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Biomedical subjects

C Anasetti

Publications and source records attributed to C Anasetti.

At least 145 records · Page 8Linked to original sources
PubMed1994

Role of the mixed lymphocyte culture (MLC) reaction in marrow donor selection: matching for transplants from related haploidentical donors.

The utility of the MLC assay as a test of HLA-D region matching and predictor of acute graft-versus-host disease (GvHD) was evaluated in 157 patients receiving marrow grafts from HLA-A, B identical related haploidentical donors. All donors and recipients were tested by HLA-DR serology, by Dw phenotyping with homozygous typing cells (HTC) and by standard MLC. Ninety-nine of the donor-recipient pairs were mismatched for a serologically defined HLA-DR antigen while 109 pairs were mismatched for the HLA-DR region by HTC typing. Donor antirecipient relative responses (RR) in MLC, corresponding to the GvHD vector in marrow transplantation, ranged from -4% to 100%, with a median of 25%. A comparison of reactivity in MLC with presence or absence of matching by Dw phenotyping, however, showed a significant overlap in the distribution of RRs from HLA-Dw matched versus Dw mismatched pairs, suggesting that the MLC was not a reliable predictor of HLA-Dw matching. Using an optimally-defined cutoff of 3% RR, the MLC was correlated with risk of developing clinically significant grades II-IV acute GvHD (p = 0.03) but not with risk of developing severe grades III-IV GvHD (p = 0.18). In contrast, matching by Dw phenotype was a significant predictor of GvHD, with Dw-compatible transplant recipients less likely to develop either grades II-IV (p = 0.004) or III-IV (p = 0.036) GvHD than Dw-incompatible transplant recipients. Overall, these results underscore the difficulty in using the MLC to measure HLA-D region compatibility and predict the risk of severe graft-versus-host disease among patients receiving related haploidentical marrow grafts. HLA-D (HTC) typing results correlate primarily with DRB compatibility, and with the advent of DRB1 allele matching by sequence-specific oligonucleotide probes (SSOP) or by direct sequencing, the precision in donor matching achievable with these methods is far greater than with either HLA-D typing or direct MLC testing.

Adolescent↗
PubMed1994

Marrow transplants from HLA matched unrelated donors: an NMDP update and the Seattle experience.

It is now possible to access more than one million HLA-A, B typed volunteer individuals willing to donate marrow and a preliminary search through the NMDP registry provides access to more than 200,000 HLA-A, B, DR typed donors. Fifty-four percent of preliminary searches yield at least one potentially HLA-matched donor but the majority of these successful searches involve patients of Caucasian origin. Substantially greater recruitment must occur among different racial and ethnic groups if minority patients are to have a better chance of finding an HLA match. This can be accomplished by recruiting diverse donors within each regional registry or by expanding worldwide the existing international registry network. Molecular typing and matching for alleles in the HLA-D region improve the precision of donor selection and the timeliness of the donor search process. Although the risk of GVHD in unrelated donor transplants remains higher than in HLA-identical sibling transplant is not as good as HLA-identical sibling transplants, newer methods of supportive care and GVHD control are providing and gradual improvement in both the safety of the procedure and long-term relapse-free survival.

Adult↗
PubMed1994

Comparison of morbidity and mortality after marrow transplantation from HLA-genotypically identical siblings and HLA-phenotypically identical unrelated donors.

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.

Adolescent↗
PubMed1994

Marrow transplants from unrelated donors.

It is now possible to access more than 1 million HLA-A, B typed volunteers willing to donate marrow. A preliminary search through the U.S. NMDP provides direct computerized access to the HLA-A, B, DR phenotypes of more than 186,000 registered donors. Fifty-one percent of preliminary searches yield at least one HLA-A, B, DR match, but a disproportional number of successful searches benefit primarily patients of Caucasian origin. Substantially greater recruitment among different racial and ethnic groups must occur if non-Caucasians are to have a better chance of finding an HLA-matched donor. Improved cooperation between registries and transplant networks in different countries remains an important goal. The optimal application of URD transplants may not be possible until an efficient and reliable worldwide marrow donor program has been established. DNA typing and matching for HLA alleles improves the timeliness of the donor search process and the precision of donor selection. HLA mismatching increases the probability and severity of GVHD, but minor mismatches for one HLA-A, B, or D/DRB1 locus does not appear to decrease survival. Although the risk of GVHD in URD transplants remains high and survival currently is not as favorable as HLA identical sibling transplants, better supportive care and GVHD control are providing a gradual improvement in the long-term disease-free survival of URD transplants.

Bone Marrow Transplantation↗
PubMed1994

Marrow transplant experience for children with severe aplastic anemia.

PURPOSE: The two major factors associated with lack of survival after allogeneic marrow transplant for severe aplastic anemia have been graft rejection and acute graft versus host disease (GVHD). As a result, survival for patients transplanted in the 1970s was approximately 68%. Improved survival during the 1980s was primarily related to the decrease in the incidence of acute GVHD with the use of combination methotrexate and cyclosporine for GVHD prophylaxis. Although the incidence of graft rejection has not changed, the time to graft rejection has been delayed. PATIENTS AND METHODS: One hundred forty children < 18 years of age received a marrow transplant for severe aplastic anemia at the Fred Hutchinson Cancer Research Center between May, 1971 and June, 1991. Four recipients of syngeneic marrow received a simple marrow infusion, 119 recipients of HLA-identical family member marrow received cyclophosphamide (CY), 200 mg/kg; most recipients of alternative donor marrow received CY plus 12.0 Gy fractionated total body irradiation. GVHD prophylaxis was MTX only for 91 recipients of HLA-identical family member marrow, and was MTX plus CSP for all other allogeneic marrow patients. Estimates of graft rejection, acute and chronic GVHD, survival and event-free survival (EFS) were determined by the Kaplan-Meier method. RESULTS: Two recipients of syngeneic marrow achieved engraftment with donor marrow infusion only and two required immunosuppression with CY. Among the 119 recipients of HLA-identical family member marrow the type of GVHD prophylaxis did not influence graft rejection but non-transfused patients had 10% incidence of rejection compared to 22% for transfused patients (p = 0.1). All patients with late graft rejection survive whereas those with early rejection usually do not. The incidence of acute GVHD was 27% and 11% for MTX recipients and MTX plus CSP recipients, respectively (p = 0.11), and the probability of chronic GVHD was 30% and 26%, respectively. Survival is 64% for recipients of MTX and 96% for recipients of MTX plus CSP (p = 0.007), but EFS was 60% and 71%, respectively (p = 0.48). Recipients of partially matched family member or unrelated marrow donor grafts have transplants complicated by infections and GVHD. Growth and development of CY only recipients is normal and several children have been born to these former patients. CONCLUSIONS: High dose CY is usually an effective preparative regimen for children with severe aplastic anemia and an HLA-identical family member marrow donor. Additional immunosuppression with anti-thymocyte globulin may result in a further decrease in graft rejection and improved EFS. Identification of a group of children who are unlikely to respond to immunosuppressive treatment could permit earlier transplantation for patients without HLA-identical family member donors available. Children who receive CY only have normal growth and development.

Anemia, Aplastic↗
PubMed1993

Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome.

We treated 93 patients with myelodysplastic syndrome using cyclophosphamide and either total body irradiation (n = 88) or busulfan (n = 5) followed by marrow transplantation. Sixty-five marrow donors were genotypically HLA-identical siblings and 28 were other family members or unrelated donors. Before transplantation all patients had either severe neutropenia or thrombocytopenia or had greater than 5% blasts in the marrow or peripheral blood. The probabilities of disease-free survival, relapse, and non-relapse mortality at 4 years were 41%, 28%, and 43%, respectively. Multivariate analysis revealed that younger age and shorter disease duration were significantly associated with improved disease-free survival and decreased non-relapse mortality. Relapse was seen only in patients with excess blasts at the time of transplantation (51% at 4 years). Patients younger than age 40 and without excess blasts had a 4-year disease-free survival of 62%. This study confirms that allogeneic marrow transplantation can cure some patients with myelodysplasia. Because of the favorable outcome in younger patients without excess blasts, we recommend that transplantation be considered early for patients younger than age 40, before disease progression or development of life-threatening cytopenias. For older patients and those with excess blasts, changes in the transplant procedure will be necessary to improve outcome.

Adolescent↗
PubMed1993

The role of HLA-DPB1 disparity in the development of acute graft-versus-host disease following unrelated donor marrow transplantation.

The role of HLA-DPB1 disparity in the development of acute graft-versus-host disease (GVHD) following unrelated donor (URD) marrow transplantation is unknown. We studied 129 patients who underwent marrow transplantation from HLA-A, -B, -DRB, and -DQB matched URDs to determine whether matching for HLA-DPB1 alleles significantly decreased the risk of developing acute GVHD. HLA-DPB1 alleles were determined by sequence-specific oligonucleotide hybridization and by the number of patient DPB1 alleles not shared by the donor scored. The Kaplan-Meier probability of developing grades II to IV acute GVHD was determined for patients incompatible for zero (group A), one (group B), or two (group C) DPB1 alleles. Of the 129 pairs, there was no recipient DPB1 incompatibility in 28 (22%), one DPB1 mismatch in 72 (56%), and two DPB1 mismatches in 29 (22%). The probability of grades II to IV acute GVHD was 0.69 (0.50, 0.86) for group A, 0.83 (0.73, 0.91) for group B, and 0.72 (0.56, 0.87) for group C (P = .63). These results indicate that matching patients and unrelated donors for HLA-A, -B, -DRB, and -DQB does not predict for matching at DPB1. However, recipient incompatibility for DPB1 alleles does not detectably influence the risk of acute GVHD. Therefore, HLA-DP disparity should not be used as an exclusion criterion for donor selection in unrelated marrow transplantation.

Acute Disease↗
PubMed1993

Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program.

In the interval from December 1987 to November 1990, 196 consecutive patients with chronic myelogenous leukemia (CML) received unrelated donor marrow transplantation using marrow procured by the National Marrow Donor Program (NMDP) at 21 NMDP-affiliated marrow transplant centers. Baseline donor and recipient data as well as follow-up data were obtained systematically in all cases by the NMDP. The median interval from the initiation of a search for an unrelated donor to bone marrow transplantation was 8.4 months (range, 1.7 to 34.6 months). Median age of the recipients was 33.3 years (4.5 to 54.5 years). Seventy-five recipients were female and 121 were male. At time of transplant, 115 patients were in chronic phase, 51 in accelerated phase, 14 in blast crisis, and 16 in a second or subsequent chronic phase. In 133 cases, donors and recipients were identical at the HLA A, B, and DR loci using standard serologic typing, and in 63 cases, there was nonidentity at one HLA locus. Patients were prepared for transplantation with a combination of high-dose chemotherapy and total body irradiation (N = 169) or with high-dose chemotherapy only (N = 27). Thirty-five patients received marrow depleted ex vivo of T lymphocytes, whereas 161 patients received non-T-depleted marrow. One hundred seventy-four of 196 patients engrafted (absolute neutrophil count > or = 500/mm3 for 3 consecutive days). The median time to engraftment was 22 days (6 to 69 days). Twenty-two patients failed to engraft, and an additional 10 patients experienced late graft failure. The incidence of grades III or IV acute graft-versus-host disease (GVHD) was 0.54 +/- 0.10, and that of extensive chronic GVHD was 0.52 +/- 0.12. A lower incidence of both grades III and IV acute GVHD (P = .0003) and of extensive chronic GVHD (P = .01) were independently associated with use of T-depleted marrow. The actuarial incidence of hematologic relapse at 2 years is 0.11 +/- 0.06. The 2-year actuarial incidence of disease-free survival for patients transplanted in first chronic phase within 1 year of diagnosis is 0.45 +/- 0.21, in chronic phase more than 1 year from diagnosis is 0.36 +/- 0.11, in accelerated phase is 0.27 +/- 0.12, in second or subsequent chronic phase is 0.22 +/- 0.21, and in blast crisis is 0. Fifteen of 55 patients transplanted at 40 to 50 years of age survive.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMed1993

Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1.

The specificity of T lymphocyte activation is determined by engagement of the T cell receptor (TCR) by peptide/major histocompatibility complexes expressed on the antigen-presenting cell (APC). Lacking costimulation by accessory molecules on the APC, T cell proliferation does not occur and unresponsiveness to subsequent antigenic stimulus is induced. The B7/BB1 receptor on APCs binds CD28 and CTLA-4 on T cells, and provides a costimulus for T cell proliferation. Here, we show that prolonged, specific T cell hyporesponsiveness to antigenic restimulation is achieved by blocking the interaction between CD28 and B7/BB1 in human mixed leukocyte culture (MLC). Secondary T cell proliferative responses to specific alloantigen were inhibited by addition to the primary culture of monovalent Fab fragments of anti-CD28 monoclonal antibody (mAb) 9.3, which block interaction of CD28 with B7/BB1 without activating T cells. Hypo-responsiveness was also induced in MLC by CTLA4Ig, a chimeric immunoglobulin fusion protein incorporating the extracellular domain of CTLA-4 with high binding avidity for B7/BB1. Cells previously primed could also be made hyporesponsive, if exposed to alloantigen in the presence of CTLA4Ig. Maximal hyporesponsiveness was achieved in MLC after 2 d of incubation with CTLA4Ig, and was maintained for at least 27 d after removal of CTLA4Ig. Accumulation of interleukin 2 (IL-2) and interferon gamma but not IL-4 mRNA was blocked by CTLA4Ig in T cells stimulated by alloantigen. Antigen-specific responses could be restored by addition of exogenous IL-2 at the time of the secondary stimulation. Addition to primary cultures of the intact bivalent anti-CD28 mAb 9.3, or B7/BB1+ transfected CHO cells or exogenous IL-2, abrogated induction of hyporesponsiveness by CTLA4Ig. These data indicate that interaction of CD28 with B7/BB1 during TCR engagement with antigen is required to maintain T cell competence and that blocking such interaction can result in a state of T cell hyporesponsiveness.

Animals↗
PubMed1993

Marrow transplantation from unrelated donors for treatment of hematologic malignancies: effect of mismatching for one HLA locus.

One hundred twelve patients less than 36 years old received marrow grafts from unrelated donors as treatment for hematologic malignancy. Seventy donor/recipient pairs were phenotypically identical for HLA-A, -B, and -D, while 42 had a "minor" disparity at one HLA locus. There was an increase in the risk of acute graft-versus-host disease (GVHD) in patients receiving HLA-partially matched grafts compared with those receiving HLA-matched grafts (51% v 36% probability of grades III-IV acute GVHD). However, in this cohort of patients, there was no significant difference in survival (at 1.5 years, 46% v 51% for good-risk patients, 44% v 30% for poor-risk patients). This finding suggests that some degree of HLA disparity can be tolerated in young patients transplanted from unrelated donors for malignant disease, thus making transplantation an option available to larger numbers of patients.

Acute Disease↗
PubMed1993

Selection of an unrelated donor for marrow transplantation facilitated by the molecular characterization of a novel HLA-A allele.

Precise HLA typing is crucial in the selection of marrow donors for the treatment of patients with hematologic malignancy. This study was undertaken to characterize an unusual variant of HLA-A30, designated HLA-A30JS, identified in a patient with leukemia who was a candidate for unrelated donor marrow transplantation. IEF and cDNA-sequencing analyses revealed that A30JS is a novel variant differing from the IEF-defined subtype A30.1 (encoded by the A*3002 allele) by a single amino acid substitution. An unrelated marrow donor was identified who was matched with the patient for HLA-A3, B7, B18, DR2, and DR3, but mismatched within the A30 antigen family for the two distinct alleles A*3002 versus A30JS. These two alleles encode a single amino acid substitution, Arg versus Gly, at position 56 in the alpha 1 domain. Position 56 is located outside the antigen-binding cleft of the class I molecule, suggesting that this substitution may not be functionally significant. Transplantation from this donor was performed and the patient is surviving free of leukemia for more than 700 days after transplant. The maximum acute GVHD observed was scored as grade II, but immunosuppressive therapy is still required for control of chronic GVHD. This study demonstrates how the molecular characterization of a novel HLA-A allele in a patient could facilitate the selection of an unrelated donor. Lacking this information, it would not have been possible to select a donor for this patient, and thus apparently successful marrow transplant could not have occurred.

Adult↗
PubMed1993

High-dose cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation in patients with lymphoid malignancies who have received dose-limiting radiation therapy.

PURPOSE: To evaluate high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) in patients with lymphoid malignancy who had received prior radiation therapy. PATIENTS AND METHODS: Fifty-seven patients with non-Hodgkin's lymphoma (NHL; n = 23), Hodgkin's disease (HD, n = 32), or acute lymphoblastic leukemia (ALL; n = 2) with a history of previous radiation therapy were treated with cyclophosphamide (Cy; 7.2 g/m2), carmustine (300 mg/m2 or 600 mg/m2), and etoposide (2,400 mg/m2) (CBV) followed by ABMT. RESULTS: The projected 2-year probabilities of survival, event-free survival (EFS), and relapse were .31, .24, and .76, respectively. For patients with intermediate- and high-grade lymphoma and HD the probabilities were .27, .10, and .14 for EFS and .57, .90, and .77 for relapse. The probability of nonrelapse mortality in the first 100 days post-ABMT was 33%. Idiopathic pneumonia syndrome (IPS) was observed in no patients who received carmustine 300 mg/m2 and 23% of patients who received carmustine 600 mg/m2 (P = .05). Eight-three percent of patients who received mediastinal radiation therapy less than 3 months before transplant developed IPS, compared with 13% who received radiation therapy more than 3 months before transplant (P = .001). CONCLUSION: ABMT following high-dose CBV resulted in long-term disease-free survival in 25% of patients with lymphoid malignancies who had previously received dose-limiting radiation therapy. Fatal IPS and a high relapse rate were major factors limiting successful outcome following ABMT. The morbidity and mortality rates associated with the administration of carmustine 600 mg/m2 were prohibitively high, especially in patients who received mediastinal radiation immediately before ABMT, and were not associated with a decrease in post-ABMT relapse.

Adolescent↗
PubMed1993

rhGM-CSF after allogeneic bone marrow transplantation from unrelated donors: a pilot study of cyclosporine and prednisone as graft-versus-host disease prophylaxis.

Cyclosporine and prednisone were administered as graft-versus-host disease (GVHD) prophylaxis to nine patients undergoing marrow transplant from HLA matched, unrelated donors. RhGM-CSF was administered at a dose of 250 micrograms/m2 daily to all patients. The median day of neutrophil recovery to > or = 500/mm3 was Day 16. Four patients developed Grade II acute GVHD and four developed Grade III acute GVHD. One patient, who survived only 25 days, did not develop GVHD at all. One patient developed systemic infection within the first 28 days after marrow infusion. Comparison of these data to a prior series of patients undergoing bone marrow transplant (BMT) from unrelated donors who were treated with rhGM-CSF along with methotrexate and cyclosporine for GVHD prophylaxis suggests that rhGM-CSF is well-tolerated, neutrophil recovery may be earlier but the severity of GVHD does not appear reduced. Selection of the GVHD prophylaxis regimen may affect the hematopoietic response to cytokine therapy. Further trials with rhGM-CSF in patients undergoing BMT from unrelated donors are required.

Adolescent↗
PubMed1993

Allogeneic marrow transplantation: the Seattle experience.

Allogeneic marrow transplantation from a normal donor provides potential life-saving therapy for a variety of inherited and acquired diseases of the hematopoietic and immune systems including malignancies. However, even with an HLA-identical sibling donor the success of allografts can be compromised by GvHD and associated complications such as opportunistic infection. Non-HLA minor histocompatibility determinants still represent significant barriers to safe and successful transplants in some cases. In the absence of an HLA-identical sibling, alternate donors, including HLA-matched unrelated volunteers and HLA partially matched relatives can provide opportunity for effective therapy, though with increased risk of graft rejection and GvHD. HLA matching appears to be a critical factor, with the incidence and severity of GvHD exceeding acceptable limits as the number of incompatible HLA antigens increases. Although the United States NMDP and the marrow donor registries in other countries that currently have more than 1.2 million HLA-typed donors have profoundly improved the likelihood of finding an HLA-matched unrelated donor for the majority of White patients, many Whites and most patients of other racial origin cannot at this time find a match. Effective and safe treatment for these patients will require improved methods for managing HLA-mismatched transplants.

Academic Medical Centers↗
PubMed1993

Adhesion of CD16+ K cells to antibody-coated targets is mediated by CD2 and CD18 receptors.

In order to investigate the function of CD2 and CD18 receptors in antibody-dependent cellular cytotoxicity (ADCC), Fab' fragments of the monoclonal antibodies 9.6 (anti-CD2) and 60.3 (anti-CD18) were preincubated with the human natural killer (NK) clone EB4.19 and tested for conjugate formation and cytotoxic function against the human B-cell line KMS and the mouse thymoma line SL-2. We concluded that: (1) the FcR CD16 does not participate in conjugate formation; (2) adhesion between target and effector cells mediated by CD2 and CD18 is a prerequisite for subsequent activation of the lytic programme through the CD16 receptor.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1993

Autologous bone marrow transplantation for acute lymphoblastic leukemia.

Between December 1979 and February 1991, 89 patients with ALL received autologous BMT. Median patient age was 18.4 years. Ten patients were in first remission, 52 were in second or greater remission and 27 were in relapse at the time of transplant. Conditioning regimens utilized chemotherapy alone (5 patients) or in combination with 10-15.75 Gy total body irradiation (84 patients). Disease-free survival at 1 year is 50% for patients transplanted in first remission, 27% for those in > or = second remission and 8% for patients in relapse. Pre- and post-transplant variables were evaluated in univariate and multivariate analyses for their effect on survival and relapse. Factors significantly associated with improved survival were being transplanted in first remission and achieving a self-sustained platelet count > or = 20 x 10(9)/l in a shorter period of time. A decreased relapse rate after transplant was associated with a lower white blood count at diagnosis, being transplanted in first remission and not being transplanted in relapse.

Adolescent↗