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In 2005, the National Institutes of Health sponsored a Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-vs-Host (GVHD) to achieve consensus about key elements of chronic GVHD research, including definitions for diagnosis, severity scoring, and response measures. To test these proposed definitions, a multi-center prospective cohort study of people with chronic GVHD is ongoing. This study will evaluate the performance of proposed prognostic factors, measures of disease activity and surrogate endpoints for therapeutic response. Data are collected at 6 month intervals in a heterogeneous population of patients reflecting modern transplant techniques and post-transplant clinical management (target enrollment 672 with chronic GVHD from ten transplant centers). This report describes the rationale, design, and methods of the chronic GVHD cohort study, and invites other investigators to collaborate with the Consortium to analyze data or specimens.

Previously, it has been shown that the lysosomotropic amine, chloroquine, is effective in the prevention of graft-versus-host disease (GVHD) using murine models. Because chloroquine and hydroxychloroquine suppress MHC class II antigen presentation, their mechanism of action is different to other immune suppressant drugs (cyclosporin A) currently used to control GVHD. It is possible that the use of cyclosporin A and chloroquine in combination may have an additive or synergistic effect on T cell responses to antigens presented in the context of MHC class II. We investigated the effects of chloroquine or hydroxychloroquine in combination with cyclosporin A on human T cell responses in vitro to tetanus toxoid, an exogenous protein antigen dependent on MHC class II presentation for proliferative responses. We demonstrate that similar levels of chloroquine and hydroxychloroquine suppress human T cell responses to tetanus toxoid and that the use of either agent in combination with cyclosporin A results in synergistic suppression. Evaluation for a direct effect by the lysosomotropic amines on T cells, in the absence of antigen presenting cells, revealed that there was inhibition of T cell responses but only at high concentrations. No significant decrease or increase was seen in surface MHC II or invariant chain expression or in cytoplasmic invariant chain after exposure to chloroquine. Thus, lysosomotropic amines in combination with cyclosporin A are synergistic in suppression of T cell proliferation. Use of these agents in combination with cyclosporin A may improve control of graft-versus-host disease.

Identifying risk factors that lead to graft failure may reduce morbidity and mortality after bone marrow transplantation (BMT) for hematologic malignancies. We evaluated engraftment of all patients with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and myelodysplastic syndrome (MDS) receiving an unmanipulated marrow allogeneic BMT at the Detroit Medical Center from 1987 to 1992 using a busulfan, cyclophosphamide +/- cytarabine preparative regimen. Three of 118 patients had graft failure (2.5%; (95% confidence interval (CI) 0.7%, 6.4%). Graft failure was high in patientsor = 15 years with 3 of 12 patients with failure (25.0%) compared with 0 of 106 patients15 years (p = 0.002). Failure to engraft was not seen in HLA-identical (related or unrelated) donor transplants (0 of 103) whereas 3 of 15 HLA-mismatched donors failed (p = 0.003). Patient diagnosis, locus of HLA-mismatch, cytarabine in the preparative regimen, marrow cell dose and the relative reactive index (RRI) were not significant factors. Altered busulfan kinetics secondary to young age was probably not a major factor since 8 of 8 HLA-identical donor transplants engrafted in children. These findings demonstrate that patients receiving an unmanipulated marrow graft using busulfan-containing regimens were at a high risk for graft failure only if they wereor = 15 years of age and had an HLA-mismatched donor. More immunosuppressive preparative regimens, possibly including total body irradiation, should be considered to prevent potential graft failure in children.

Recent studies show that costimulation of T cells with anti-CD28 Mab (anti-CD28) enhances anti-CD3 Mab (anti-CD3)-induced proliferative responses and cytokine production. This study determines if coactivation with anti-CD3 and anti-CD28 corrects defects in proliferation and IL-2 secretion in peripheral blood lymphocytes (PBL) from bone marrow transplant (BMT) recipients. PBL or T cells from 5 of 16 autologous and 5 of 22 allogeneic recipients increased their anti-CD3-induced proliferation responses by50% after coactivation. In short-term (180 days after BMT) autologous recipients, the group mean response increased after anti-CD3 activation from 62,900 to 97,800 cpm after coactivation. In long-term (180 day after BMT) autologous recipients, the group mean response after anti-CD3 activation increased from 62,600 to 78,400 cpm after coactivation. The long-term autologous recipient group had costimulated responses from PBL that were significantly higher than the paired anti-CD3-induced responses (p0.01); in contrast, such differences were not seen in allogeneic recipient groups. After anti-CD3 stimulation, the mean response of 88,000 cpm for PBL from short-term allogeneic recipients and the mean response of 83,600 cpm for PBL from long-term allogeneic recipients were higher than those in PBL from autologous recipients were higher than those in PBL from autologous recipient groups. The amount of IL-2 secreted by T cells from three autologous and three allogeneic recipients was enhanced 0.9-25-fold by coactivation. Coactivation of PBL from selected recipients increased proliferation into the normal range and increased IL-2 secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-one patients (median age = 34, range = 10-49; F:M = 7:14) received a preparative regimen consisting of busulfan 4 mg/kg/day x 4, cytosine arabinoside 2 g/m2/12 h x 4 and cyclophosphamide 60 mg/kg/day x 2 ('BAC' regimen) for allogeneic bone marrow transplantation. Out of 12 patients with acute myeloid leukemia (AML), two were in first remission, six were in second remission and four had resistant, relapsed disease or prolonged marrow aplasia after induction chemotherapy. Five of the 12 patients with AML had secondary AML. Four patients had transfusion-dependent myelodysplastic syndrome. Three patients with chronic myeloid leukemia were in the accelerated phase and two were in the blastic phase. Organ toxicities related to the preparative regimen were graded. Liver toxicity occurred in 11 patients, two of these were fatal veno-occlusive disease (VOD) (10%). Nineteen of the 21 patients had grade 2 or less diarrhea, and 13 also had mucositis. One patient developed grade 3 cardiac toxicity, and one other patient had grade 1 skin toxicity. Four patients had gross hematuria related to treatment (19%). No renal, pulmonary or CNS toxicities were encountered. Ten patients have died, two from regimen-related hepatic VOD. Of the remaining eight deaths, four were from respiratory failure in four patients (one case each of Pneumocystis pneumonia, CMV pneumonia, bronchiolitis obliterans associated with chronic graft-versus-host disease, and interstitial pneumonitis complicated pulmonary emboli), and one patient each from GI bleeding, cardiac arrhythmia, sepsis and CNS bleeding. Thus far, only one patient transplanted for secondary AML in second remission relapsed at day 230.(ABSTRACT TRUNCATED AT 250 WORDS)