Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As there is concern regarding the high carcinogenic potential of melphalan (Mel), 725 patients with haematological malignancies who received allogeneic (n = 714) or syngeneic (n = 11) transplants over the last 26 years were followed-up to evaluate if melphalan was more likely to result in secondary malignant neoplasms (SMNs) than cyclophosphamide (Cy). Three hundred and ninety-five were treated with Cy/TBI and 330 with Mel/TBI. Twelve patients developed non-haematological SMN. Median time to develop a SMN was 7 years (range 2-17 years). Age-adjusted rate was significantly higher than in the general population (observed 12 expected 1.2, risk 10; P < 0.0001). The cumulative overall risk of developing a SMN at 2, 5, 10 and 15 years post transplant was 0.4% (95% CI 0.1-2.6%), 1.7% (95% CI 0.6-4.4%), 6.4% (95% CI 2.8-10.8%) and 6.6% (95% CI 3.4-12.4%), respectively. Even though age-adjusted rates were higher than the general population melphalan/TBI was not associated with higher age-adjusted risk than Cy/TBI (increased risk 7.9 vs 11.4; P = NS). The cumulative overall risk of SMNs was not different with CY/TBI or Mel/TBI (8/393 vs 4/363; 10 year risk 4.4%, 95% CI 1.8-10.6 vs 8.4%, 95% CI 2.9-22.9; P = NS). The risk was significantly higher with use of additional cranial or cranio-spinal irradiation (17.5% vs 2.7% at 10 years; P = 0.0241). Transplants for acute lymphatic leukaemia resulted in a higher incidence of SMNs than did transplants for other diseases (ALL: 17.4%, 95% CI 6.3-42.6%; other diseases: 3.4% (95% 1.3-8.5%, P = 0.0469). The risk of SMN for patients with chronic GVHD was 8.4% (95% CI 3.7-18.7%) as compared to 3.5% (95% CI 1-11.1%) for patients without chronic GVHD (P = NS). No factor was associated with independently increased risk in multivariate analysis. Use of melphalan and TBI for transplant conditioning does not appear to be associated with higher risk of second malignant neoplasms than cyclophosphamide and TBI.
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PMID:Melphalan/TBI is not more carcinogeneic than cyclophosphamide/TBI for transplant conditioning: follow-up of 725 patients from a single centre over a period of 26 years. 1072 78

The clinical course of 59 children, who underwent BMT during 1988-1998 with a matched unrelated donor (MUD), was compared with 59 case controls receiving a sibling donor marrow. Thirty-eight patients had haematological malignancies while 21 had a nonmalignant disorder. The cumulative incidence of acute GVHD grade II-IV was 28% for MUD recipients vs 11% (P = 0.014) for sibling recipients. Extensive chronic GVHD was rare in both groups. The 5-year probability of survival was 52% for MUD vs 77% for sibling recipients (P= 0.014). For children with malignancies the 4-year probability of survival was 52% for MUD vs 67% for sibling recipients with a RFS of 49% vs 62%. In the ALL patients the survival of the MUD recipients was 77% and equalled that of the sibling group. For SAA survival was 43% vs 86% (P = 0.09) and for metabolic disorders 63% vs 89% (P = 0.025). The transplant-related mortality was higher in the MUD group, while death due to relapse was equally distributed. These results of MUD BMT in children compare favourably with most previous reports, and support the use of alternative donors in cases who lack an HLA-identical siblings. Bone Marrow Transplantation (2000).
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PMID:Unrelated bone marrow transplantation in children: outcome and a comparison with sibling donor grafting. 1082 66

To circumvent aGVHD in the early phase after allogeneic stem cell transplantation but to provide GVL activity later on, we performed alloPBSCT with CD34+ selected grafts followed by delayed add-back of CD3+ T cells. Ten consecutive patients having an HLA-identical sibling donor were enrolled on to this trial. Four patients were in first CR of high-risk ALL, another four in first CR of AML, one was in second myeloid blast crisis of CML, and one was in PR of relapsed NHL. Conditioning consisted of 2 x 60 mg/kg CY plus 12 Gy TBI. G-CSF (Filgrastim) mobilized peripheral cells were CD34+ selected using the Isolex 300i system in nine patients and the CliniMacs system in one. Median CD34+ purity was 86%. A median of 2.8 x 10(6)/kg CD34+ cells were transplanted. The number of CD3+ cells in the allografts was 5.7 x 10(4)/kg (median) after Isolex 300i, and 0.2 x 10(4)/kg after CliniMacs. All patients received G-CSF (Filgrastim) and engrafted rapidly. Standard-dose CsA was administered, and until day +60 no aGVHD occurred. At that time point, seven patients received 2 x 10(6)/kg CD3+ cells while CsA had been tapered to 50% of the starting dose. One of these patients died after a second T cell boost given on day +90 without concomitant immunosuppression due to grade IV intestinal aGVHD. Three others developed cutaneous cGVHD. Taken together, T cell depletion by CD34+ selection does not impair rapid engraftment in the HLA-identical sibling donor setting. Using standard-dose CsA the risk for acute GVHD seems to be minimized. Add-back of 2 x 10(6)/kg CD3+ cells on day +60 with CsA protection is feasible. However, whether this is the optimal time point and number of T cells remain to be further elucidated.
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PMID:CD34 selected alloPBSCT and adoptive immunotherapy. 1093 76

Peripheral blood stem cell transplants (PBSCT) from unrelated donors (n = 37) were compared with bone marrow transplants (BM, bone marrow group, n = 37) in a matched pair analysis. Ten patients (2, class 1) in the alloPBSCT group and seven patients (2, class 1) in the BM group had one HLA locus mismatch donor, respectively. The following factors were matched: HLA-compatibility, diagnosis, disease stage, age and gender. The median age in the PBSC group was 37 years (19-56, excluding one 6-year-old child) and in the BM group 37 years (18-53). The BM group consisted of 12 females and 25 males, 17 females and 20 males were in the PBSC group. Twelve patients in the BM and 11 patients in the PBSC group were diagnosed with AMI,; 7/7, ALL; 15/15, CML; 2/3, MDS; 1/1, NHL. Thirty-four (14/20) of the 74 patients (45%) were considered as high risk patients. The conditioning regimen was BU/CY for standard risk patients with myeloid diseases (31 patients) and TBI/CY for ALL and NHL patients (36 patients); six patients received intensified conditioning with VP16 (2 patients), thiotepa (2 patients) or melphalan (1 patient). The GVHD prophylaxis regimen was used according to the Seattle protocol. DFS was 51% (19 patients) with a median of 352 days and 59% (21 patients) with a median of 760 days, in PBSC and BM transplants, respectively. The median time to leukocyte engraftment in PBSC patients was 14 days (range 6-26 days) and in the BM group 19 days (range 9-29 days; P < 0.02). The time of platelet engraftment did not differ significantly between the groups. The incidence of grade II-IV acute GVHD was 40% (four patients died, 13%) in the PBSC group and 20)% (three patients died, 8%) in the BM group, respectively (P < 0.05, log-rank). No signs of aGVHD were found in 19% of the patients in the PBSC and 27% in the BM group. Our results indicate that allogeneic PBSCT does lead to a significantly faster leukocyte engraftment. The significant increase with regard to the incidence and shorter time of onset of severe aGVHD in PBSC patients, compared to marrow transplant patients, need to be confirmed in a randomised trial.
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PMID:A comparative study of peripheral blood stem cell vs bone marrow transplantation from unrelated donors (MUD): a single center study. 1093 83

There is limited experience in the use of peripheral blood progenitor cells (PBPC) for allogeneic transplantation in children. In the present study we compared engraftment kinetics, incidence of acute and chronic graft-versus-host disease (GVHD) and the outcome and economic costs of allogeneic PBPCT vs BMT in children with ALL in a single institution. All children were transplanted in complete remission (CR) with a similar conditioning regimen and the same GVHD prophylaxis. Patients undergoing PBPCT achieved myeloid and platelet engraftment before patients undergoing BMT (P < 0.001). Platelet recovery was faster for the PBPCT group (P < 0.014 for 50 x 10(9)/l and P < 0.039 for 100 x 10(9)/l). Incidence and severity of acute and chronic GVHD were similar in both groups (acute grade 1-2: 9/13 for PBPCT vs 9/11 for BMT; chronic GVHD: 5/12 for PBPCT vs 3/8 for BMT). Hospital stay was shorter for the PBPCT than for the BMT group (28.8 days vs 42.9 days, respectively) and the PBPCT group used less clinical resources, resulting in overall lower cost for PBPCT (US $14,046) compared to BMT (US $19,840). There was no statistically significant difference in DFS between PBPCT and BMT (68.4% vs 50%, respectively).
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PMID:Clinical and economic comparison of allogeneic peripheral blood progenitor cell and bone marrow transplantation for acute lymphoblastic leukemia in children. 1096 64

Patients with acute leukemias relapsing within 1 year of an allogeneic BMT have a poor prognosis. We studied the use of melphalan 180 mg/m2 followed by allogeneic peripheral blood stem cells (PBSC) as salvage treatment for patients relapsing after related (n = 7) or matched unrelated transplants (n = 3). Diagnoses were AML (n = 4), ALL (n = 3), biphenotypic acute leukemia (n = 2) and CML in blast crisis (n = 1). Eight patients were beyond first relapse and none were in remission. The median time from previous transplant to relapse was 146 days (range 66-206). The melphalan dose was 90 mg/m2 intravenously on days -4 and -3 with PBSC infusion on day 0. GVHD prophylaxis consisted of cyclosporine and methylprednisolone. The median time to an absolute neutrophil count >0.5 x 10(9)/l and to a platelet count >20 x 10(9)/l was 11 and 13 days, respectively. All engrafting patients (n = 8) had 100% donor cells. Two patients died before day 30, but no other grade 3 or 4 toxicity occurred. Acute GVHD grades II-III occurred in two subjects, and chronic GVHD in four. Seven patients achieved CR, but relapsed at a median of 116 days (range 56-614). Leukemia was the cause of death in eight patients. Median survival was 149 days (range 6-614). This treatment produced responses in the majority of this poor prognosis group. However, durable remissions were not observed, and new treatments to consolidate the responses achieved in this setting are needed. This regimen could be considered for short-term disease control to facilitate donor lymphocyte infusion-based immunotherapy or other measures to prevent disease recurrence.
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PMID:High-dose melphalan and allogeneic peripheral blood stem cell transplantation for treatment of early relapse after allogeneic transplant. 1096 75

A 15-year-old female received an unrelated three of six HLA antigen matched umbilical cord blood (UCB) transplant for refractory, relapsed T-cell ALL. Conditioning consisted of TBI, melphalan, and anti-thymocyte globulin (ATG), with cyclosporin A (CsA) and solumedrol for GVHD prophylaxis. She engrafted and a day 34 bone marrow aspirate showed 100% donor cells and no evidence of leukemia. The post-transplant course was complicated by mild grade I acute GVHD involving skin, and limited chronic GVHD of the gut which resolved with the addition of 1 mg/kg/day of steroids to her CsA prophylaxis. One hundred and ninety days after transplantation the patient developed pancytopenia and was subsequently found to have a leukemic relapse. Immunosuppression was discontinued and she was started on G-CSF and erythropoietin. Moderate skin and gut GVHD developed which was treated with both topical and low-dose oral steroids. Over the next few weeks she became transfusion independent and a follow-up bone marrow aspirate showed complete remission. She continued in complete remission for 4 months, at which time localized leukemic relapse was found in a soft tissue breast mass in spite of continued bone marrow remission. While the patient ultimately died of progressive disease, this case demonstrates that mismatched UCB in conjunction with G-CSF is capable of generating a GVL effect that can induce a complete remission.
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PMID:Graft-versus-leukemia-induced complete remission following unrelated umbilical cord blood transplantation for acute leukemia. 1114 43

We investigated the use of 'prophylactic' donor lymphocyte infusions (DLI) containing 1 x 107 CD3+ cells, given at 30, 60 and 90 days post-allogeneic blood and marrow transplantation (BMT), following conditioning with fludarabine 30 mg/m(2)/4 days and melphalan 70 mg/m(2)/2 days. GVHD prophylaxis consisted of cyclosporin A (CsA) 2 mg/kg daily with early tapering by day 60. Our goals were the rapid achievement of chimerism and disease control, providing an immunological platform for DLIs to treat refractory patients with hematological malignancies. Twelve heavily pre-treated patients with life expectancy less than 6 months were studied; none were in remission. Diagnoses were AML (n = 4), MDS (n = 1), ALL (n = 3), CML (n = 3) and multiple myeloma (n = 1). Response rate was 75%. Three patients are alive at a median of 450 days (range, 450-540). Two patients are in remission of CML in blast crisis and AML for more than 14 months. Median survival is 116 days (range, 25-648). Six patients received 12 DLIs; three patients developed acute GVHD after the first infusion and were excluded from further DLIs, but no GVHD occurred among patients receiving subsequent DLIs. One patient with CML in blast crisis went into CR after the first DLI. The overall incidence of acute GVHD was 70%. Primary causes of death were infections (n = 3), acute GVHD (n = 3), chronic GVHD (n = 1) and disease relapse (n = 2). We observed high response and chimerism rates at the expense of an excessive incidence of GVHD. DLI given at day +30 post BMT caused GVHD in 50% of the patients, and its role in this setting remains unclear.
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PMID:Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease. 1124 40

A 16-year-old boy in complete remission of ALL, undergoing oral maintenance therapy, developed intestinal perforation related to EBV-associated lymphoproliferative disease (LPD). He was successfully managed with surgical resection, acyclovir, immunoglobulins and discontinuation of maintenance therapy. Leukemic marrow relapse occurred 3 months later, treated by polychemotherapy followed by unmanipulated BMT from a matched unrelated EBV seropositive donor. Donor lymphocytes were infused twice after transplant because of delayed immunologic recovery and severe CMV colitis. This was followed by acute GVHD requiring prolonged immunosuppressive treatment. Despite intensive and prolonged immunosuppression, recurrence of LPD was not observed. Following EBV-related LPD, allogeneic BMT can be performed if indicated. Selection of an EBV seropositive donor is of major importance for the prevention of LPD recurrence as the recipient may be protected by passive transfer of EBV-specific cytotoxic T cells.
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PMID:Epstein-Barr virus-related lymphoproliferative disease complicating childhood acute lymphoblastic leukemia: no recurrence after unrelated donor bone marrow transplantation. 1124 44

Acute lymphocytic leukemia remains a difficult disease to treat in adults. Allogeneic bone marrow transplantation can cure some patients with ALL, but GVHD transplant-related mortality and disease relapse remain problematic. Immunotherapeutic approaches aimed at eliminating minimal residual disease and enhancing the GVL effect may decrease relapse rates and improve overall survival. Because of the rarity of this disease in adults, every new patient should be entered in well-designed, peer-reviewed, investigational trial.
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PMID:Allogeneic stem cell transplantation for acute lymphocytic leukemia in adults. 1125 11


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