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Biomedical subjects

C Anasetti

Publications and source records attributed to C Anasetti.

At least 55 records · Page 3Linked to original sources
PubMed2000

HLA matching in hematopoietic cell transplantation.

Progress in hematopoietic cell transplantation has been greatly facilitated by our increasing knowledge of the HLA system, as well as by improved therapies for achieving sustained engraftment, preventing graft-versus-host disease, and protecting the patient from infection. Disparity for HLA genes can cause graft rejection and graft-versus-host disease and decrease survival in patients receiving grafts from both related and unrelated donors. The presence of patient alloantibodies against donor antigens demonstrated by a positive crossmatch is a strong risk factor for graft rejection. The availability of matched donors for patients lacking a genotypically HLA-matched sibling has been greatly improved by the establishment of international registries of HLA-typed volunteer donors. The development of accurate and reproducible high-resolution DNA-based typing methods has significantly improved the prospects for identifying unrelated donors who are well matched with the patient for HLA. The use of these methods to optimize donor selection will improve both donor identification and the success of unrelated donor transplants.

Alleles↗
PubMed2000

Second allogeneic transplantation after failure of first autologous transplantation.

We evaluated the outcome of second allogeneic bone marrow transplantations (BMTs) in 59 patients aged 1-57 years who relapsed after initial autologous transplantation. Patients received a second transplantation for recurrent acute myeloid leukemia (AML) (n = 24), acute lymphoblastic leukemia (ALL) (n = 13), lymphoma (n = 18), multiple myeloma (n = 3), or chronic myelogenous leukemia (n = 1) from an HLA-matched related (n = 14), mismatched related (n = 25), or matched unrelated (n = 20) donor. The probabilities of nonrelapse mortality, relapse, and disease-free survival (DFS) 2 years after the second BMT were 51%, 26%, and 23%, respectively. The 2-year DFS estimates for AML, ALL, and lymphoma were 46%, 23%, and 0%. Univariate analysis demonstrated that superior DFS was associated with age < or =17 years at the time of the second transplantation, remission before the second transplantation, total-body irradiation-based preparative regimen for the second transplantation, and the diagnosis of AML. These data demonstrate that an allogeneic transplantation after a failed autologous transplantation can result in disease-free survivors, especially in the young. The outcomes after a second transplantation for patients aged >17 years and for those with lymphoma were especially grim. These data suggest that pediatric patients may be appropriate candidates for a second transplantation. In adults, however, the use of an allogeneic transplantation as salvage therapy after failure of the initial autologous transplantation is generally unsuccessful. Alternative experimental strategies, such as low-dose nonmyeloablative allogeneic minitransplantations, should be considered.

Adolescent↗
PubMed2000

Changing from cyclosporine to tacrolimus as salvage therapy for chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is the principal cause of transplantation-related morbidity and nonrelapse mortality late after allogeneic hematopoietic stem cell transplantation. The safety and potential efficacy of tacrolimus for the salvage treatment of chronic GVHD was evaluated in a single-arm, open-label phase 2 study. A total of 39 evaluable patients with chronic GVHD who failed previous immunosuppressive therapy with cyclosporine and prednisone were treated with tacrolimus starting at a median of 20 months (range, 3-68 months) after transplantation. At 3 years after the start of treatment, 5 patients (13%) had discontinued tacrolimus and were in complete remission, and 3 were considered clinically stable but not able to discontinue tacrolimus. A total of 31 patients (79%) experienced treatment failure; 22 (56%) who failed therapy had a change in immunosuppressive regimen because of progression (n = 18) or toxicity (n = 4). Nine patients (23%) died during continued treatment with tacrolimus. Two patients were lost to follow-up, at 11 and 19 months. The median duration of treatment with tacrolimus was 9 months (range, 1-29 months). Infections (144 episodes) were the most frequent adverse event. Nephrotoxicity occurred in 16 patients (41%); tacrolimus was discontinued in only 2 patients because of progressive deterioration in renal function. The Kaplan-Meier estimate of survival was 64% (95% confidence interval, 49%-79%) at 3 years posttransplantation. Seven patients had discontinued all immunosuppression at last contact, leading to an estimated 29% probability of stopping all immunosuppression by 3 years posttransplantation. Four patients died after relapse of malignancy. The response rate is consistent with previous reports of salvage treatment for chronic GVHD, indicating that a small group of patients failing cyclosporine may respond or stabilize with tacrolimus.

Adolescent↗
PubMed2000

Granulocyte colony-stimulating factor given to donors before apheresis does not prevent aplasia in patients treated with donor leukocyte infusion for recurrent chronic myeloid leukemia after bone marrow transplantation.

We conducted 2 sequential studies of donor leukocyte infusion (DLI) in 26 patients with chronic myeloid leukemia in hematologic relapse after unmodified allogeneic bone marrow transplantation. In the first study, cells for DLI were collected from 13 donors who were not treated with granulocyte colony-stimulating factor (G-CSF) (group 1). In the second study, cells were collected from 13 donors who received G-CSF before apheresis (group 2) in an attempt to avoid aplasia after DLI. Patients in group 2 received 550-fold more CD34+ cells than those in group 1. We found no significant difference in the incidence (31% versus 22%), onset time (41 vs. 48 days), or duration (15 vs. 14 days) of cytopenia after DLI in the 2 groups. G-CSF given to donors before collection of cells did not prevent aplasia. These findings support the hypothesis that the pathogenesis of aplasia after DLI is not restricted to the destruction of recipient hematopoietic cells but also involves failure of donor hematopoiesis by undefined mechanisms.

Adolescent↗
PubMed2000

Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience.

Between 1985 and 1998, 161 patients with primary acute myeloid leukemia (AML) received T-replete bone marrow transplantation (BMT) from unrelated donors in Seattle. Median age was 30 (range 1-55) years. Conditioning for BMT consisted of cyclophosphamide and total body irradiation in 154 (96%) cases and graft-versus-host disease prophylaxis was the standard methotrexate and cyclosporine combination in 134 (83%) cases. Median post-transplant follow-up was 2.9 years. Leukemia-free survival (LFS) at 5 years was 50+/-12% for transplants during first complete remission (n = 16), 28+/-8% during second CR (n = 40), 27+/-17% during subsequent CR (n = 8), 7+/-3% during relapse (n = 81) and 19+/-10% during primary induction failure (n = 16). The cumulative incidences of relapse were 19%, 23%, 25%, 44% and 63%, for the five groups, respectively. Transplantation during remission, a marrow cell dose above 3.5 x 10(8)/kg, and cytomegalovirus seronegative status before BMT in both patient and donor were favorable prognostic factors. Adults in any CR who received a marrow cell dose above 3.5 x 10(8)/mg had a LFS of 54+/-9% at 5 years. These data extend our previous findings on the association between a high marrow cell dose and improved survival and support the use of unrelated donor BMT for treatment of patients with high risk AML when a family match is not available.

Acute Disease↗
PubMed2000

Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities.

This retrospective study describes the outcome in 53 patients who had immunosuppressive treatment changed from cyclosporine (CSP) to tacrolimus for resistant acute GVHD (n = 23), hemolytic uremic syndrome (HUS) (n = 13) or CSP-associated neurotoxicity (n = 17). Tacrolimus was administered at doses of 0.03 mg/kg/day intravenously or 0.12 mg/kg/day orally in divided doses, as tolerated. Median time of conversion to tacrolimus after transplant was day 47. Nineteen patients had treatment changed to tacrolimus for resistant acute GVHD grades III or IV, with the median day of conversion being day 49 after transplant. Two of 20 evaluable patients had a complete resolution of GVHD after changing treatment to tacrolimus, with 18 showing no improvement. Eleven evaluable patients had therapy changed to tacrolimus for CSP-associated neurotoxicity at a median of 36 days after transplant. Eight patients had resolution of neurotoxicity and three had partial improvement. Eleven evaluable patients had therapy changed to tacrolimus for HUS at a median of 46 days after transplant. One patient had complete resolution of HUS and 10 showed no response. Side-effects related to tacrolimus included renal toxicity (34%), neurotoxicity (15%) and HUS (9%). Nine (17%) patients remain alive, including six patients who had therapy changed to tacrolimus for CSP-associated neurotoxicity. While often successful for dealing with neurotoxicity, only a rare patient improved after therapy was changed from CSP to tacrolimus for HUS or resistant acute GVHD.

Acute Disease↗
PubMed2000

Transplantation of hematopoietic stem cells from alternate donors in acute myelogenous leukemia.

The number of allogeneic transplants from unrelated donors has grown in the past decade in part because of the expansion of the donor registry size. Patient survival has improved due to the selection of more closely matched donors and the development of effective infection prophylaxis. Relapse-free survival remains limited in patients with a large tumor burden at the time of transplantation. A higher marrow cell dose is the major factor to minimize transplant-related death. Future studies of peripheral blood stem cell transplants should be considered for patients with acute leukemia with the goal of enhancing the stem cell dose and improving survival.

Acute Disease↗
PubMed2000

Treatment of chronic myelomonocytic leukaemia by allogeneic marrow transplantation.

We evaluated the outcome of allogeneic bone marrow transplantation (BMT) in 21 patients with chronic myelomonocytic leukaemia (CMML) who were treated at the Fred Hutchinson Cancer Research Center between 1990 and 1998. There were 11 male and 10 female patients with a median age of 47.4 years (range 1.0-62.9). Patients were conditioned either with total body irradiation (TBI) and chemotherapy, with or without antithymocyte globulin (n = 19), or with chemotherapy alone (n = 2). The marrow donor was an HLA-identical sibling in 12 patients, an HLA-non-identical related donor in three patients and an unrelated volunteer donor in six patients. All evaluable patients achieved sustained engraftment. Fifteen patients developed grades II-IV acute graft-versus-host disease (GVHD). Nine patients (43.0%) are surviving disease free at 0.7-8.1 years (median 6.9) after transplantation. Five patients relapsed 75-660 d after transplant and all died. Five patients died with organ failure and two died with GVHD and associated infections. The Kaplan-Meier estimates of disease-free survival and relapse at 3 years were 39% and 25% respectively. The probability of survival was improved in patients with shorter disease duration compared with those with a long interval from diagnosis to BMT. Thus, as with other myeloproliferative diseases or myelodysplastic syndromes, BMT offers curative therapy for a proportion of patients with CMML. We suggest that patients with CMML who have a suitable donor should be considered for transplantation, probably early in their disease course. However, it will be important to develop new regimens with enhanced antileukaemic efficacy without further increasing regimen-related toxicity and mortality.

Adolescent↗
PubMed2000

Improving availability and safety of unrelated donor transplants.

Transplants of hematopoietic stem cells from unrelated donors have become feasible for a growing population of patients with hematologic malignancy. More than 2,000 patients with acute and chronic leukemia, lymphoma, myeloma, and myelodysplasia are transplanted each year worldwide using marrow or blood stem cells from unrelated volunteers. Many patients have achieved complete immunologic tolerance and have become long-term survivors. The probability of finding a suitable donor has increased, because of the expansion of the network of registries containing more than 5 million HLA-typed donors worldwide. The selection of compatible donors has become more effective, thanks to the discovery of new HLA alleles and the development of precise and efficient HLA typing methods using DNA technology. Prophylaxis of viral and fungal infections has decreased morbidity and improved survival. The availability of more selective immunosuppressive agents provides the opportunity to decrease treatment-related toxicity and graft-versus-host disease.

Graft vs Host Disease↗
PubMed1999

Visualization, fate, and pathogenicity of antigen-specific CD8+ T cells in the graft-versus-host reaction.

To follow the fate of alloreactive T cell effectors in graft-vs-host disease, Ld-specific CD8+ T cells from C57BL/6 2C TCR-transgenic donors were transplanted into sublethally irradiated (750 cGy) Ld+ or Ld- recipients. In Ld- C57BL/6 or (BALB/c-dm2 x C57BL/6)F1 recipients, naive 2C T cells engrafted and survived long term, but did not acquire effector function. In Ld+ (BALB/c x C57BL/6)F1 recipients, 2C T cells engrafted, expanded, became cytolytic, destroyed host B cells and double-positive thymocytes, and later disappeared. Despite marked damage to lymphoid and hemopoietic cells by 2C T cells, no significant pathology was detected in other organs, and recipients survived. Ld+ (BALB/c x C57BL/6)F1 recipients died when LPS/endotoxin was administered on day 7 after cell transfer, while Ld- (BALB/c-dm2 x C57BL/6)F1 recipients survived. Our findings show that under certain conditions, a CD8+ T cell population recognizing an extremely limited repertoire of Ags can initiate graft-vs-host disease.

Animals↗
PubMed1999

A phase I-II clinical trial to evaluate removal of CD4 cells and partial depletion of CD8 cells from donor marrow for HLA-mismatched unrelated recipients.

We conducted a phase I-II clinical trial to test the hypothesis that removal of CD4 cells from an HLA-mismatched unrelated marrow graft would substantially reduce the risk of grades III-IV graft-versus-host disease (GVHD) and that retention of a specified number of CD8 cells in the graft would be sufficient to prevent rejection. Patients were eligible for this study when an HLA-A, -B, or -DRB1-matched unrelated donor could not be identified. HLA matching of the donor and recipient was based on typing of HLA-A and -B antigens by serologic methods and by typing of HLA-DRB1 alleles by molecular methods, and donors were selected when disparity was limited to a single HLA-DRB1 allele or a single HLA-A or -B antigen. Twenty-seven patients with hematologic malignancy or aplastic anemia were prepared to receive a transplant with conventional regimens of cyclophosphamide and fractionated total body irradiation, and a standard regimen of methotrexate and cyclosporine was given for GVHD prophylaxis. CD4 cells were removed from the donor marrow, and the numbers of CD8 cells were adjusted systematically in graded steps for successive patients, depending on the occurrence of grades III-IV GVHD or graft failure in previously enrolled patients. Removal of CD4 cells did not cause graft rejection or appreciably decrease the risk of grades III-IV GVHD. Depletion of CD8 cells was associated with an increased risk of rejection with either HLA-DRB1 disparity or with HLA-A or -B disparity. With either type of disparity, the risk of grades III-IV GVHD is likely to be higher than 15% at any dose of CD8 cells associated with less than 5% risk of graft failure. The absence of graft failure associated with CD4 depletion supports the hypothesis that donor CD4 cells are not essential for preventing marrow graft rejection in humans. The correlation between graft failure and the number of CD8 cells in the donor marrow supports the hypothesis that donor CD8 cells help to prevent marrow graft rejection.

Adolescent↗
PubMed1999

HuM291, a humanized anti-CD3 antibody, is immunosuppressive to T cells while exhibiting reduced mitogenicity in vitro.

BACKGROUND: OKT3, a mouse monoclonal antibody (Ab) specific for the human CD3 complex on T cells, is a potent immunosuppressive agent used for the treatment of acute allograft rejection. The utility of the drug has been limited by a neutralizing anti-mouse Ab response and adverse side effects resulting from T cell activation and systemic cytokine release. T cell activation is caused by OKT3-mediated cross-linking of T cells and Fc receptor-bearing cells. Studies in the mouse model have shown that global T cell activation is not necessary for immunosuppression, as Fc receptor-nonbinding anti-CD3 Abs can suppress graft rejection in the absence of the activation effects seen with Fc receptor-binding Abs. Thus, a humanized anti-CD3 antibody with a low affinity for Fc receptors might improve immunosuppressive therapy by reducing the side effects associated with OKT3. METHODS: We developed a mouse monoclonal Ab, M291, which competes with OKT3 for binding to T cells. Humanized, complementary-determining region-grafted versions of M291 featuring various Fc were engineered, including a previously described IgG2 mutant deficient in Fc receptor binding (HuM291). RESULTS: Compared with OKT3 and HuM291-IgG1, HuM291 was significantly less mitogenic to T cells in vitro and induced the release of much lower levels of the cytokines tumor necrosis factor-alpha, interferon-gamma, and interleukin-10. Despite this reduction in T cell activation, HuM291 retained the ability to modulate the CD3 complex and inhibit the mixed lymphocyte reaction. CONCLUSIONS: When evaluated in vivo, HuM291 may be an immunosuppressive agent associated with less of the acute toxicity and immunogenicity seen with OKT3 therapy.

Amino Acid Sequence↗
PubMed1999

Effect of HLA mismatches on the outcome of hematopoietic transplants.

Hematopoietic cell transplantation from unrelated volunteer donors for the treatment of hematological malignancy can be optimized by complete and precise matching for HLA class I and II alleles between the donor and recipient. Survival is improved when the donor and recipient are matched for HLA-A, -B, -C, -DRB, -DQB1 and -DPB1 alleles. The risks of clinically severe graft-versus-host disease, graft failure and mortality are increased in the presence of multilocus mismatching. These findings demonstrate that HLA allelic differences are biologically relevant in human transplantation.

Graft Rejection↗
PubMed1999

Reduced dose intravenous immunoglobulin does not decrease transplant-related complications in adults given related donor marrow allografts.

Graft-vs.-host disease (GVHD) and infection are major complications of allogeneic bone marrow transplantation. Intravenous immunoglobulin (IVIg) given at a dose of 500 mg/kg/wk has been shown to decrease the risk of acute GVHD, interstitial pneumonia, and infection in adults early after allogeneic transplantation. The current study is a controlled trial to determine whether a lower total dose of IVIg given with pretransplant loading reduces the incidence of transplant-related complications. In a randomized trial of 241 patients > or =20 years of age who were given related donor marrow allografts, 121 individuals receiving Ig prophylaxis (500 mg/kg/d loading from day -6 to -1 and then 100 mg/kg every 3 days from day 3 to 90) were compared with 120 control patients who did not receive IVIg. Randomization was stratified by human leucocyte antigen-matching, remission status of malignancy, GVHD prophylaxis, and cytomegalovirus (CMV) serology. The study was powered to detect a reduction in acute GVHD by 18% and a decrease in transplant-related mortality by 17%. Pretransplant IVIg loading and posttransplant maintenance achieved median serum IgG levels >1350 mg/dL, which were approximately twofold greater than the untreated controls (p<0.01). White blood cell and platelet recoveries were similar for the two groups, although control patients required fewer units of platelets per day (2.5 vs. 3.3, p = 0.008). No significant differences in the incidence of CMV infection, interstitial pneumonia, or bacteremia were observed. The incidence of acute GVHD did not differ between the two groups; however, acute GVHD was less frequent among IVIg recipients achieving maximum serum IgG levels >3000 mg/dL (60 vs. 79%). Neither transplant-related mortality nor disease-free survival was significantly altered by Ig prophylaxis. However, the cumulative incidence of relapse of malignancy was higher in IVIg recipients than in controls (31 vs. 18%, p = 0.03). Multivariable regression analysis demonstrated a 1.89 increased relative risk of relapse for individuals given IVIg (p = 0.021). We conclude that pretransplant loading and a shorter course and lower total dose of IVIg prophylaxis did not appear to decrease the risk of acute GVHD or mortality among adults receiving related donor marrow transplants. Note, IVIg administration may be associated with an increased risk of recurrent malignancy, a finding that warrants further investigation.

Acute Disease↗
PubMed1999

Allogeneic hematopoietic stem-cell engraftment and graft failure.

Two immunologically mediated reactions, the graft-versus-host (GvH) and host-versus-graft (HvG) responses, form primary and opposing barriers to successful transplantation of allogeneic hematopoietic stem-cells (HSC). The HvG barrier is set by the strength of the allogeneic immune response, which is determined by antigenic stimulation provided by donor cells, owing to differences in histocompatibility antigens, and the capacity of host immune cells to generate a response. Risk of graft failure must be viewed as the interplay of multiple factors, including degree of human leukocyte antigen and minor histocompatibility antigen disparity, capacity of host immune response, and the capacity of donor hematopoietic and immunologic cells for overcoming residual host immunity.

Child↗