over 2 days following CY/ATG. The TBI dose was to be escalated in increments of 200 cGy if graft failure occurred in the absence of prohibitive toxicity, and de-escalated for toxicity in the absence of graft failure. Twenty-one female and 29 male patients aged 1.3 to 46.5 years (median age, 14.4 years) underwent transplantation at 14 medical centers. The time interval from diagnosis to transplantation was 2.8 to 264 months (median, 14.5 months). All patients had been transfused multiple times and all had received 1 to 11 courses (median, 4 courses) of immunosuppressive treatment and other modalities of treatment. In 38 cases, the donors were HLA-A, -B and -DR phenotypically matched with the patients, and, in 12 cases, the donor phenotype differed from that of the recipient by 1 HLA antigen. Recipients of mismatched transplants were considered separately for TBI dose modification, and this study is still ongoing. Seven patients did not tolerate ATG and were prepared with 6 x 200 cGy of TBI plus 120 mg/kg of CY. Of the HLA-matched recipients prepared with CY/ATG/TBI, all 20 who received 3 x 200 or 2 x 200 cGy of TBI achieved engraftment, and 10 are alive. Of the 13 patients who received 1 x 200 cGy of TBI, 1 failed to engraft, and 8 are alive. Each of 10 patients who received an HLA-nonidentical transplant achieved engraftment, and 3 of 6 who were given 3 x 200 cGy of TBI, and 4 of 4 who were given 2 x 200 cGy are alive. Pulmonary toxicity occurred in 8 of 30 patients who were given 3 x 200 or 2 x 200 cGy of TBI concurrently with ATG and CY at 200 mg/kg, and in 2 of 13 patients who received 1 x 200 cGy of TBI, a pattern that suggests a decrease in toxicity with TBI dose de-escalation. Overall, the highest probability of survival (73%) was observed among patients who underwent transplantation within 1 year of diagnosis, compared with patients who underwent transplantation after a longer period of disease. In addition, younger patients (aged < or = 20 years) were more likely to survive than older patients (aged > 20 years). Thus, for patients with an HLA-matched, unrelated donor, a TBI dose of 200 cGy (in combination with CY/ATG) was sufficient to allow for engraftment without inducing prohibitive toxicity. As in previous studies, patient age and pretransplantation disease duration remain important prognostic factors.
Biology of Blood and Marrow Transplantation 01/2001; 7(4):208-15. · 3.87 Impact Factor
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ABSTRACT: Given recent improvements in the technology of transplantation and histocompatibility testing, it is now possible to contemplate using related or unrelated allogeneic hematologic stem cell donors with high degrees of HLA disparity. This paper is a follow-up of an earlier publication on the probability of finding a matched donor (Transplantation 60:778-783, 1995) and addresses the probability of finding a partially mismatched donor. Assuming that a four of six antigen HLA-A, -B, -DR match is acceptable, it is possible to find unrelated donors for patients of any race from a putative registry with fewer than 10,000 potential donors. Further, storing cord blood from newborns in families with a known genetic disease would yield an acceptable future stem cell transplant product in nearly 40% of cases. These results show the potential impact of cord blood donors and emphasize the importance of improvements in transplantation using partially mismatched donors.
Human Immunology 09/2000; 61(8):834-40. · 2.84 Impact Factor
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ABSTRACT: It is possible that post-transplant relapse in patients with breast cancer may result, in part, from residual tumor in the autologous PBSC product. It is unclear from the literature what effect residual breast tumor cells have on clinical outcome and whether purging tumor cells would be beneficial. We hypothesized that lack of standardization of assays for detection of residual breast tumor may be responsible for the inconclusive clinical data.
We compared two assays routinely for detection of cytokeratin (CK)-positive cells in stem-cell grafts, immunohistochemistry (IHC) and flow cytometry (FCM). The patient population consisted of individuals with breast cancer, non-epithelial cell-derived tumors and normal donors. A rigorous statistical model was developed for evaluation of the data.
We found that the IHC assay out-performed the FCM assay. Importantly, both assays detected CK-positive cells in PBSC collections of patients with non-epithelial cell-derived tumors and in normal donors. No distinguishing morphological characteristics could be identified to differentiate potentially malignant from non-malignant CK-positive cells. Due to the inability to distinguish true positive from false positive results, we developed a statistical model to establish a quantitative threshold to discriminate positive from negative samples. Among the patients tested, no clinical outcome differences were detected, regardless of where the threshold of CK-positive cells was set.
We conclude the more stringent criteria and more specific markers, rather than the presence or absence of CK-positive cells, need to be established to determine the clinical significance of minimal residual disease in autologous breast-cancer
Cytotherapy 01/1999; 1(5):389-9. · 3.63 Impact Factor
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ABSTRACT: The graft-versus-host disease (GVHD) seen in human leukocyte antigen (HLA)-matched sibling bone marrow transplants is by definition due to the "minor" histocompatibility antigens (mHAs) encoded outside the HLA region of human chromosome 6. Few of these antigens have been characterized in humans, and in general the locations of the encoding loci are unknown. Genetic experiments performed in mice have identified many mHAs, but only a few genes have been identified. Using T lymphocyte clones reactive with specific mHAs, combined with genetic linkage analysis, we identified two distinct loci in a single patient, each locus encoding an antigen presented to a T cell clone by HLA-B7. The technique used in this study should allow a rough enumeration of the number of mHAs in humans that are capable of eliciting T cell responses in vivo. Whether these T cell responses correlate with clinical GVHD is not yet clear.
Experimental Hematology 10/1998; 26(10):976-81. · 2.90 Impact Factor
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P G Beatty
Experimental Hematology 11/1997; 25(11):1195-208. · 2.90 Impact Factor
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ABSTRACT: As of May 1, 1995, the National Marrow Donor Program had a donor registry consisting of over 1.35 million HLA-typed volunteers recruited from most major cities and states in the United States. This registry represents the largest single HLA-typed pool of normal individuals in the world.
We analyzed the HLA-A, -B, -DR locus phenotypes of the National Marrow Donor Program donors in order to estimate gene and haplotype frequencies for major racial groups of the United States: Caucasian American, Asian American, African American, Latin American, and Native American. The large size of the database allowed us to calculate the frequencies of relatively rare antigens and haplotypes with more accuracy than previous studies.
We observed 89,522 distinguishable HLA-A, -B phenotypes in 1,351,260 HLA-A, -B-typed donors and 302,867 distinguishable HLA-A, -B, -DR phenotypes in 406,503 HLA-A, -B, -DR-typed donors. Gene and haplotype frequencies differed remarkably among the five racial groups, with African Americans and Asian Americans having a large number of haplotypes that were specific to their racial groups, whereas Caucasian Americans, Latin Americans, and Native Americans shared a number of common haplotypes.
These data represent an important resource for investigators in the fields of transplantation and population genetics. The gene and haplotype frequencies can be used to aid clinicians in advising patients about the probability of finding a match within a specific ethnic group, or to determine donor recruitment goals and strategies. The information is also a valuable resource for individuals who are interested in population genetics, selection and evolution of polymorphic human genes, and HLA-disease association.
Transplantation 11/1997; 64(7):1017-27. · 4.00 Impact Factor
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ABSTRACT: Immunosuppressive therapy is commonly used in the management of autoimmune disorders. As marrow-derived lymphocytes appear to play a key role in these diseases, lymphoid ablation followed by replacement with autologous or allogeneic stem cells may be a therapeutic option. We report a 5-year-old boy with severe Evans syndrome which consists of immune thrombocytopenia and Coombs-positive hemolytic anemia. He was rendered into complete remission with marrow ablation followed by rescue with an HLA-identical sibling cord blood transplant. He unexpectedly died 9 months following transplant from acute hepatic failure of unknown etiology.
Bone Marrow Transplantation 10/1997; 20(5):427-9. · 3.75 Impact Factor
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ABSTRACT: In human allogeneic bone marrow transplantation, graft-vs-host disease and graft rejection can occur even if the patient and donor are genotypically matched by inheritance for HLA. By definition, these allogeneic reactions are due to disparities in minor histocompatibility Ags (minor HAs). Minor HAs are presented to T lymphocytes as peptides bound to HLA molecules, and appear to be encoded by genes throughout the genome. We derived T lymphocyte clones from the PBL of a patient suffering from chronic graft-vs-host disease after bone marrow transplant from his HLA-identical sister. Clones reactive against minor HAs were selected on the basis of reactivity with pretransplant patient cells, and absence of reactivity with donor cells. One clone (MD2) was found to use HLA-B7 as a restricting element. A plasmid vector (pHEBo) containing cDNA encoding the HLA-B7 molecule was transfected into lymphoblastoid cell lines derived from two large families that previously had been saturation mapped for hundreds of polymorphic loci. When clone MD2 was tested against family K1362, it was found to be reactive with three of four grandparents, both parents, and eight of eleven offspring. The same clone was tested with family K1331, with two of three tested grandparents reactive, one of two parents, and nine of eleven offspring. Computer analysis showed that both family segregation patterns linked to an area on the long arm of chromosome 22, localizing the gene encoding this minor HA near the platelet-derived growth factor-beta and IL-2Rbeta genes.
The Journal of Immunology 01/1997; 157(12):5448-54. · 5.79 Impact Factor
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ABSTRACT: Approximately 65% of the patients requiring bone marrow transplantation do not have an HLA-A, -B, -DR identical sibling and therefore need to find a phenotypically matched unrelated donor. As of June 30, 1996, the National Marrow Donor Program maintains a registry of 2.31 million volunteer donors, 35% of whom are fully typed for HLA-A, -B, -DR loci. Because a majority of the donors has not been DR typed, a patient who does not find a complete match at the time of the preliminary search may elect to prospectively DR type A, B matched and A, B one-antigen mismatched donors. An efficient strategy is therefore needed for determining the likelihood that an appropriate donor exists and for deciding which of the donors that have not yet been DR typed should be tested for DR matching with the candidate. We developed a mathematical algorithm and computer program to facilitate the search for a suitable donor by donor race and phenotype. The program provides information on the likelihood of 1) finding at least one HLA-A, -B, -DR phenotypically matched donor, 2) the likelihood of finding at least one DR match among m A, B matched donors who have not yet been DR typed, and 3) the likelihood of an A, B one antigen mismatched donor of a specific phenotype being a DR match with the patient. The mathematical models underlying the program are based on basic population genetics theory and utilize HLA-A, -B, DR haplotype frequencies derived from the NMDP registry. The results of the validation study show that the prediction is highly accurate at the level of broad antigens. The algorithm and program have the potential to assist patients and physicians in optimizing their decisions regarding clinical management and resource allocation on the process of searching for a suitable unrelated bone marrow donor.
Biology of Blood and Marrow Transplantation 11/1996; 2(3):134-44. · 3.87 Impact Factor
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ABSTRACT: As successful organ or marrow transplantation correlates with the degree of HLA-compatibility between patient and donor, registries have been developed to facilitate matching. However, racial minority groups have a lower chance of finding a match. We evaluate the impact of the biology of racial genetic polymorphism upon the probability of finding an HLA match for patients of different racial groups. The National Marrow Donor Program has compiled the HLA types of 20,449 patients and 1,625,159 potential volunteer donors. These HLA types were used to estimate the probability of finding an HLA-matched donor for patients of different racial groups. We estimated the HLA haplotype frequencies for different races, and then determined the probability of finding matched donors, given several hypothetical registry sizes. We confirmed that patients of minority races searching the current National Marrow Donor Program registry have low probabilities of finding matches. This was only partly due to the smaller number of donors from these racial minorities, as the observation persisted even when hypothetical donor registry sizes were the same for all racial groups. We demonstrate that African-Americans are more polymorphic with respect to HLA, and are hence less likely to find donors at any given registry size. An increase in the recruitment of minority racial groups for organ and marrow donors will only partially alleviate the problem of equal access to HLA matches for patients belonging to racial minority groups. It will therefore be important to attempt to improve methods for transplantation using HLA-mismatched donors.
Transplantation 11/1995; 60(8):778-83. · 4.00 Impact Factor
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ABSTRACT: A prospective study of the value of surveillance cultures was performed in a bone marrow transplant (BMT) unit among 48 consecutive patients. All patients were admitted to laminar airflow or high-efficiency particulate air (HEPA) filtered rooms, maintained on reduced microbial diets and received oral non-absorbable antibiotics. With the onset of neutropenia, all patients received imipenem/cilastatin and 17 patients received low-dose amphotericen B 0.1 mg/kg/day. Pre-transplant and weekly post-transplant cultures of the stool, throat and urine were obtained on all patients. Nasal and vaginal cultures were performed on 26 patients. Sixteen patients developed 23 documented infections. The sensitivity of surveillance cultures for all infections was 38%, specificity 25%, positive predictive value 20% and negative predictive value 44%. When stratified by organisms, the sensitivity, specificity, positive predictive value and negative value were: Gram positive infections, 33%, 36%, 11%, 70%, Gram negative infections, 17%, 88%, 17%, 88%; fungal infections 37%, 50%, 11%, 75%; and Candida albicans, 100%, 57%, 14%, 100%. These data suggest that surveillance cultures may be useful to exclude C. albicans infections but are of limited value in predicting other types of infections in recipients of BMT.
Bone Marrow Transplantation 04/1995; 15(3):469-73. · 3.75 Impact Factor
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ABSTRACT: As of January 1996, more than 4,000 marrow transplants have been performed using unrelated donors provided by the NMDP. With more than 1.9 million donors listed in the registry, over 70% of patients now find an HLA-A, -B, -DR phenotypic match at the initial search. The success rate is dramatically lower for patients in racial minorities. For instance, African-Americans find donors only 34% of the time on the initial search. Analysis of the first 462 transplants, showed disease-free survival rates at 2 years to be approximately 40% in low-risk patients, and 20% in high-risk patients. A more recent analysis in single centers shows an increase in the probabilities to 60-70%. This increase in success is likely related to a number of factors, including the ability to control complications, such as GVHD, plus an increase in accuracy of HLA typing primarily based on DNA-based methodology.
Clinical transplants 02/1995;
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ABSTRACT: To evaluate the efficacy of prophylactic low-dose amphotericin B (0.1 mg/kg per day) (LDA) in preventing fungal infections in patients who have had a bone marrow transplant (BMT).
Double-blind, randomized, controlled trial in which patients undergoing bone marrow transplantation received intravenous LDA or similar-appearing placebo from the onset of neutropenia until the absolute neutrophil count remained > 0.5 x 10(9)/L, or until high-dose amphotericin B was initiated. Weekly surveillance cultures were obtained from all patients.
Five of 18 patients (28%) randomized to placebo developed documented systemic fungal infections within the first 30 days after transplantation, compared to none of 17 patients who received LDA (P = 0.045). LDA recipients received fewer days of high-dose amphotericin B (P = 0.04) and fewer days of antibiotics (P = 0.008). There were trends towards fewer days of hospitalization (P = 0.14) and improved survival (P = 0.08); these differences were statistically significant among recipients of allogeneic BMT. No adverse effects occurred with LDA therapy.
LDA appears to be safe and to reduce early systemic fungal infections in BMT recipients. Improved survival was observed among LDA recipients, but this was not directly attributable to the prevention of fungal infection.
The American Journal of Medicine 12/1994; 97(6):509-14. · 5.43 Impact Factor
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P G Beatty
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ABSTRACT: It is now clear that it is not necessary to use an HLA genotypically identical donor to have a successful marrow transplant. However, it is equally clear that the likelihood of complications increases with each increment in histoincompatibility. The implication is that histocompatibility testing must be of the highest possible precision to choose the optimal donor, and to predict the risk of adverse alloreactivity. Most clinicians would seriously consider transplantation from a one locus-mismatched relative or an HLA-matched unrelated donor in virtually any situation in which transplantation from a matched sibling would be felt to be the standard of care. More thought would need to go into transplantation from a two or three locus-mismatched relative or a mismatched unrelated donor.
Transfusion Medicine Reviews 02/1994; 8(1):45-58. · 3.58 Impact Factor
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ABSTRACT: The nature and incidence of life-threatening or fatal toxicity after marrow transplantation were analyzed in 52 patients who received HLA-A, B, DR, Dw-phenotypically identical marrow transplants from unrelated volunteer donors (URD). An age and disease-matched cohort of 104 patients transplanted from HLA-genotypically identical siblings was used as a comparative group. The actuarial probability of grade 3 or 4 regimen-related toxicity was 31% after URD transplants and 21% after matched sibling transplants (log-rank p = 0.1041). The median duration of first hospitalization was 33 days for recipients of genotypically-identical marrow and 36 days for recipients of URD marrow (p = 0.0244). Sixty percent of genotypically identical marrow recipients and 51% of unrelated volunteer donor marrow recipients were discharged home from Seattle free of disease at a median of 99 days post-transplant (p = 0.5095). The percentage of patients requiring readmission to hospital and the actuarial probability of requiring either hemodialysis or mechanical ventilation were not statistically different between the two groups. We conclude that matched URD marrow transplantation is not associated with significantly greater regimen-related toxicity or mortality than transplantation from HLA-genotypical siblings.
Bone Marrow Transplantation 02/1994; 13(1):31-5. · 3.75 Impact Factor
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P G Beatty
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ABSTRACT: Although allogeneic marrow transplantation has evolved into the treatment of choice for many otherwise fatal diseases, most patients are not candidates as they do not have an HLA-matched sibling donor. The Seattle Marrow Transplant Team, among others, has shown that patients who receive grafts from relatives who are partially matched for HLA (5 of 6 HLA-A,-B,-DR antigens) have an increased risk of graft-versus-host disease, but an overall survival that is comparable to that of similar patients receiving grafts from HLA-matched siblings. Similarly, patients receiving grafts from HLA-matched unrelated donors are at high risk for GVHD, but can look forward to favorable outcomes nearly as frequently as those who receive grafts from matched relatives. Grafts from more HLA-disparate donors, either related or unrelated, are at substantially increased risk of complications and death.
Bone Marrow Transplantation 02/1994; 14 Suppl 4:S39-41. · 3.75 Impact Factor
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Transplantation 01/1994; 56(6):1531-3. · 4.00 Impact Factor
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ABSTRACT: In an experiment to increase recruitment of unrelated bone-marrow donors, Ss were selected from a list of people who had donated blood within the past 24 months. They were randomly assigned to 3 groups. Members of the experimental group, 2 months before receiving a mailed brochure about a bone-marrow registry, were complimented on being blood donors and asked to complete a self-descriptive questionnaire. One control group received only the mailed brochure, and the other did not receive any mailing. The experimental group joined the registry at over 2 times the control-group rates. These results appear to be attributable to an attitude change associated with being recognized as a special group that contributed to the community's welfare.
Health Psychology 08/1993; 12(4):272-6. · 3.87 Impact Factor
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Leukemia 08/1993; 7(7):1123-9. · 9.56 Impact Factor
