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N J Chao

Publications and source records attributed to N J Chao.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prevention of acute graft-vs.-host disease: effect on chronic graft-vs.-host disease and long-term survival.

Graft-vs.-host disease (GVHD) is a major predictor of outcome following allogeneic bone marrow transplantation (BMT). For patients alive at day 100 after BMT, the presence or absence of chronic GVHD is one of the most important determinants of survival and quality of life. We wished to determine the effects on chronic GVHD of two regimens used for the prophylaxis of acute GVHD: cyclosporine, methotrexate, and prednisone (CSA/MTX/PSE) and cyclosporine and prednisone (CSA/PSE). One hundred forty-nine evaluable patients were entered into the acute GVHD study. As of 31 March 1997, 63 months after the last patient underwent BMT, the median survival time was 4.5 years (range 0.09-9.9). The incidence of chronic GVHD was independent of the prophylactic regimen (55 vs. 54%), and extensive chronic GVHD occurred in 25 and 24% of patients receiving CSA/MTX/PSE and CSA/PSE, respectively. Of note, the median Karnofsky performance status of both groups was 100% (range 70-100%), reflecting the low incidence of extensive chronic GVHD. Survival rates free of chronic GVHD were 52 vs. 42% (p = 0.29) for patients receiving CSA/MTX/PSE vs. CSA/PSE. The incidence of relapse was also similar in both groups of patients. These data suggest that the combinations of CSA/MTX/PSE and CSA/PSE result in comparable chronic GVHD-free survival without an increase in leukemic relapse.

Acute Disease↗
PubMed1999

Pathophysiologic mechanisms of acute graft-vs.-host disease.

Graft-vs.-host disease (GVHD) remains the major toxicity of allogeneic bone marrow transplantation. Mechanistic studies in experimental animal models provide a better understanding of the complex relationships and cascade of events mediated by cellular and inflammatory factors. Also, advances in basic immunology have cleared the way for a more precise view of allogeneic reactions between donor and host. In addition, the use of mutant mice lacking critical cytolytic proteins has helped map out the molecular pathways by which GVHD targets organ damage. In this article, these mechanisms are reviewed and synthesized into a coherent conceptual framework, providing a state-of-the-art summary of the pathophysiology of acute GVHD.

Acute Disease↗
PubMed1999

Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support.

PURPOSE: We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy. PATIENTS AND METHODS: Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses. RESULTS: The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P =.0041), smaller metastatic foci (</= 2 v > 2 cm) (P =. 0165), a longer disease-free interval from initial diagnosis to diagnosis of metastases (</= 2 v > 2 years) (P =.0051), and prior treatment with tamoxifen (P =.0152) were good prognostic signs for overall survival. Patients who had received prior adjuvant therapy (P =.0001) and those who developed liver metastases (P =.0001) had decreased long-term survival. In the subgroup of responders to AFM induction, multivariate analysis showed that those with visceral metastases did less well (P =.0006), as did patients who had received prior adjuvant therapy (P =.0023). However, those who had received tamoxifen therapy in the adjuvant setting did better (P =. 0143). CONCLUSION: The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive-patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.

Adult↗
PubMed1999

A feasibility study of multiple cycle therapy with melphalan, thiotepa, and paclitaxel followed by mitoxantrone, thiotepa, and paclitaxel with autologous hematopoietic cell support for metastatic breast cancer.

Dose-intensive chemotherapy appears to be important in the treatment of patients with recurrent solid tumors. Expanding upon our prior experience, we report the results of our most recent approach to administering dose-intensive therapy using four cycles of moderately high-dose chemotherapy with hematopoietic cell support for patients with metastatic breast cancer. This outpatient therapy includes high-dose melphalan, thiotepa, and paclitaxel for two cycles followed by mitoxantrone, thiotepa, and paclitaxel for two cycles, with each cycle supported with autologous peripheral blood progenitor cells (PBPCs). Between December 1994 and June 1996, 16 patients with recurrent or refractory breast cancer were enrolled in this prospective study. They had received a median of two previous chemotherapy regimens, with a median of nine prior cycles of chemotherapy. For mobilization of autologous PBPCs, patients received cyclophosphamide, 4 g/m2, followed by granulocyte colony-stimulating factor (G-CSF). PBPCs were collected by apheresis. Each day's collection was divided into four equal fractions, and each fraction was infused after each cycle of combination therapy. Cycles 1 and 2 consisted of melphalan, 80 mg/m2, thiotepa, 300 mg/m2, and paclitaxel, 200 mg/m2. Cycles 3 and 4 were comprised of mitoxantrone, 30 mg/m2, and thiotepa and paclitaxel at the same doses as in the first two cycles. The cyclophosphamide infusion was administered in the hospital, whereas all subsequent infusions of chemotherapy and PBPCs were performed on an outpatient basis. The first seven patients were randomized to receive alternate cycle G-CSF or placebo on day +1 of each cycle. Including the initial pulse of cyclophosphamide, 67 (84%) of a planned 80 total courses of chemotherapy were delivered. Of the planned 64 cycles of high-dose combination chemotherapy, 52 cycles (81%) were delivered. Treatment was discontinued for progressive disease (one patient) or morbidity (five patients). Twelve of 16 patients completed at least three cycles of therapy. Nine patients completed all four cycles. One death resulted from fungal sepsis. In 20 cycles delivered to the first seven patients, day +1 G-CSF versus placebo was administered, with a median WBC recovery of 10 versus 13 days, respectively (P = 0.048 in cycle 1). The median duration of response was almost 9 months, and the median survival was 18 months after therapy. With a median follow-up of 1.5 years and longest follow-up of 4.2 years, two patients continue to be without evidence of disease. The 3-year event-free survival, freedom from progression, and overall survival are 19%, 20%, and 31%, respectively. This four-cycle regimen of high-dose combination therapy supported with hematopoietic progenitor cells is feasible, but it is associated with a range of posttransplant complications. The efficacy of such a treatment would have to be substantially superior to that of other currently available therapies, including single autologous transplant procedures, to justify the prolonged period of treatment, multiple episodes of pancytopenia, and associated toxicities, including infectious risks. G-CSF administration after each PBPC infusion appears to accelerate time to neutrophil recovery but does not affect red cell or platelet engraftment.

Adult↗
PubMed1999

A predictive model for relapse in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplant.

High-dose chemotherapy (HDCT) is currently under evaluation for high-risk primary breast cancer (HRPBC), defined by extensive axillary nodal involvement or inflammatory breast carcinoma. Phase II studies of HDCT for HRPBC show that 30-40% of patients eventually relapse. We retrospectively reviewed 176 patients enrolled in clinical trials of HDCT for HRPBC at the University of Colorado and analyzed 23 potential predictive variables for relapse. All of the patients received the same regimen, with cyclophosphamide, cisplatin, and BCNU. Nine patients who experienced a toxic death were excluded from this analysis. The resulting predictive model was subsequently tested in an independent patient set treated at Duke University with the same HDCT regimen. Nodal ratio (number of involved nodes:number of sampled nodes), tumor size, grade, stage, estrogen receptor, progesterone receptor, and clinical inflammatory breast carcinoma correlated with risk of relapse. Nodal ratio, tumor size, and the combined estrogen receptor/progesterone receptor status were independent predictors. A scoring system using those three variables determines the risk of relapse, with a sensitivity and specificity of 60 and 90%, respectively, and a positive and negative predictive value of 65 and 88%, respectively. The differences in relapse-free survival and overall survival between high- and low-score patients were highly significant (P<0.000001). This model was subsequently validated in the Duke patient set. This model can identify two subgroups of HRPBC patients with low (12%) and high (65%) risk for recurrence after HDCT. Future research that tests new therapies will focus on those patients with a high score.

Adult↗
PubMed1998

Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant.

PURPOSE: To determine the incidence of myelodysplasia (MDS) and/or acute leukemia (AL) in breast cancer patients after high-dose chemotherapy (HDC) with a single conditioning regimen and autologous bone marrow transplant (ABMT), and analyze the cytogenetic abnormalities that arise after HDC. PATIENTS AND METHODS: We retrospectively reviewed the records of 864 breast cancer patients who underwent ABMT at Duke University Medical Center, Durham, NC, from 1985 through 1996 who received the same preparative regimen of cyclophosphamide 1,875 mg/m2 for 3 days, cisplatin 55 mg/m2 for 3 days, and BCNU 600 mg/m2 for 1 day (CPB). Pretransplant cytogenetics were analyzed in all patients and posttransplant cytogenetics were evaluated in four of five patients who developed MDS/AL. RESULTS: Five of 864 patients developed MDS/AL after HDC with CPB and ABMT. The crude cumulative incidence of MDS/AL was 0.58%. The Kaplan-Meier curve shows a 4-year probability of developing MDS/AL of 1.6%. Pretransplant cytogenetics performed on these five patients were all normal. Posttransplant cytogenetics were performed on four of five patients and they were abnormal in all four, although only one patient had the most common cytogenetic abnormality associated with secondary MDS/AL (chromosome 5 and/or 7 abnormality). CONCLUSION: Whereas MDS/AL is a potential complication of HDC with CPB and ABMT, the incidence in this series of patients with breast cancer was relatively low compared with that reported in patients with non-Hodgkin's lymphoma who underwent ABMT. The cytogenetic abnormalities reported in this group of breast cancer patients were not typical of those seen in prior reports of secondary MDS/AL and appear to have occurred after HDC.

Acute Disease↗
PubMed1997

T helper 2-dominant antilymphoma immune response is associated with fatal outcome.

The precise role of the endogenous immune system in modulating cancer development remains unclear. Tumor cells are generally thought to be nonimmunogenic because they are of 'self' origin. However, tumor-reactive lymphocytes can be isolated from patients with many types of cancer. It is unclear what role these lymphocytes play and why they fail to protect the host. Using a murine B-cell leukemia/lymphoma (BCL1) model, we showed the development of a vigorous antitumor T-cell response in the tumor-susceptible host. Specific T-cell responses against BCL1 developed as early as day 4. However, the nature of this nonprotective response is different from the protective response produced in a major histocompatibility complex-matched tumor-resistant host. Susceptible hosts developed a T helper 2 (Th2)-dominant response, whereas resistant hosts developed a Th1-dominant response to BCL1. Cytolytic activity against BCL1 developed in both resistant and susceptible hosts, but in the susceptible host, this response was weaker and delayed compared with that in the resistant host. Thus, tumor susceptibility does not necessarily mean the absence of an antitumor immune response. Rather, the nature of the antitumor immune response is critical in determining clinical outcome.

Animals↗
PubMed1997

Administration of a CD31-derived peptide delays the onset and significantly increases survival from lethal graft-versus-host disease.

The CD31 monoclonal antibody, LYP21, binds to the CD31 domain 6 and inhibits the human mixed-lymphocyte reaction (MLR) in a specific and dose-dependent fashion. A synthetic CD31 peptide based on human CD31 epitope (amino acids 551 to 574) recognized by LYP21 is equally effective in inhibiting the MLR. In this study, we used the murine homolog of CD31 peptide 551 to 574 and a control peptide to study the role of CD31 molecule on T-cell activation. In vitro, CD31 peptide inhibited the MLR across several major and minor histocompatibility differences in a specific and dose-dependent fashion, similar to the results observed in the human system. Maximal inhibition was achieved at a dose of 200 microg/mL. In the cytotoxic T-lymphocyte (CTL) assay, CD31 peptide inhibited CTL responses by 97%. To study the in vivo effect of this peptide, graft-versus-host disease (GVHD) across minor histocompatibility barriers was induced in the B10.D2 (H-2d) --> BALB/c (H-2d) model. BALB/c recipients received CD31 peptide (100 microg/d), or phosphate-buffered saline (PBS), or control peptide (100 microg/d) intraperitoneally (IP) for the first 5 weeks. CD31 peptide delayed onset of graft-versus-host disease and significantly increased long-term survival. Twelve of 14 mice receiving CD31 peptide survived more than 100 days after transplantation, as compared with none of 10 mice receiving PBS and none of five mice receiving control peptide (P = .0001). Long-term engraftment of allogeneic bone marrow was documented in all transplanted mice by polymerase chain reaction (PCR) analysis of microsatellite region in the interleukin (IL)-1beta gene. Our data suggest that the CD31 molecule has an important functional role in T-cell activation in vitro and in vivo.

Amino Acid Sequence↗
PubMed1997

High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices.

One hundred nineteen patients with relapsed or refractory Hodgkin's disease (HD) received high-dose therapy followed by autologous hematopoietic progenitor cell transplantation. Three preparatory regimens, selected on the basis of prior therapy and pulmonary status, were employed. Twenty-six patients without a history of prior chest or pelvic irradiation were treated with fractionated total body irradiation, etoposide (VP) 60 mg/kg and cyclophosphamide (Cy) 100 mg/kg. Seventy-four patients received BCNU 15 mg/kg with identical doses of VP and Cy. A group of 19 patients with a limited diffusing capacity or history of pneumonitis received a novel high-dose regimen consisting of CCNU 15 mg/kg, VP 60 mg/kg and Cy 100 mg/kg. Twenty-nine patients (24%) had failed induction therapy and 35 (29%) had progressive HD within 1 year of initial chemotherapy. At 4 years actuarial survival was 52%, event-free survival was 48% and freedom from progression (FFP) was 62%. No significant differences were seen in survival data with the three preparatory regimens. Six patients died within 100 days of transplantation and 5 died at a later date of transplant-related complications. Secondary malignancies have developed in 6 patients, including myelodysplasia/leukemia in four patients and solid tumors in two patients. Regression analysis identified systemic symptoms at relapse, disseminated pulmonary or bone marrow disease at relapse and more than minimal disease at the time of transplantation as significant prognostic factors for overall and event-free survival and FFP. Patients with none of these factors enjoyed an 85% FFP at 4 years compared with 41% for patients with one or more unfavorable prognostic factors (P = .0001). Our results confirm the efficacy of high-dose therapy and autografting in recurrent or refractory HD. Although longer follow-up is necessary to address ultimate cure rates and toxicity, our data indicate that a desire to reduce late effects should drive future research efforts in favorable patients whereas new initiatives are needed for those with less favorable prognoses.

Adolescent↗
PubMed1997

Studies on the mechanism and specificity of the effect of the synthetic random copolymer GLAT on graft-versus-host disease.

Graft-versus-host disease (GVHD), which occurs when donor T-cells recognize multiple minor host histocompatibility antigens as non-self, presents the major limitation to successful allogeneic bone-marrow transplantation. The synthetic random copolymer of the amino acids, L-Glu, L-Lys, L-Ala and L-Tyr, termed GLAT, with promiscuous binding to multiple MHC class II alleles, reduces the incidence, onset and severity of disease in the BIO.D2 --> BALB/c model of lethal GVHD. GLAT inhibited the proliferative response towards host of both spleen cells from mice with GVHD and also of the effector T cell line established from these mice. Administration of GLAT for a limited period after transplantation completely abolished the cytotoxic activity toward host cells exerted by spleen cells from mice with GVHD. Whereas spleen and bone marrow cells from control mice with GVHD secreted IL-2 and INF-gamma when cocultured with host cells, these inflammatory cytokines could not be detected in supernatants of cells from GLAT treated mice. Moreover spleens and bone marrow cells from GLAT treated mice secreted small but significant amounts of IL-4 and IL-6 when cocultured with GLAT, suggesting that GLAT not only inhibits pro-GVHD cytokines but also causes a beneficial effect by inducing secretion of Th2 type cytokines. GLAT binds strongly to MHC molecules of host as well as donor haplotype. D-GLAT, identical to GLAT but composed of D-amino acids is also effective in preventing GVHD. D-GLAT does not cross-react with L-GLAT, but still binds strongly to MHC-class II molecules. These findings indicate that MHC blocking is involved in the therapeutic effect of GLAT on GVHD. The cumulative data demonstrate that GLAT modulates the effector mechanisms involved in GVHD, and can be potentially used for the prevention of GVHD across minor histocompatibility barriers.

Animals↗
PubMed1997

Value of skin biopsies in assessing prognosis and progression of acute graft-versus-host disease.

Skin biopsies are commonly performed after allogeneic bone marrow transplantation (BMT) to help establish the origin of a new skin rash in a transplant recipient. Histologic criteria and a grading system for acute graft-versus-host reaction of the skin are well established. Histologic diagnosis, however, can be difficult and is based on interpretation of subtle changes that show significant overlap with features seen in other entities that can be responsible for a skin rash in the posttransplantation period such as drug reactions, viral exanthems, and the effects of chemotherapy. We retrospectively reviewed 179 skin biopsies from 137 patients who had undergone allogeneic BMT. We compared 98 skin biopsies from 71 patients with acute graft-versus-host disease (GvHD) with 81 biopsies from 66 patients who underwent biopsy to exclude GvHD but did not go on to develop the disease on clinical grounds. Two observers reviewed each slide without knowledge of the clinical situation and graded 16 histologic parameters. No single parameter (e.g., dyskeratotic keratinocytes, basal vacuolization, satellitosis, necrotic cells in appendages) achieved statistical significance on univariate analysis. A search for factors to separate GvHD biopsies from non-GvHD biopsies using logistic regression failed to reveal a single best predictor or a combination of predictors. We conclude that skin biopsies after allogeneic BMT are of limited use in predicting the progression of a skin rash to clinical grade II or higher GvHD.

Acute Disease↗
PubMed1997

Treatment of non-Hodgkin's lymphoma with high-dose therapy and hematopoietic stem cell support.

Standard therapies for advanced low-grade lymphomas are not likely to provide a cure, prompting the use of more aggressive approaches. Patients with low-grade lymphoma who receive high-dose therapy with stem cell support appear to have a prolonged disease-free survival, although the benefit to overall survival remains unproven. Patients with chemotherapy-sensitive intermediate- or high-grade relapsed disease have improved survival with high-dose therapy, and those with high-risk disease may benefit from early consolidation while in first remission. Significant questions remain in terms of the proper timing of high-dose therapy, appropriate stratification by risk factors, the value of purging, the role of radiotherapy after transplantation, and the most appropriate source of stem cells for transplantation.

Antineoplastic Agents↗
PubMed1997

Influence of age on the outcome of 500 autologous bone marrow transplant procedures for hematologic malignancies.

PURPOSE: To determine the effect of age on the outcome of autologous bone marrow transplantation (ABMT) and/or peripheral-blood progenitor-cell (PBPC) transplantation. PATIENTS AND METHODS: A retrospective analysis was performed on 500 consecutive patients who ranged in age from 1 to 65 years (median, 40) with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), multiple myeloma (MM), or acute nonlymphoblastic leukemia (AML) who underwent autologous hematopoietic-cell transplant procedures at Stanford University Medical Center. RESULTS: The actuarial 5-year event-free survival (EFS) rate was 44%, the relapse rate 47%, and the regimen-related mortality (RRM) rate 8.6%. Disease status at time of transplantation, categorized as either minimal or advanced disease, was the strongest predictive factor for EFS (relative risk (RR) for advanced-disease group, 1.8; P < .0003) and relapse rate (RR for advanced-disease group, 1.9; P < .0004). Patients with minimal or advanced disease had an EFS rate of 48% and 30% and relapse rates of 43% and 72%, respectively. The EFS rate of patients less than 50 years verus > or = 50 years of age was 46% versus 34% (P = .03). Cox regression analysis showed that age was predictive for EFS (RR for patients 50 to 65 years, 1.4; P = .03). The actuarial RRM rate for these age groups was 7.4% versus 12.7% (P = .07), respectively. Multivariate analysis demonstrated that age (odds ratio [OR] for patients 50 to 65 years, 1.9; P < .05) and period of transplantation (OR for most recent years [1991 to 1995], 0.6; P = .06) were the most predictive factors for RRM. CONCLUSION: Although age greater than 50 years is associated with an inferior outcome following autologous hematopoietic-cell transplantation, it does not appear to be warranted to limit this potentially curative procedure based solely on age. The upper age limit of high-dose therapy with autologous progenitor-cell and/ or bone marrow support remains to be defined.

Adolescent↗
PubMed1997

Fractionated total-body irradiation, etoposide, and cyclophosphamide followed by allogeneic bone marrow transplantation for patients with high-risk or advanced-stage hematological malignancies.

Myeloablative therapy followed by allogeneic bone marrow transplantation (BMT) has proven to be curative therapy in patients with hematologic malignancies. Relapse, however, remains a major cause of treatment failure for patients with advanced disease. During the past 15 years, we have gained considerable experience with the combination of fractionated total-body irradiation (FTBI) and etoposide followed by allogeneic BMT for hematologic malignancies. In an attempt to decrease post-transplant relapse rates, 67 patients under the age of 50 years with high-risk or advanced-stage hematological malignancies received an intensified regimen of FTBI and etoposide plus cyclophosphamide followed by BMT from a genotypically-matched related donor. The regimen consisted of 1320 cGy of FTBI in 11 fractions, 60 mg/kg of etoposide (VP-16), and 60 mg/kg of cyclophosphamide (CY). Fifty-three patients received cyclosporine and prednisone for graft-vs.-host disease (GVHD) prophylaxis and 14 patients received cyclosporine, methotrexate, and prednisone. Diagnosis at BMT included 45 patients with acute leukemia, 7 patients with chronic leukemia, and 15 patients with high-grade non-Hodgkin's lymphoma (NHL). Actuarial disease-free survival (DFS) at 3 years was 42% +/- 12% for the entire group with a median follow-up of 50 months (range 20-74) for 28 patients who remain alive in continued complete remission (CR). Actuarial 3-year-DFS was 38% +/- 14% in 52 patients with acute or chronic leukemia and 60% +/- 25% in 15 patients with NHL with relapse rates of 45% +/- 16% and 21% +/- 11%, respectively. DFS at 3 years was 40% +/- 18% in 32 patients with acute leukemia in 1st relapse or 2nd CR or chronic myelogenous leukemia in accelerated phase, and was 32% +/- 22% in 20 patients with more advanced disease. Regimen related mortality occurred in 9 patients (4, veno-occlusive disease of the liver; 2, multi-organ failure; 1, diffuse alveolar hemorrhage; 1, central nervous system (CNS) hemorrhage; 1, adult respiratory distress syndrome (ARDS). The combination of FTBI, etoposide, and cyclophosphamide followed by allogeneic BMT is an effective and relatively well-tolerated regimen for patients with advanced hematologic malignancies. The role for this regimen should be further defined by prospective clinical trials.

Adolescent↗
PubMed1996

High dose etoposide-based myeloablative therapy followed by autologous blood progenitor cell rescue in the treatment of multiple myeloma.

BACKGROUND: A number of studies have demonstrated that high dose chemotherapy, with or without radiotherapy, with autologous marrow and/or peripheral blood progenitor cell support can result in improved overall and complete response rates in patients with multiple myeloma, and a minority of patients become long term survivors. Based on their favorable experience with high dose etoposide-based regimens in patients with Hodgkin's disease and non-Hodgkin's lymphoma, the authors explored the use of these regimens prior to autologous progenitor cell rescue in patients with multiple myeloma. METHODS: Thirty-four patients (median age, 49 years; range, 38-65) with multiple myeloma who were responsive to standard chemotherapy were enrolled in this study. Blood progenitor cells were collected after treatment with cyclophosphamide at a dose of 4 g/m2 followed by granulocyte-colony stimulating factor (G-CSF) at a dose of approximately 10 micrograms/kg/day subcutaneously, and the collection continued daily until the target number of mononuclear cells had been obtained. The preparative regimen consisted of fractionated total body irradiation (FTBI) of 1200 centigray in 10 fractions on Day -8 to Day -5, etoposide 60 mg/kg intravenously (i.v.) on Day -4, and cyclophosphamide 100 mg/kg i.v. on Day -2. Day 0 was the day of progenitor cell infusion. Patients who were older than 50 years or had received prior radiation therapy that precluded FTBI received carmustine 15 mg/kg i.v. or lomustine 15 mg/kg orally on Day -6 rather than FTBI. G-CSF (5 micrograms/kg/day) was begun the day after progenitor cell infusion and continued until engraftment. RESULTS: Recovery of granulocytes to 500/microL occurred at a median of 9 days (range, 7-13), and platelet recovery to 20,000/microL occurred without transfusion at 9 days (range, 6-88) after progenitor cell infusion. Thirty-two patients were evaluable for response. Eleven patients (34%) achieved a complete remission, 17 (53%) achieved a partial remission, and 4 (13%) had stable disease following high dose therapy and progenitor cell rescue. The actuarial event free survival at 4 years for the entire group was 26%, and overall survival was 36%. The median time to progression of disease was 13 months (range, 2-42). Two patients died of regimen-related toxicity, one of venoocclusive disease of the liver and the other of multiorgan failure. In a multivariate analysis, only the extent of prior therapy was a significant prognostic factor for event free survival, and no significant factors were identified for overall survival. CONCLUSIONS: High dose etoposide-based myeloablative regimens followed by autologous blood progenitor cell rescue are relatively well tolerated and effective for the treatment of multiple myeloma, and a minority of patients become long term disease free survivors.

Adult↗
PubMed1996

A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo.

Graft-versus-host disease (GVHD) is a T-cell-mediated disease of transplanted donor T cells recognizing host alloantigens. Data presented in this report show, to our knowledge, for the first time that a synthetic copolymer of the amino acids L-Glu, L-Lys, L-Ala, and L-Tyr (molecular ratio, 1.9:6.0:4.7:1.0; Mr, 6000-8500) [corrected], termed GLAT, with promiscuous binding to multiple major histocompatibility complex class II alleles is capable of preventing lethal GVHD in the B10.D2 --> BALB/c model (both H-2d) across minor histocompatibility barriers. Administration of GLAT over a limited time after transplant significantly reduced the incidence, onset, and severity of disease. GLAT also improved long-term survival from lethal GVHD: 14/25 (56%) of experimental mice survived > 140 days after transplant compared to 2/26 of saline-treated or to 1/10 of hen egg lysozyme-treated control mice (P < 0.01). Long-term survivors were documented to be fully chimeric by PCR analysis of a polymorphic microsatellite region in the interleukin 1beta gene. In vitro, GLAT inhibited the mixed lymphocyte culture in a dose-dependent fashion across a variety of major barriers tested. Furthermore, GLAT inhibited the response of nylon wool-enriched T cells to syngeneic antigen-presenting cells presenting minor histocompatibility antigens. Prepulsing of the antigen-presenting cells with GLAT reduced the proliferative response, suggesting that GLAT inhibits antigen presentation.

Animals↗
PubMed1996

Polymorphism of adhesion molecule CD31 and its role in acute graft-versus-host disease.

BACKGROUND: Graft-versus-host disease (GVHD) caused by poorly defined minor (i.e., other than HLA) histocompatibility antigens remains a serious problem in recipients of bone marrow transplants. We sought to determine whether the CD31 adhesion molecule is a minor alloantigen. METHODS: We directly sequenced samples of complementary DNA (cDNA) encoding CD31 molecules from 21 unrelated normal subjects. Sequence-specific primers were then designed to amplify alleles by the polymerase chain reaction, thereby permitting CD31 typing of genomic DNA from additional normal subjects. To assess the relevance of CD31 matching to bone marrow transplantation, we performed CD31 typing of 46 recipients of bone marrow (32 without GVHD and 14 with severe [grade III or IV] acute GVHD) and their HLA-identical sibling donors. The immunoreactivity of CD31 phenotypes with anti-CD31 monoclonal antibodies was compared by flow cytometry. RESULTS: Direct sequencing of cDNA for CD31 from the 21 normal subjects identified a single polymorphism, CTG-->GTG (Leu-->Val), at codon 125; we designated the resulting alleles CD31.L and CD31.V, respectively. The CD31 genotypes of these and 142 other unrelated subjects were of the expected frequencies. Among the transplant recipients, 71 percent of those with acute GVHD had CD31 genotypes that were not identical to the donor's genotype, as compared with 22 percent of the recipients without GVHD (P = 0.004). The binding of anti-CD31 monoclonal antibodies as measured by fluorescence-activated cell sorting correlated with the CD31 types of homozygous cell lines. CONCLUSIONS: The adhesion molecule CD31 is polymorphic. When donor and recipient genotypes are not identical, the risk of GVHD increases. Prospective CD31 typing may reduce the risk of acute GVHD.

Adolescent↗