Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
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Biol. Blood Marrow Transplant. · May 2004
Clinical TrialOutcomes of adults with acute myelogenous leukemia in remission given 550 cGy of single-exposure total body irradiation, cyclophosphamide, and unrelated donor bone marrow transplants.
On the basis of observations from dog models and human studies, we hypothesized that a low-dose (550 cGy), single-exposure total body irradiation (TBI)-based regimen would result in improved survival when given to adult patients with acute myelogenous leukemia (AML) who were undergoing unrelated donor bone marrow transplantation in complete remission (CR). The regimen consisted of single exposure (550 cGy) of TBI given at a high dose rate (30 cGy/min) and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of cyclosporine, methotrexate, and corticosteroids. ⋯ Graft failure was not observed. Relapse occurred in 22% of patients. This low-dose (550 cGy), single-exposure TBI-based regimen resulted in good survival and a low risk of fatal regimen-related organ toxicity in adult patients with AML who underwent unrelated donor bone marrow transplantation in CR.
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Biol. Blood Marrow Transplant. · May 2004
Clinical TrialSirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation.
Methotrexate in combination with a calcineurin inhibitor is a standard graft-versus-host disease (GVHD) prophylactic regimen in allogeneic stem cell transplantation. However, methotrexate is associated with delayed engraftment, mucositis, idiopathic pneumonia syndrome, and other transplant-related complications. Sirolimus, a novel immunosuppressant without methotrexate's toxicities, has been used successfully in solid organ transplantation. ⋯ Sirolimus in combination with tacrolimus is a promising alternative to methotrexate-based regimens for GVHD prophylaxis after matched related donor peripheral blood stem cell transplantation. Mucositis was modest, engraftment was prompt, and transplant-related toxicity was modest. Methotrexate-free, sirolimus-based GVHD prophylactic regimens should be tested in randomized trials against the current standard of care.
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Biol. Blood Marrow Transplant. · Apr 2004
Clinical TrialA pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients.
Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). ⋯ Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.
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Biol. Blood Marrow Transplant. · Mar 2004
Cytolytic effector mechanisms and gene expression in autologous graft-versus-host disease: distinct roles of perforin and Fas ligand.
The administration of cyclosporin A (CsA) after autologous stem cell transplantation (SCT) paradoxically elicits a systemic autoimmune syndrome that resembles graft-versus-host disease (GVHD); this is termed autologous GVHD (autoGVHD). Although dominated by activated CD8+ cytotoxic T lymphocytes, the complex cellular reaction also includes CD4+ T cells and involves multiple effector mechanisms. To determine the temporal development and relative importance of these mechanisms in autoGVHD, perforin/granzyme, Fas ligand (FasL), interferon-gamma (IFN-gamma), tumor necrosis factor (TNF)-alpha, and interleukin-18 gene expression in peripheral blood mononuclear cells was examined in 36 patients treated with CsA after SCT. ⋯ Surprisingly, FasL mRNA levels were significantly decreased, with a progressive loss of FasL mRNA expression as autocytolytic activity increased. These findings suggest that IFN-gamma/perforin-based CD8+ cytotoxic T lymphocytes seem to play a dominant role in autoGVHD and that TNF-alpha/perforin-based CD4+ cells may amplify this autoaggressive syndrome. The FasL pathway may play an important role in the regulation of this immune syndrome.
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Biol. Blood Marrow Transplant. · Mar 2004
Donor chimerism does not predict response to donor lymphocyte infusion for relapsed chronic myelogenous leukemia after allogeneic hematopoietic cell transplantation.
We studied the effect of donor chimerism level on the outcome of donor lymphocyte infusion (DLI) therapy in 42 patients with persistent or relapsed hematologic malignancies after non-T cell-depleted allogeneic hematopoietic cell transplantation. Seventy-five percent of chronic myelogenous leukemia (CML) and 39% of non-CML patients entered remission after DLI therapy. Remission and survival rates were similar for CML patients irrespective of their pre-DLI donor chimerism levels; however, remission occurred sooner in patients with > or =10% pre-DLI donor chimerism. ⋯ The 2-year survival rates after DLI were 75% for CML and 17% for non-CML patients. We conclude that a low level of donor marrow chimerism is not an adverse prognostic factor for response to DLI in CML patients, but for non-CML patients it may confer worse outcomes. Better methods to augment the response to DLI for patients with hematologic malignancies other than CML that recur after allogeneic hematopoietic cell transplantation are needed, whereas for relapsed CML patients, combination therapies including imatinib mesylate or other promising antileukemic agents may provide outcomes superior to those with DLI alone.