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)

Cyclosporin A (CsA) absorption is variable in bone marrow transplant (BMT) patients compromising the efficacy of graft-versus-host disease prevention. Neoral, a new microemulsion formulation of CsA which has an improved bioavailability, increases intestinal absorption of the drug with less variable pharmacokinetic parameters in non-BMT patients. In order to predict the best dosage of Neoral when patients are switched from i.v. to oral administration we performed a randomised study comparing two oral doses, either the same or twice the last i.v. dose used after BMT. Fourteen adults were randomised around day 25 after BMT. Whole blood CSA concentrations were measured 2 and 12 h after the oral administration of Neoral on days 0, 7 and 14 to determine residual and maximum concentration, and modified whenever necessary to maintain blood level CsA concentration within therapeutic range (150-250 ng/ml). We found that patients who received twice the last i.v. dose had better concentrations than patients from the other group while toxicity was identical in both groups. We conclude that doubling the last i.v. dose during the switch to oral administration of Neoral gives the best therapeutic range concentration and should be recommended for graft-versus-host prevention.
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PMID:New oral formulation of cyclosporin A (Neoral) pharmacokinetics in allogeneic bone marrow transplant recipients. 1080 64

Umbilical cord blood (UCB) is being increasingly used for hematopoietic stem cell transplantation and has been associated with a reduced incidence of severe graft-versus-host disease (GVHD). To further investigate the relative merits of unrelated donor UCB versus bone marrow (BM), a matched-pair analysis comparing the outcomes of recipients of 0 to 3 human leukocyte antigen (HLA)-mismatched UCB and HLA-A, B, DRB1-matched BM was performed. UCB patients, who received cyclosporine (CSA) and methylprednisolone (MP), were matched for age, diagnosis, and disease stage with BM patients, who received either methotrexate (MTX) and CSA (26 pairs) or T-cell depletion (TCD) and CSA/MP (31 pairs). Patients were predominantly children (median age, 5 years) undergoing transplantation for malignancy, storage diseases, BM failure, and immunodeficiency syndromes between 1991 and 1999. Although neutrophil recovery was significantly slower after UCB transplantation, the probability of donor-derived engraftment at day 45 was 88% in UCB versus 96% in BM-MTX recipients (P =.41) and 85% in UCB versus 90% in BM-TCD recipients (P =.32), respectively. Platelet recovery was similar in UCB versus BM pairs. Furthermore, incidences of acute and chronic GVHD were similar in UCB and BM recipients, with 53% of UCB versus 41% of BM-MTX recipients alive (P =.40) and 52% of UCB versus 56% of BM-TCD recipients alive at 2 years (P >.80), respectively. These data suggest that despite increased HLA disparity, probabilities of engraftment, GVHD, and survival after UCB transplantation are comparable to those observed after HLA-matched BM transplantation. Therefore, UCB should be considered an acceptable alternative to HLA-matched BM for pediatric patients.
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PMID:Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis. 1134 17

Liver disease associated with chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity. Steroids and cyclosporin (CSA), which are the standard therapy, give rather disappointing results, and toxicity is high. Tacrolimus (FK506) is a potent macrolide lactone immunosuppressant that is used in the prevention of solid organ rejection. This study evaluated the therapeutic role of FK506 in the treatment of severe cGVHD-mediated liver disease that did not respond to combined steroids and CSA therapy. Fifteen patients with various hematological disorders who underwent allogeneic stem cell transplantation were enrolled in the study. All patients had severe cholestatic liver disease disturbances and underwent liver biopsy, which was compatible with cGVHD-mediated liver disease. All the patients were negative for markers of chronic liver disease, including viral serology. They received FK506 orally (4-20 mg/day according to serum levels), and were evaluated biweekly by physical examination and liver function tests. Patients were followed for a median of 12 months (range 3-24 months). FK506 treatment ameliorated liver functions in 9 of 15 patients (60%), 5 of whom demonstrated complete normalization of liver enzymes (33%). In 5 patients, no major effect was observed, and 1 patient showed deterioration of his liver functions. Mean GGT levels decreased from 171.5 to 55.6 within 6 months of treatment. Median time to response was 3 months (range 1-11). Side effects were generally transient. Treatment with FK506 was found to be effective in the majority of patients with steroid and CSA-resistant cGVHD-associated liver disease, with manageable side effects. In view of these findings, FK506 may yet evolve into first line therapy for cGVHD induced liver toxicity.
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PMID:Amelioration of steroid-resistant chronic graft-versus-host-mediated liver disease via tacrolimus treatment. 1145 16

Second-line therapies for steroid-resistant acute GVHD have been used with limited success. We have reviewed the responses of 79 hematopoetic stem cell transplant (HSCT) patients uniformly treated from 1990-1998 with equine antithymocyte globulin (ATG) for steroid-resistant acute GVHD, defined as progression of acute GVHD after 4 days of treatment with prednisone or no improvement of acute GVHD after 7 days of treatment with prednisone. Patients received HSCT from 34 related (32 matched sibling/2 partially matched) and 45 unrelated (14 HLA-A, -B, -DRB1 matched/31 partially matched) donors. Prior to ATG therapy, severe (grade III-IV) GVHD was observed in 34 patients (43%). Organs involved included skin in 81% of patients, lower GI tract in 52%, upper GI tract in 28%, and liver in 11%. Treatment consisted of 1-5 courses (median, 2 courses) of ATG (15 mg/kg per dose bid x 5 days) given for a median of 16 days (range, 5 to 44 days) after the onset of GVHD. All patients continued to receive prednisone, 60 mg/m2 per day (or methylprednisolone IV equivalent), plus CSA (75%) or tacrolimus (4%). At day 28 of treatment, overall improvement was observed in 54% of patients; durable (> or = 28 days) complete response was observed in 20% of patients, and partial response was observed in 34% of patients. In multivariate analysis, patients with CML or a malignant disease other than acute leukemia had a greater likelihood of overall response than did those with nonmalignant diseases. Patients with acute skin GVHD (with or without other organ involvement) responded most frequently. Chronic GVHD developed in 51% of patients by 1 year after HSCT. One patient developed EBV lymphoproliferative disease. For the entire cohort, the probability of survival at 1 year was 32% (95% CI, 22%-42%). In multivariate analysis, factors associated with better survival included earlier onset of acute GVHD, shorter time from initial treatment for GVHD to treatment with ATG, and the use of non-T-cell-depleted stem cell grafts. These data suggest that treatment with ATG can be an active therapy, especially in patients with skin GVHD and early signs of steroid resistance.
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PMID:Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease. 1185 89

Seventeen patients and their family donors HLA 2 - 3 antigen mismatched of 2 - 3 loci were enrolled in the study of haploidentical transplants from February 1999 to March 2001. Among patients with leukemia, most patients were classified as high risk. Eleven patients with ALL were all in more than second remission but one was in relapse. Patients with AML were one in CR1, one in CR2 while 4 patients with CML were two in CP and two in AP. The male-to-female ratio was 14:3 and the median age was 15 (range from 8 to 35). Conditioning regimens included Ara-C 3.0 g/m(2), 2 times per day x 3 d, on day 7, 6 and 5 pre-transplantation, CTX 45 mg/(kg per d) x 2 d on day 5 and 4 pretransplantation. TBI with 1000 cGy by 2 fractions on day 2 and 1 pretransplantation. The fresh and unmanipulated marrow was infused on day 0. Donors were received G-CSF (Lenograstim) at 3 - 4 microg/(kg per d) x 7 d. The BM cells were collected on eighth day. In GVHD prophylaxis, CSA, MTX, ATG (Antithymocyte globulin, Rabbit Fresenius S) and MMF (mycophenolate mofetic) were used in different periods. The dose of CSA was 1.5 mg/(kg per d) on day 7 to 1 pretransplantation, then 3 mg/(kg per d) from day 1 pretransplantation. MTX was 15 mg/m(2) on day 1 and 10 mg/m(2) on day 3, 6 and 11 posttransplantation. ATG was administered day 4 to 1 pretransplantation at 5 mg/(kg per d) and MMF dose was 1.0 g/d from day 7 posttransplantation. All patients established successful engraftment after initial transplantation. The median days of neutrophil exceeding 0.5 x 10(9)/L and platelet exceeding 20 x 10(9)/L were 18 (range 13 - 23) and 20 (range 16 - 32) days, respectively. Patients were monitored up to day 100 for the sign of aGVHD. The established grades II to IV aGVHD occurred in 5 out of 17 patients (29.4%). Eleven patients were surviving at a median follow-up of 13 months (range 3 - 27 months). Six out of the 17 patients died those 3 of them died of severe aGVHD, 2 of infection and 1 of leukemia relapse. Severe regimen-related toxicities were not experienced in all patients. The median follow-up period was 13 (range 3 - 27) months. Eleven patients were alive in disease-free situation with a Karnofsky performance status of 100%. This could be caused by the low overall incidence of aGVHD as a result of BM primed with G-CSF. The four-agent of immunosuppressive combined prophylaxis against GVHD in different periods may be highly effective.
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PMID:[Successful engraftment of T-cell undepleted haploidentical transplants by donor primed with G-CSF and additional use of ATG and MMF for recipients]. 1251 19

To explore the feasibility of using CD25 monoclonal antibody (Basiliximab) in T-cell undepleted allo-BMT with graft from haplotype-matched related donor for acute GVHD prophylaxis. Twenty-eight patients with leukemia received allo-BMT from HLA two or three loci mismatched related donors. The donors were given G-CSF (Lenograstim) 250 micro g/d for 7 doses prior to marrow harvest. CSA, MTX, ATG and mycophenolate mofetil (MMF) were combined for GVHD prophylaxis. ATG 5 mg/(kg.d) was infused from day 4 to day 1 before transplantation and MMF was administered from day 7. In the study group, the patients received additional CD25 monoclonal antibody for aGVHD prophylaxis. CD25 20 mg each by 30 min intravenous infusion on 2 hours before transplantation and day 4 after transplantation was administered while no application of CD25 in the controls. The outcomes of transplantation were compared between the stud y and control groups. The results showed that the median number of CD34(+) cell in graft was 5.9 x 10(6)/kg in the control group and 7.9 x 10(6)/kg in the study group. The median number of CD3(+) cell was 48 x 10(6)/kg and 52 x 10(6)/kg respectively (P > 0.05). All patients showed 100% donor-typed hematopoietic cells after transplantation by cytogenetic evidence. Five out of fifteen patients in the control group experienced II - IV acute GVHD. While none of thirteen in the study group developed the II - IV acute GVHD. However, none in both groups developed extensive cGVHD. The median follow-up duration was 8 (3-15) months in the study group and 26 (15-36) months in control. In the study group, one patient died from transplant related mortality (CMV infection); no one relapsed; and 12/13 patients survived in disease-free situation within the period of follow-up. In the control group, six patients died from transplant related mortality (3 GVHD, 2 infection and 1 relapsed) and 9/15 patients survived in disease-free situation. The one-year probabilities of disease-free survival (DFS) in two groups were significantly different (P < 0.05). It is concluded that the transplant from haploidentical donors used CD25 antibody is effective and feasible in preventing acute severe GVHD and improving DFS. The major histocompatibility barrier in the haploidentical related allo-BMT could be crossed by donors primed with G-CSF and GVHD prophylaxis with CD25 antibody in the hosts.
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PMID:[A clinical study of haploidentical and G-CSF primed bone marrow transplantation by using CD25 for aGVHD prophylaxis]. 1251 46

Administration of the immunosuppressive drug cyclosporine (CSA) after autologous peripheral blood stem cell transplantation (APBSCT) induces a systemic auto-immune syndrome resembling graft-versus-host disease (GVHD), this syndrome termed autologous GVHD has significant antitumor activity, it can reduce the incidence of tumor relapse after APBSCT. The antitumor effect of this auto-aggression syndrome can be enhanced by the administration of gamma-interferon (gamma-IFN). Five consecutive patients who received APBSCT received therapy inducing autologous GVHD. Intravenous administration of CSA [1 mg/(kg.d) for 28 days] was begin on the day of transplantation. gamma-interferon (0.025 mg/m(2) qod) was administered sub-cutaneously from days 7 throngh 28 after transplatation. Results showed that four of five occured autologous GVHD-skin demage, five in control didn't occur autologous GVHD. The relapse rate of the treated cases was 20% (1/5) versus 60% (3/5) of the control, and the median survival time of the treated cases was 20 (4 - 30) months versus 10 (2 - 20) months of the control. The data indicates that autologous GVHD results in low relapse rate of the patients rececving APBSCT.
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PMID:[GVHD Following Autologous Peripheral Blood Stem Cell Trasplantation Reduced Malignancy Relapse] 1257 10

Haploidentical transplantation has become a clinical option for patients lacking a compatible donor. However, patients are still referred at advanced stages and are usually heavily pretreated. This results in a high risk of toxicity, relapses and infections. We therefore started a donor lymphocyte infusion (DLI) dose-finding protocol, to try to improve both relapse rate and immunity reconstitution. In all, 12 consecutive patients were investigated. All had a refractory, some progressive, disease. Conditioning consisted of TBI, melphalan, ATG, fludarabine and CSA pretransplant. In four rapidly progressive patients, Ara-C had to be given 1 week preconditioning. The graft was T- and B-cell depleted with a fixed reinfused CD3 dose of 5 x 10(4)/kg. All patients engrafted before day 20. G-CSF was given from day 5 post-transplant and replaced with GM-CSF in the last three patients. Nonrelapse related mortality was 0/12 at 1 year. DLI were started at day 28 (3 x 10(4) CD3/kg) in the two first patients. This resulted in acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD) in both, but they did not relapse. The next dose was 1 x 10(4)/kg monthly for 3 months. This was well tolerated with only one grade I GVHD. Given the high relapse rate, we escalated doses (1, 3 and 10 x 10(4)/kg). This produced GVHD in all. We next moved, to GM-CSF and 1 x 10(4) CD3/kg monthly. Overall, 6/12 patients relapsed and received therapeutic DLI, starting at 1 x 10(5) CD3/kg with escalation every 2 weeks. We conclude that prophylactic DLI are feasible in adult haploidentical transplantation, without GVHD at a monthly dose of 1 x 10(4) CD3/kg. They result in faster CD4 recovery and a low rate of infections. The impact of GM-CSF remains to be further investigated. This scheme seems ideal for patients transplanted early in the course of their disease. In very bad prognosis patients, it remains insufficient to rapidly induce a GVL effect. Escalated doses are feasible but the price is aGVHD. Therapeutic DLI can be given at higher doses, depending on the time post-transplant. Haploidentical transplantation with low-dose DLI is a safe procedure that should be considered in all patients needing a transplant, but lacking a matched donor, early in the course of the disease.
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PMID:Donor lymphocyte infusions in adult haploidentical transplant: a dose finding study. 1262 5

We describe the treatment of a 10-year-old girl with autosomal recessive Dyskeratosis congenita (DC), neutropenia, thrombocytopenia and combined immunodeficiency by nonmyeloablative hematopoietic stem cell transplantation. The conditioning regimen consisted of fludarabine 30 mg/m(2)/day (days -5, -4, -3) and 2 Gy TBI (0.07 Gy/min; day 0). For graft-versus-host disease (GVHD) prophylaxis a course of intravenous MMF and CSA was administered. At 2 years after transplantation of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells from a healthy 11-year-old HLA-identical brother, peripheral blood counts and T- and B-cell functions have completely normalized and donor chimerism was 100% in all cell lineages. No GVHD occurred. Neurological examination and lung function remained normal. The current transplantation regimen appears suitable, safe and efficacious in patients with DC.
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PMID:Nonmyeloablative allogeneic hematopoietic stem cell transplantation for treatment of Dyskeratosis congenita. 1263 34

Allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning was evaluated in 22 patients (median age 53, range 36-66 years) with multiple myeloma with progression after an autologous SCT. Seven patients received a transplant from a human leucocyte antigen (HLA)-identical sibling and 15 patients (68%) from an unrelated donor [including 3/22 (14%) from a HLA-mismatched unrelated donor]. Graft-versus-host disease (GVHD) prophylaxis consisted of serotherapy with antithymocyte globulin (ATG) and cyclosporine (CSA) (n = 12) or CSA plus mycophenolate mofetil (n = 10). Despite of heavy pretreatment, the transplant-related mortality (TRM) for all grafted patients was acceptable at 5/22 patients (23%). Seven of 21 patients (33%) that were evaluated developed grade II GVHD and one (5%) patient developed grade III/IV acute GVHD. Seven patients developed chronic GVHD (cGVHD), but only one was extensive. Eleven patients died of progressive disease within a median of 7 months (2-19 months) post transplant. Thirteen of all 22 patients (59%) achieved a partial or complete remission with six of these 13 patients (46%) remaining event free at a median of 24 months (range 8-36 months) post allografting. Estimated 2 year overall and event-free survival was, respectively, 25.5% and 22.0% for the whole patient group, and 62.5% and 57.1% for patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation (P = 0.0182) and absence of cGVHD (P = 0.069) were associated with shorter event-free survival. Thus long-term disease control can be achieved, but is restricted to patients responding to prior salvage chemotherapy.
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PMID:Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. 1271 63


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