Biomedical subjects

T Gooley

Publications and source records attributed to T Gooley.

At least 37 records · Page 2Linked to original sources

PubMed2001

Secondary failure of platelet recovery after hematopoietic stem cell transplantation.

After primary recovery of platelet counts after transplantation, there can be a late persistent decline called secondary failure of platelet recovery (SFPR), which may occur although the counts of other cell lineages remain within the normal range. SFPR was defined as a decline of platelet counts below 20,000/microL for 7 consecutive days or requiring transfusion support after achieving sustained platelet counts > or = 50,000/microL without transfusions for 7 consecutive days after hematopoietic stem cell transplantation (HSCT). The study population consisted of 2871 consecutive patients receiving transplants from January 1990 to March 1997. After primary recovery of platelet counts, SFPR not due to relapse of the underlying disease was observed in 285 of 1401 (20%) patients undergoing allogeneic transplantation and 36 (8%) of 444 patients undergoing autologous transplantation, with a median time of onset after transplantation at day 63 (range, day 21-156) and day 44 (range, day 24-89), respectively. Concomitant neutropenia was seen in 57 (20%) of 285 patients undergoing allogeneic HSCT and 7 (19%) of 36 patients undergoing autologous HSCT with SFPR. By multivariable analysis, the following were factors significantly associated with SFPR after allogeneic HSCT: a transplant from an unrelated donor; a graft-versus-host disease (GVHD) prophylaxis other than methotrexate and cyclosporine; development of grade 2 through 4 acute GVHD; impaired renal or liver function; conditioning with the combination of busulfan, cyclophosphamide, and total body irradiation; stem cell dose; and infections. Cytomegalovirus infection after engraftment and source of stem cells were the only significant risk factors after autologous HSCT. The hazard rate of death was significantly higher in patients who experienced SFPR (hazard ratio = 2.6 for allogeneic HSCT; hazard ratio = 2.2 for autologous HSCT). SFPR was associated with serious complications and poor outcome after transplantation. The identification of the characteristics and risk factors for SFPR could improve patient counseling and management and lead to the design of effective treatment strategies.

Adolescent↗

PubMed2001

Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation.

Lipopolysaccharide (LPS) has been implicated in the pathogenesis of graft-versus-host disease (GVHD). The toll-like receptor (TLR)-4 has been recently identified as a major receptor for LPS. Mutations of TLR4 have been associated with LPS hyporesponsiveness. We hypothesized that TLR4 mutations reduce the risk of acute GVHD in allogeneic marrow transplant recipients. In a preliminary study to determine the frequency of TLR4 mutations and their possible association with GVHD, we tested 237 patients and their HLA-identical sibling donors for 2 TLR4 polymorphisms. All patients received methotrexate and cyclosporine for GVHD prophylaxis. One or more mutants were detected in 10.8% of patients and 10.6% of donors. Multivariable logistic regression models were used to analyze the association between TLR4 mutations and probability (1-sided) of GVHD. The odds ratio (adjusted for advanced disease, total body irradiation dose, and patient age) for development of grades II to IV GVHD when a mutation was present in the recipient was 0.63 (95% confidence interval [CI], 0.25-1.60; P = .16). When a mutation was present in the donor, the adjusted odds ratio was 0.88 (95% CI, 0.36-2.17; P = .40). When a mutation was present in both recipient and donor, the odds ratio was 0.72 (95% CI, 0.22-2.32; P = .29). Among 24 patients with TLR4 mutations in either donor or recipient, 4 (16.7%) developed gram-negative bacteremia. Among 213 patients without mutations, 14 (6.6%) developed gram-negative bacteremia (P = .09). The data indicate that a reduced risk of acute GVHD is associated with TLR4 mutations and that TLR4 mutations may increase the risk for gram-negative bacteremia. However, these associations are not statistically significant in recipients of HLA-matched sibling marrow transplants who are prophylactically treated for infections and GVHD. A much larger study population would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans.

Bacteremia↗

PubMed2001

Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience.

Community respiratory viruses (CRVs) are an important cause of morbidity and mortality among recipients of hematopoietic stem cell transplants (HSCT). At the Fred Hutchinson Cancer Research Center, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) infections in HSCT recipients have been studied intensively for more than a decade. Over time, mortality from these infections has declined as the approach to diagnosis has become more aggressive and more stringent preventive measures have been instituted. However, mortality among HSCT recipients with RSV or PIV pneumonia remains high. Uncontrolled studies at our center suggest that prompt therapy with aerosolized ribavirin has reduced mortality from RSV pneumonia but does not appear to affect the course of established PIV pneumonia. Two controlled clinical trials of ribavirin therapy for RSV infection in HSCT recipients are in progress.

Clinical Trials as Topic↗

PubMed2000

Non-Fc receptor-binding humanized anti-CD3 antibodies induce apoptosis of activated human T cells.

Human trials in organ allografts have demonstrated that murine anti-CD3 mAbs are immunosuppressive. By mimicking Ag, anti-CD3 can produce T cell activation, anergy, or death. Activation of resting T cells in vivo results in dose-limiting cytokine release and is caused by Ab-mediated cross-linking of T cells and Fcgamma receptor (FcR)-bearing cells. With the goal of minimizing cytokine-induced toxicity, anti-CD3 have been engineered to lower Fc binding avidity. Preclinical murine studies have indicated that non-FcR-binding anti-CD3 can induce apoptosis of Ag-activated T cells. Since induction of T cell apoptosis may be an important mechanism of immunosuppression by anti-CD3, we tested whether Fc mutations affect the ability of anti-human CD3 to induce apoptosis of activated T cells. We compared wild-type murine anti-CD3, M291, and OKT3 and their humanized, FcR- and non-FcR-binding structural variants in quantitative assays of T cell apoptosis. Non-FcR-binding variants produced more sustainable phosphorylation of extracellular signal-regulated kinase-2, greater release of IFN-gamma, and more effectively caused activation-dependent T cell apoptosis. Non-FcR-binding variants dissociated more quickly from the T cell surface and caused less internalization of the TCR, which then remained available in greater abundance on the cell surface for signaling. Cross-linking of non-FcR-binding variants by antiglobulin enhanced TCR internalization and minimized induction of T cell apoptosis. We conclude that non-FcR-binding, humanized anti-CD3 have improved ability to induce apoptosis of activated T cells, presumably by allowing durable expression of the TCR and sustained signaling.

Adult↗

PubMed2000

Polyclonal hematopoiesis with variable telomere shortening in human long-term allogeneic marrow graft recipients.

Donor-derived hematopoiesis was assessed in 17 patients who received allogeneic marrow grafts from HLA-matched siblings between 1971 and 1980. Complete blood counts were normal or near normal in all patients except one. Chimerism analyses, using either dual-color XY-chromosome fluorescence in situ hybridization (FISH) or analysis of variable number tandem repeat loci, indicated that 15 out of 16 patients had greater than 97% donor-derived hematopoiesis, whereas 1 patient had indeterminate chimerism. All 12 recipients of grafts from female donors exhibited polyclonal hematopoiesis by X-linked clonal analysis with the use of molecular probes. Of the 17 recipients, 9 exhibited a less than 1.0-kilobase shortening of granulocyte telomere length compared with their respective donors, according to terminal restriction fragment analysis or flow-FISH with a fluorescein-labeled peptide nucleic acid probe. These data suggest that under standard transplantation conditions, the stem cell proliferative potential is not compromised during hematopoietic reconstitution. (Blood. 2000;96:3991-3994)

Adolescent↗

PubMed2000

A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.

Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 ((131)I)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg (131)I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of (131)I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of (131)I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.

Adult↗

PubMed2000

Increased apoptosis of peripheral blood T cells following allogeneic hematopoietic cell transplantation.

Lymphopenia and immune deficiency are significant problems following allogeneic hematopoietic cell transplantation (HCT). It is largely assumed that delayed immune reconstruction is due to a profound decrease in thymus-dependent lymphopoiesis, especially in older patients, but apoptosis is also known to play a significant role in lymphocyte homeostasis. Peripheral T cells from patients who received HCT were studied for evidence of increased cell death. Spontaneous apoptosis was measured in CD3(+) T cells following a 24-hour incubation using 7-amino-actinomycin D in conjunction with the dual staining of cell surface antigens. Apoptosis was significantly greater among CD3(+) T cells taken from patients 19-23 days after transplantation (30.4% +/- 12.5%, P <.05), and 1 year after transplantation (9.7% +/- 2.8%, P <.05) compared with healthy controls (4.0% +/- 1.5%). Increased apoptosis occurred preferentially in HLA (human leukocyte antigen)-DR positive cells and in both CD3(+)/CD4(+) and CD3(+)/CD8(+) T-cell subsets, while CD56(+)/CD3(-) natural killer cells were relatively resistant to apoptosis. The extent of CD4(+) T-cell apoptosis was greater in patients with grade II-IV acute graft-versus-host disease (GVHD) (33. 9% +/- 11.3%) compared with grade 0-I GVHD (14.6 +/- 6.5%, P <.05). T-cell apoptosis was also greater in patients who received transplantations from HLA-mismatched donors (39.5% +/- 10.4%, P <. 05) or HLA-matched unrelated donors (32.1% +/- 11.4%, P <.05) compared with patients who received transplantations from HLA-identical siblings (19.6% +/- 6.7%). The intensity of apoptosis among CD4(+) T cells was significantly correlated with a lower CD4(+) T-cell count. Together, these observations suggest that activation of T cells in vivo, presumably by alloantigens, predisposes the cells to spontaneous apoptosis, and this phenomenon is associated with lymphopenia. Activation-induced T-cell apoptosis may contribute to delayed immune reconstitution following HCT. (Blood. 2000;95:3832-3839)

Acute Disease↗

PubMed2000

Cutting edge: persistent fetal microchimerism in T lymphocytes is associated with HLA-DQA1*0501: implications in autoimmunity.

The host's MHC genotype plays a critical role in susceptibility to autoimmune diseases. We previously proposed that persistent fetal microchimerism from pregnancy contributes to the pathogenesis of autoimmune diseases such as scleroderma. In the current study, we investigated whether the specific host MHC genotype is associated with persistent microchimerism among T lymphocytes in women with scleroderma and in healthy women. Fetal microchimerism among T lymphocytes was strongly associated with HLA DQA1*0501 of the mother (odds ratio (OR) = 13.5, p = 0.007, p corrected (pc) = 0.06) and even more strongly with DQA1*0501 of the son (OR = infinity; p = 0. 00002, pc = 0.0002). This is the first description of an association between persistent fetal microchimerism in maternal T lymphocytes and specific HLA class II alleles. Although the association was observed in both healthy women and in women with scleroderma, the finding suggests an additional route by which HLA genes might contribute to susceptibility to autoimmune disease.

Adolescent↗

PubMed2000

Adoptive immunotherapy in canine mixed chimeras after nonmyeloablative hematopoietic cell transplantation.

Development of nontoxic and nonmyeloablative regimens for allogeneic hematopoietic stem-cell transplantation will decrease transplantation-related mortality caused by regimen-related toxic effects. In pursuit of this goal, a dog model of stable mixed hematopoietic chimerism was established in which leukocyte-antigen-identical litter mates are given sublethal total-body irradiation (2 Gy) before stem-cell transplantation and immunosuppression with mycophenolate mofetil and cyclosporine afterward. In the current study, we examined whether donor lymphocyte infusion (DLI) could be used as adoptive immunotherapy to convert mixed to complete donor chimerism. First, 8 mixed chimeras were given unmodified DLI between day 36 and day 414 after stem-cell transplantation. After a 10- to 47-week follow-up period, there were no significant changes in the percentage of donor engraftment. Next, we immunized the donor to the minor histocompatibility antigens (mHA) of the recipient by means of repeated skin grafting. Lymphocytes from the mHA-sensitized donor were infused between day 201 and day 651 after transplantation. All 8 recipients of mHA-sensitized DLI had conversion to greater than 98% donor chimerism within 2 to 12 weeks of the infusion. Complications from mHA-sensitized DLI included graft-versus-host disease in 2 dogs and marrow aplasia in 1. These results showed that the low-dose transplant regimen establishes immune tolerance, and mHA-sensitized DLI is required to break tolerance, thereby converting mixed to complete donor chimerism. We propose that mixed chimerism established after nonmyeloablative allogeneic stem-cell transplantation provides a platform for adoptive immunotherapy that has clinical potential in the treatment of patients with malignant diseases.

Animals↗

PubMed2000

Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors.

BACKGROUND: Survival following metastatic or recurrent Ewing sarcoma family tumors (ESFT) remains <25%. Myeloablative therapy with hematopoietic stem cell transplantation (HSCT) may improve survival for poor-risk ESFT. We describe the toxicity and efficacy of a myeloablative chemotherapy regimen, followed by a second myeloablative radiotherapy regimen as consolidation treatment for poor-risk ESFT. PROCEDURE: Sixteen patients with poor-risk ESFT were treated with myeloablative therapy followed by HSCT. All patients received busulfan, melphalan, and thiotepa (BuMelTT) as chemotherapy conditioning. Nine patients received total marrow irradiation (TMI) as a second myeloablative therapy, also followed by HSCT. Seven patients were excluded from TMI because of inadequate peripheral blood stem cell harvest, extensive prior radiation therapy, early disease progression, orpatient refusal. The disease status prior to my eloablative therapy was first complete response (CR1) in three patients, CR2 in nine, second partial response (PR2) in one, CR3 in one, and progressive disease (PD) in two. RESULTS: One patient died of regimen-related toxicity, one from late pulmonary toxicity, and one following allogeneic transplantation for myelodysplasia. Eight developed recurrent disease (median time to progression 6.8 months). Six survive without relapse from 27 to 66 months following BuMelTT (median follow-up 42 months), all of whom received both BuMelTT and TMI patients (3-year event-free survival 36%). CONCLUSIONS: Dual myeloablative therapy with BuMelTT and TMI was a feasible and promising treatment approach for patients with poor-risk ESFT. Inability to collect sufficient PBSC and extensive previous radiation therapy limit the ability to deliver TMI as a second HSCT conditioning regimen.

Adolescent↗

PubMed2000

Phase I topotecan preparative regimen for high-risk neuroblastoma, high-grade glioma, and refractory/recurrent pediatric solid tumors.

We evaluated the toxicity and maximum tolerated dose of topotecan in a novel myeloablative regimen as treatment for high-risk pediatric tumors. Patients received an assigned topotecan dosage in combination with fixed doses of carboplatin and thiotepa, followed by autologous hematopoietic stem cells infusion. Topotecan dose was escalated in cohorts of four patients until the maximum tolerated dose of topotecan was defined or until accrual of 30 patients. Pharmacokinetics of topotecan were examined, and event-free survival was estimated. We describe preliminary results following treatment of 25 pediatric patients with high-risk solid tumors.

Antineoplastic Agents↗

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

Clinical outcome of breast and ovarian cancer patients treated with high-dose chemotherapy, autologous stem cell rescue and THERATOPE STn-KLH cancer vaccine.

The purpose of this study was to evaluate the toxicity and potential efficacy of administering the THERATOPE STn-KLH cancer vaccine to ovarian and breast cancer patients after an autologous stem cell transplant. Forty patients (11 high-risk stage II/III breast cancer, 22 stage IV breast cancer, and seven stage III/IV ovarian cancer patients) were treated with high-dose chemotherapy followed by autologous/syngeneic stem cell rescue and vaccination with THERATOPE STn-KLH (Sialyl-Tn-KLH with Detox-B Stable Emulsion). Each patient was scheduled to receive a total of five vaccinations beginning on days 30-151 after stem cell infusion. The vaccine was well tolerated. Induration and erythema at the site of injection were the most common side-effects. When one compares the outcome of patients vaccinated with 66 breast and ovarian cancer patients who were not, following risk-adjustment analysis, vaccinated patients appeared more likely to survive (P = 0.07) and less likely to relapse (P = 0. 10). Vaccinated patients with the greatest specific lytic activity against STn+OVCAR tumor cells relative to nonspecific killing of Daudi cells tended to remain in remission longer than patients who displayed less specific immune activity (P = 0.057). We conclude that the THERATOPE STn-KLH cancer vaccine is well tolerated in breast and ovarian cancer patients after autologous transplant and, while not statistically significant, the trends in data support the concept that THERATOPE vaccine may decrease the risk for relapse and death and thus warrants further study. Bone Marrow Transplantation (2000) 25, 1233-1241.

Adult↗

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

Negative regulators of hemopoiesis and stroma function in patients with myelodysplastic syndrome.

The mechanism that leads to hemopoietic failure in patients with myelodysplastic syndrome (MDS) is not well understood. There is evidence, however, that regulatory molecules such as tumor necrosis factor (TNF)-alpha, Fas (CD95), and Fas-ligand, which negatively affect hemopoiesis by way of apoptosis are upregulated. Here we analyzed marrow samples from 80 patients with MDS in regard to TNF-alpha and Fas-ligand levels and a possible correlation with various disease parameters and risk factors. TNF-alpha levels were elevated in comparison to samples from normal marrow donors, however, no significant correlation with FAB subtype, cytogenetic risk group or score by the International Prognostic Scoring System (IPSS) was observed. However, there was an inverse correlation between the cytogenetic risk category (low, intermediate, high) and levels of soluble Fas-ligand. The major source of TNF-alpha were mononuclear (non-stromal) cells which appeared to produce TNF-alpha at maximum levels. Limiting dilution analysis of CD34+ precursor cells showed that individually assayed cells, removed from companion cells that presumably provided negative signals such as TNF-alpha or Fas-ligand, were able to generate progressively increasing numbers of colonies. Stromal layers derived from MDS marrow did not have an inhibitory effect. In fact, higher colony numbers were obtained from both normal and MDS marrow derived hemopoietic precursors propagated on irradiated stromal layers from MDS marrow than on stromal layers from normal marrow. These results show that substantial numbers of normal hemopoietic precursors persist in MDS marrow. However, differentiation into mature cells is inhibited by negative signals originating from accessory or abnormal hemopoietic precursors in the non-adherent marrow fraction.

Adolescent↗

PubMed1999

Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graft-versus-host disease after allogeneic marrow transplantation.

Results of a previous study suggested that recipient mismatching for the minor histocompatibility antigen HA-1 is associated with acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. In that study, most patients received either cyclosporine or methotrexate for GVHD prophylaxis, and a cytotoxic T-cell clone was used to test for HA-1 disparity. To facilitate large-scale testing, we developed a method that uses genomic DNA to identify HA-1 alleles. A retrospective study was conducted to correlate HA-1 disparity and the occurrence of acute GVHD in 237 HLA-A2-positive white patients who had received a marrow or peripheral blood stem cell transplant from an HLA-identical sibling. All patients received both methotrexate and cyclosporine for GVHD prophylaxis. The presence of HLA-A*0201 was confirmed in 34 of the 36 HA-1 disparate pairs by sequencing the HLA-A locus. Grades II-IV GVHD occurred in 22 (64.7%) of these 34 patients, compared with 86 (42.8%) of the 201 patients without HA-1 disparity (odds ratio, 2. 45; 95% confidence interval [CI], 1.15 to 5.23; P =.02). Recipient HA-1 disparity showed a trend for association with acute GVHD (odds ratio, 2.1; 95% CI, 0.91 to 4.68; P =.08) when a multivariable logistic regression model was used to include additional risk factors. These data are consistent with results of the previous study, suggesting an association between HA-1 disparity and risk of acute GVHD, but the strength of this association may be lower in patients who received both methotrexate and cyclosporine than in those who received methotrexate or cyclosporine alone.

Acute Disease↗

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↗