Unrelated Marrow Research Articles

Allogeneic bone marrow transplantation from unrelated donors using in vivo anti-T-cell globulin.

Despite improvements in HLA typing, graft-versus-host disease (GVHD) continues to impair the results after volunteer unrelated donor bone marrow transplantation (VUD-BMT) in adult patients compared with matched sibling BMT. Here, the outcome after VUD-BMT using a specific regimen with high-dose anti-T-lymphocyte globulin (ATG) was analysed. Fifty-five adult patients, median age 34 years (range 17-55 years), with acute or chronic leukaemia or myelodysplastic syndrome (MDS) were transplanted in first complete remission (CR1)/first chronic phase (CP1) (early disease) (n = 21) or in advanced (CR2/CP2, no remission) disease (n = 34) from an unrelated marrow donor. GVHD prophylaxis consisted of ATG-S (Fresenius) 60-90 mg/kg b.w. prior to transplantation, in addition to cyclosporin A and short-course methotrexate. Graft failure did not occur and white blood cell count (WBC) > 1.0 x 10(9)/l was reached at median day +16. The cumulative incidence of acute (a)GVHD grade II-IV was 15% [95% CI (8%, 28%)] and of chronic GVHD was 51% [95% CI (38%, 68%)]. The cumulative incidence of relapse within 1 year was 0% [95% CI (0%, 19%)] and 21% [95% CI (11%, 40%)] for patients with early and advanced disease respectively. With a median follow-up of 28 months (range 16-45 months), 2-year disease-free and overall survival for patients transplanted in CR1/CP1 was 81% and 81% [95% CI (64%, 98%)], respectively, and for patients with advanced disease was 33% [95% CI (17%, 50%)] and 40% [95% CI (23%, 57%)] respectively. Complete and persistent donor chimaerism was seen in 77.5% of 40 patients evaluated. All 14 chronic myeloid leukaemia (CML)-CP1 patients became bcr-abl negative within 250 d. High-dose ATG pretransplant results in a low incidence of severe aGVHD without compromising donor chimaerism or elimination of minimal residual disease. Our results are similar to data obtained after matched sibling donor transplantation.

HLA-B44 subtyping in the Catalan population using reference strand mediated conformation analysis. Implications for the selection of unrelated bone marrow donors.

Cytotoxic T lymphocytes (CTLs) reactive against the disparity between HLA-B*4402 and HLA-B*4403 have been reported after unrelated donor bone marrow transplantation. These CTLs have been associated with acute graft-versus-host disease and graft rejection. This study describes the HLA-B44-subtyping in the Catalan population using reference-strand mediated conformation analysis. It has been performed on 297 unrelated HLA-B44+ cord blood units from the Barcelona Cord Blood Bank (Barcelona, Spain). We have found a predominance of HLA-B*4403 (66.04%) over HLA-B*4402 (33.02%), whereas the predominant HLA-B44 allele in Northern Europe and the United States is HLA-B*4402. This inverted proportion between HLA-B44 subtypes in Mediterranean populations compared with other Caucasian populations suggests that HLA-B44 subtyping should be performed when an HLA-B44+ unrelated donor marrow is identified.

Probability of finding HLA-mismatched related or unrelated marrow or cord blood donors

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.

Graft-versus-host disease and donor-directed hemagglutinin titers after ABO-mismatched related and unrelated marrow allografts: evidence for a graft-versus-plasma cell effect

The gradual disappearance of host antidonor isohemagglutinins after major ABO-mismatched hematopoietic stem cell (HSC) allografts has been attributed to the gradual destruction of host plasma cells by graft-versus-host effects. To corroborate this hypothesis, we retrospectively analyzed results from 383 major or major/minor ABO-mismatched unrelated and related HSC allografts performed between 1983 and 1998. All patients were conditioned by high-dose pretransplant therapy and given methotrexate/cyclosporine for graft-versus-host disease (GvHD) prophylaxis. Of the 383 patients, 155 had HLA-matched related and 228 had unrelated grafts. We asked whether unrelated recipients experienced a more rapid disappearance of isohemagglutinins than related recipients, and whether, within the groups of related and unrelated recipients, the titer disappeared faster in patients with GvHD than in those without GvHD. The median time to reach undetectable antidonor IgG and IgM titers was significantly shorter in unrelated recipients (46 versus 61 days; P = .016). In addition, related recipients with GvHD had a 2.2-fold increased likelihood (1.12-4.39,95% CI; P = .02) of reaching undetectable titers within 100 days than patients without GvHD. The persistence of antidonor isohemagglutinins led to significantly increased red blood cell (RBC) transfusion requirements in the ABO-mismatched related patients compared with ABO-matched counterparts. However, time to neutrophil and platelet engraftment, incidence of GvHD, and survival were not influenced by ABO incompatibility. In conclusion, our results corroborate the hypothesis that the rate of disappearance of antidonor isohemagglutinins after ABO-mismatched allogeneic HSC grafts is influenced by the degree of genetic disparity between donor and recipient, suggesting a graft-versus-plasma cell effect.

Graft-versus-host disease and donor-directed hemagglutinin titers after ABO-mismatched related and unrelated marrow allografts: evidence for a graft-versus-plasma cell effect

AbstractThe gradual disappearance of host antidonor isohemagglutinins after major ABO-mismatched hematopoietic stem cell (HSC) allografts has been attributed to the gradual destruction of host plasma cells by graft-versus-host effects. To corroborate this hypothesis, we retrospectively analyzed results from 383 major or major/minor ABO-mismatched unrelated and related HSC allografts performed between 1983 and 1998. All patients were conditioned by high-dose pretransplant therapy and given methotrexate/cyclosporine for graft-versus-host disease (GvHD) prophylaxis. Of the 383 patients, 155 had HLA-matched related and 228 had unrelated grafts. We asked whether unrelated recipients experienced a more rapid disappearance of isohemagglutinins than related recipients, and whether, within the groups of related and unrelated recipients, the titer disappeared faster in patients with GvHD than in those without GvHD. The median time to reach undetectable antidonor IgG and IgM titers was significantly shorter in unrelated recipients (46 versus 61 days; P = .016). In addition, related recipients with GvHD had a 2.2-fold increased likelihood (1.12-4.39,95% CI; P = .02) of reaching undetectable titers within 100 days than patients without GvHD. The persistence of antidonor isohemagglutinins led to significantly increased red blood cell (RBC) transfusion requirements in the ABO-mismatched related patients compared with ABO-matched counterparts. However, time to neutrophil and platelet engraftment, incidence of GvHD, and survival were not influenced by ABO incompatibility. In conclusion, our results corroborate the hypothesis that the rate of disappearance of antidonor isohemagglutinins after ABO-mismatched allogeneic HSC grafts is influenced by the degree of genetic disparity between donor and recipient, suggesting a graft-versus-plasma cell effect.

Induction of apoptosis of human CD3 and CD56 cells by an antibody to CD44

Graft rejection remains an obstacle to successful outcome sin MHC-mismatched allogeneic marrow transplants. In preclinical canine studies of transplants of MHC-mismatched unrelated marrow, mAb S5, directed to the cellular adhesion molecule CD44, was found effective in enhancing engraftment. This effect could be mediated by inhibitory action(s) of S5 on residual host immunologic effector cells, including apoptosis of immunocompetent cells. S5 was shown to interfere with the function of NK cells, which are known to contribute to rejection of MHC-mismatched marrow. Therefore, we tested the ability of S5 to induce apoptosis in PBMCs from healthy human donors. In this study, normal PBMC were incubated with the anti-CD44 mAb S5, control mAb 31A or medium. Early apoptotic cells were measured as percent Annexin V+/propidium iodide− cells by FACS analysis. Time course analysis from PBMCs (n=10) after 12/18h revealed a significant increase in apoptotic cells when incubated with S5 as compared to 31A (p=.002 and .002 at 12 and 18h, respectively) or S5 compared to medium (p=.002 and .002 at 12 and 18h, respectively). At 24h, the S5-induced apoptosis continued to be higher than with 31A or medium, though this was no longer significant (p=.15 and .20, respectively). PBMCs were sorted for CD3+ T cells and CD56+/CD3− NK cells via a cell sorter or autoMACS®. The incubation of CD3+ cells with S5 significantly increased the median difference (Δ) in percent of apoptosis compared to 31A (median Δ 16%, p=.02), or medium (median Δ 16%, p=.02). Similarly, CD56+/CD3− cells were highly sensitive to S5-induced apoptosis as compared to 31A (median Δ 11%, p=.02) or medium (median Δ 8%, p=.02). Taken together, these data indicate that anti-CD44 antibody S5 induces apoptosis in human T cells and NK cells by a yet unidentified mechanism. Reducing the number of immunocompetent cells inthe host before TBI could be one mechanism whereby S5 exerts its effect on facilitating engraftment in the MHC-nonidentical transplant setting.

Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the National Marrow Donor Program

Over a period of 8.5 years (February 1988 to October 1996), 1423 patients with chronic myelogenous leukemia (CML) underwent unrelated donor (URD) bone marrow transplants (BMTs) facilitated by the National Marrow Donor Program (NMDP) at 85 transplant centers. One hundred thirty-seven evaluable (9.9%) patients failed to engraft, and an additional 83 (6.6%) evaluable patients experienced late graft failure. Grade III/IV acute graft-versus-host disease (GVHD) developed in 33% of patients (95% confidence interval [CI], 30%-36%). The incidence of extensive chronic GVHD was 60% (95% CI, 56%-63%) at 2 years. Only 5.7% of patients (95% CI, 3.6%-7.8%) transplanted in chronic phase developed hematologic relapse at 3 years. Several factors were independently associated with improved disease-free survival (DFS), including transplant in chronic phase, transplant within 1 year of diagnosis, younger recipient age, a cytomegalovirus seronegative recipient, and development of no or mild acute GVHD. The combined effect of these factors on outcome is manifest in a subset (n = 157) of young (less than 35 years), chronic phase patients transplanted within 1 year of diagnosis using HLA-matched donors who had 63% (95% CI, 53%-73%) DFS at 3 years. URD BMT therapy for CML is both feasible and effective with more frequent and more rapid identification of suitable donors. Early URD transplant during chronic phase yields good results and should be considered in CML patients otherwise eligible for transplant but without a suitable related donor.

Pediatric marrow transplantation for acute leukemia using unrelated donors and T-replete or -depleted grafts: a case-matched analysis.

A retrospective, case-matched analysis of the short-term toxicity, risk of GVHD and relapse as well as outcome in pediatric unrelated marrow transplantation was conducted by comparing recipients of T-replete and -depleted grafts in a two-center setting. Both groups contained 30 patients with acute leukemia matched by age at transplant, gender, primary diagnosis and disease status. Acute (90% vs 53%) and chronic (48% vs 0%) GVHD were more common among recipients of T-replete grafts. No significant differences in graft rejection/failure or viral infections were encountered between the two groups. Relapses were more prevalent (37% vs 15%) among recipients of T-depleted grafts. Outcome (EFS) was similar in the two groups. Consequently, in the analysis of transplant outcome, the higher risk of procedure-related, toxic complications among pediatric recipients of T-replete marrow grafts appears to be balanced by an increased risk of relapse among the recipients of T-depleted grafts.

Vorinostat for Graft vs Host Disease Prevention in Children, Adolescents and Young Adults Undergoing Unrelated Donor Blood and Marrow Transplantation

Vorinostat for Graft vs Host Disease Prevention in Children, Adolescents and Young Adults Undergoing Unrelated Donor Blood and Marrow Transplantation

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.

Marrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy.

Allogeneic marrow transplantation offers curative therapy for patients with aplastic anemia. We analyzed retrospective results in 141 patients with severe aplastic anemia who received transplants between 1988 and 1995 from an unrelated volunteer donor identified through the National Marrow Donor Program (NMDP). All patients had failed one or more courses of immunosuppressive therapy. Of the patients, 121 (86%) received a radiation-containing conditioning regimen, and 20 (14%) were given chemotherapy only. Based on serologic human leukocyte antigen (HLA) typing (class I and II), 105 patients (74%) received HLA-matched marrow, and 36 (26%) received marrow mismatched for at least one HLA-A, -B, or -DR antigen. Allele-level (molecular) typing for HLA-DRB1 was available in 108 donor-recipient pairs; 77 patients received DRB -matched and 31 DRB1-mismatched transplants. All but 13% of patients were given a cyclosporine-containing regimen for graft-vs.-host disease (GVHD) prophylaxis, and 45 patients (32%) received marrow that was T cell-depleted. Among 131 evaluable patients, 116 (89%) achieved sustained engraftment and 15 (11%) did not. Among patients with engraftment, acute GVHD of grades II-IV developed in 60 patients (52%) and extensive chronic GVHD in 24 patients at risk (31%). Currently, 51 patients (36%) are surviving at 11-94 months (median 36) after transplantation. All but five have Karnofsky scores > or =80. Patients who received a serologically matched transplant fared somewhat better than did patients given a serologically mismatched transplant p = 0.03). Patients with donors matched by both serology and allele-level DRB1 typing had significantly better survival than DRB1-mismatched patients with 56 vs. 15% surviving at 3 years p = 0.001). Outcome in patients transplanted within 3 years of diagnosis was superior to that among patients transplanted with greater delay. Major causes of death were graft failure, GVHD, and infections. These data suggest that unrelated marrow transplantation offers successful therapy for a proportion of patients who have failed immunosuppressive therapy.

Probability of finding HLA-matched unrelated marrow donors for Koreans and Japanese from the Korean and Japan Marrow Donor Programs.

This study was performed to assess the probability of finding HLA-matched donors for Korean and Japanese patients from unrelated marrow donor registries of both countries. A simulation study of donor search was carried out using the donor pools of the Korean Marrow Donor Program (KMDP) with 10,244 and the Japan Marrow Donor Program UMDP) with 53,411 HLA-A, -B, -DR typed donors. The records of a total of 184 actual Korean patients and 1,302 simulated Japanese patients were searched and A, B, DR-matched donors were found for 28% of Korean and 76% of Japanese patients from the KMDP and JMDP pools, respectively. Of those patients who could not find matched donors in the registry of their own country, 30% of Koreans could find matched donors in the JMDP and 10% of Japanese in the KMDP pools. It can be concluded that future international collaboration between Korea and Japan would be very effective for unrelated bone marrow transplantations.

Unrelated donor marrow transplantation for treatment of childhood hematologic malignancies-effect of HLA disparity and cell dose.

Marrow and hematopoietic cell transplants provide the possibility of a cure for patients with high risk and therapy-resistant leukemia. However the minority of patients are fortunate enough to have an HLA identical sibling. Transplants from HLA matched unrelated donors were of only theoretical interest given the very high degree of polymorphism among HLA antigens throughout the human population and the lack of organized groups of HLA-typed volunteer donors. Demonstration in the early 1980’s that unrelated marrow transplants were medically feasible gave great impetus to the creation of publicly supported donor registries (1-3). In the U.S., a national registry was authorized by congressional legislation in 1984, and in 1986 a federal contract initially administered by the Office of Naval Research was awarded to a consortium of investigators and centers headed by Dr. Jeffrey McCullough of the University of Minnesota (4). This consortium grew to become a comprehensive network of donor recruitment groups, donor centers, marrow and stem cell collection centers, and transplant centers known as the National Marrow Donor Program (NMDP). The NMDP currently consists of 96 donor centers and 127 transplant centers, including 8 donor centers located in countries outside the United States. National registries also exist in several other countries.

Optimizing Outcome After Unrelated Marrow Transplantation by Comprehensive Matching of HLA Class I and II Alleles in the Donor and Recipient

In unrelated marrow transplantation, the benefit of matching class II HLA-DRB1 and DQB1 alleles of the donor and recipient is well documented. Little is known about the clinical relevance of matching for class I HLA-A, B, and C alleles. We used DNA-amplification methods to identify the HLA-A, B, and C alleles of 300 patients and their donors. The incidence of graft failure was correlated with multiple class I mismatching in the donor. The risk of grades III-IV acute graft-versus-host disease was highest with class II mismatching in the recipient. Mismatching for a single class I or class II allele had no effect on survival, but mortality was increased by mismatching for more than one class I allele and by simultaneous mismatching for class I and class II alleles. We conclude that matching HLA class I and class II alleles of the donor and recipient can improve outcome after unrelated marrow transplantation.

Association Between Pretransplant Interferon-α and Outcome After Unrelated Donor Marrow Transplantation for Chronic Myelogenous Leukemia in Chronic Phase

Treatment options for patients diagnosed with chronic myelogenous leukemia (CML) in chronic phase (CP) who lack a suitable related donor for marrow transplantation include hydroxyurea, interferon-α (IFN-α), or transplantation from an unrelated donor (URD). Most studies support the view that treatment with IFN-α results in prolonged survival compared with hydroxyurea therapy. Some patients are offered URD transplantation as a second-line treatment; however, the impact of pretransplant IFN-α on the outcome of URD transplantation is uncertain. To address this question, we evaluated the effect of pretransplant IFN-α therapy in 184 patients undergoing URD transplantation for CML in CP at a single center. Of the 184 patients, 114 did not receive IFN-α, whereas 22, 23, and 25 patients received IFN-α for, respectively, 1 to 5, 6 to 12, and more than 12 months before transplant. Pretransplant IFN-α therapy administered for ≥6 months was associated with an increased risk of severe (grades III-IV) acute graft-versus-host disease (GVHD; relative risk [RR], 3.0; 95% confidence interval [CI], 1.4 to 6.2; P = .004) and mortality (RR, 2.1; 95% CI, 1.3 to 3.5; P = .003) relative to less than 6 months or no IFN-α therapy. Increased mortality occurred between 100 and 365 days after transplant (P = .005), was limited to patients with severe acute GVHD, and was due to chronic GVHD refractory to immunosuppressive therapy. Other variables associated with mortality included HLA-DRB1 or DQB1 (but not HLA-A or B) mismatched donors, age greater than 50 years, weight ≥110% of ideal body weight, and the absence of cytomegalovirus (CMV) or fungal prophylaxis. For patients treated with IFN-α for less than 6 months before transplant, who were ≤50 years of age, received a HLA-A, B, DRB1, and DQB1 matched URD transplant, and received CMV and fungal prophylaxis after transplant (n = 48), survival was 87% ± 5% at 5 years. These data provide a rationale for immediate transplantation in preference to extended treatment with IFN-α when the patient is ≤50 years of age and has an HLA-compatible unrelated volunteer donor.

#633 HLA-DQBI disparity between patients and unrelated marrow donors (URD) matched for HLA-A, B, and -DRBI by DNA typing

#633 HLA-DQBI disparity between patients and unrelated marrow donors (URD) matched for HLA-A, B, and -DRBI by DNA typing

Booster marrow or blood cells for graft failure after allogeneic bone marrow transplantation.

Twenty allogeneic bone marrow transplant patients were treated with an additional dose of donor cells (boost dose) for graft failure (n = 7), partial graft failure (n = 11) or extensive hemolysis caused by remaining recipient cells producing anti-erythrocyte antibodies (n = 2). Donors were in 12 cases HLA-identical siblings, three mismatched related donors and five unrelated donors. Cell source was in 13 cases bone marrow and in seven peripheral blood progenitor cells. Median time from BMT to booster dose was 3.4 months (range 0.7-59.3). Median infused cell dose was 2.4 x 10(8)/kg patient (range 0.5-19.0). As GVHD prophylaxis most patients were already receiving different combinations of cyclosporine, prednisolone and methotrexate. No preparative treatment was given prior to boost in 16 patients; four received ATG. After boost, 11 patients developed acute GVHD, six grade I, four grade II and one grade III. Except for one patient, acute GVHD after boost was less, or the same grade as after BMT. Six patients developed chronic GVHD, three limited and three extensive. Five patients died within 30 days of the boost. Nine of 15 (60%) evaluable patients became transfusion independent within 30 days and three more within 60 days. Causes of death were: infections six (IP four, pneumonia two), relapse three; and GVHD three. Three out of five patients transplanted with unrelated marrow suffered from severe immunological reactions and died 2-3 months after the boost dose. Patient survival 1 and 3 years after boost was 55% and 43%, respectively. Among patients with hematological malignancies, leukemia-free survival at 3 years was 41%.

Successful unrelated marrow transplantation for patients over the age of 40 with chronic myelogenous leukemia.

Some older patients (> or =40 years) with chronic myelogenous leukemia (CML) who lack human leukocyte antigen (HLA)-identical sibling donors are not offered unrelated marrow transplantation because of concerns over excessive regimen-related toxicity, in particular due to graft-vs.-host disease (GVHD). The purpose of this study was to determine the efficacy and toxicity of unrelated marrow transplantation in older CML patients using a regimen designed to minimize the severity of GVHD. Thirty-one consecutive patients over the age of 40 with CML received unrelated marrow transplants between January 1988 and June 1997. Twenty-one patients were transplanted in chronic phase while ten were transplanted in the accelerated phase of their disease. Fifteen patients received transplants from phenotypically matched donors while 16 received marrow grafts from donors who were mismatched at one HLA locus. GVHD prophylaxis consisted of ex vivo T cell depletion of the donor marrow graft plus posttransplant cyclosporine administration. Durable engraftment was achieved in 29 of 31 patients (94%). The probability of developing grades II-IV or severe grades III-IV acute GVHD was 39.2 and 7.1%, respectively. There was no difference in the incidence of grades II-IV acute GVHD between patients transplanted with marrow grafts from phenotypically matched (38.1%) vs. those transplanted from mismatched unrelated donors (40%, p = 0.99). The 2-year probability of relapse for the entire population was 29.4%. Relapse was significantly higher for patients transplanted in accelerated phase (60%) than for those in chronic phase (13.8%, p = 0.027). The 2-year probability of overall survival and disease-free survival for the entire cohort was 56 and 45%, respectively. There was no significant difference in survival or disease-free survival for patients receiving phenotypically matched vs. mismatched marrow grafts. Immunological reconstitution for this cohort was compared with a younger (<40 years) patient population that had been similarly transplanted over the same time period. Immune function as assessed by total T cell, B cell, NK cell, and T cell subset reconstitution posttransplant was quantitatively equivalent in the two groups with most parameters normalizing within 18 months of transplant. We conclude that CML patients over the age of 40 who have either phenotypically matched or one antigen-mismatched unrelated donors can successfully undergo allogeneic marrow transplantation. T cell depletion of the marrow graft may be advantageous in these older patients by reducing GVHD severity, particularly in those patients transplanted with HLA-disparate marrow grafts.

Unrelated and HLA-nonidentical related donor marrow transplantation for thalassemia and leukemia. A combined report from the Seattle Marrow Transplant Team and the International Bone Marrow Transplant Registry.

Allogeneic marrow transplantation is curative therapy for thalassemia, but fewer than 30% of patients have an HLA-identical sibling marrow donor. Selection of alternative donors of hematopoietic stem cells (unrelated individuals or HLA-nonidentical family members) has been aided by establishment of world-wide donor registries now exceeding 3.6 million volunteers and by DNA-based HLA typing to more closely match potential donors. Coupled with improved methods to control graft-versus-host disease and prevent fungal and cytomegalovirus infection, remarkable progress has been made in alternative donor transplantation. For patients 50 years of age or younger, with recently diagnosed chronic myelogenous leukemia (CML) in chronic phase, 1- and 5-year survivals after HLA-A, B, DRB1 identical unrelated marrow transplantation in Seattle are 82% and 74%, respectively. These results are essentially identical to outcome in similar patients given HLA-matched sibling allografts. However, the world-wide number of alternative donor transplants for thalassemia remains limited to date: 4 unrelated and 60 HLA-nonidentical related transplants have been reported to the IBMTR since 1969 with actuarial overall survival of 75%. Using the paradigm of CML, it is likely that access to curative therapy of thalassemia will improve with optimal HLA typing and donor selection early in the course of disease.

Epitope Specificity of CD44 for Monoclonal Antibody–Dependent Facilitation of Marrow Engraftment in a Canine Model

AbstractPrimary graft rejection after marrow transplantation occurs more frequently in patients receiving HLA-haploidentical compared with HLA-identical sibling transplants. Both human and experimental animal data suggest that the cells responsible for this phenomenon are either host natural killer (NK) cells, T cells, or both. To investigate the mechanisms of graft rejection, we have developed a canine model of marrow transplantation, which uses DLA-nonidentical unrelated donors in the absence of postgrafting immunosuppression. In this model most animals rejected their marrow grafts after a preparative regimen of 9.2 Gy total body irradiation (TBI). However, engraftment of DLA-nonidentical marrow can be facilitated when the recipients are pretreated with monoclonal antibody (MoAb) S5, which recognizes CD44. In this report, we extended these observations by first cloning the canine CD44 and, next, mapping the epitope recognized by S5, which was located in a region conserved among human and canine CD44 and was distinct from the hyaluronan binding domain. However, in vitro binding of S5 caused a conformational change in CD44, which allowed increased hyaluronan binding. Then, we reexamined the in vivo model of marrow transplantation and compared results with MoAb S5 to those with two other anti-CD44 MoAbs, IM7 and S3. Only MoAb S5 significantly increased the engraftment rate of DLA-nonidentical unrelated marrow, whereas the two other anti-CD44 MoAbs were ineffective. The enhanced in vivo effect was not related to differences in the MoAbs' avidities, since both S5 and IM7 had equivalent binding to CD44, but most likely related to the specific epitope that S5 recognizes. Thus, this study shows that the effect of the anti-CD44 MoAb S5 in facilitating engraftment is epitope specific and if one is to use an anti-CD44 to facilitate engraftment of marrow in humans, one cannot assume that any anti-CD44 would work.