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

A 17-year-old male with AML FAB M4 relapsed 4 months after myeloablative conditioning and peripheral blood stem cell transplantation (PBSCT) from an HLA-identical unrelated donor. A second PBSC harvest was infused 2 days after completion of cytoreductive therapy with mitoxantrone 7 mg/m(2)/day i.v. for 3 days (total dose 21 mg/m(2)), fludarabine 30 mg/m(2)/day i.v. for 6 days (total dose 180 mg/m(2)) and Ara-C 125 mg/m(2)/day i.v. for 5 days (total dose 625 mg/m(2)). Neutrophil recovery occurred on day +10 and was associated with GVHD grade III of the skin which was treated with cyclosporin A (CsA) and prednisone. Because of fever of unknown origin and progressive fatigue combined with hypotension on day +15 after second PBSCT, echocardiography was performed which revealed a dramatic decrease in systolic function compared to the status pre-transplant. On the same day acute heart failure with consecutive ventricular fibrillation occurred. Although resuscitation was performed immediately the patient died. The autopsy revealed massive infiltration by donor CD8-positive lymphocytes with concomitant extensive damage of the heart tissue. Acute myocarditis of viral origin was excluded by in situ hybridization and nested PCR techniques. In this patient, myocardial involvement by acute GVHD seems to have triggered a fatal arrhythmia and heart failure.
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PMID:Acute heart failure after allogeneic blood stem cell transplantation due to massive myocardial infiltration by cytotoxic T cells of donor origin. 1124 47

Chimerism is an exceptional immunogenetic state, characterized by the survival and collaboration of cell populations originated from two different individuals. The prerequisites to induce chimerism are immunosuppression, myeloablation or severe immunodeficiency of the recipients on one side and donor originated immuno-hematopoietic cells in the graft on the other. Special immunogenetic conditions to establish chimerism are combined with bone marrow transplantation, transfusion and various kinds of solid organ grafting. There are various methods to detect the type of chimera state depending on the immunogenetic differences between the donor and recipient. The chimera state seems to be one of the leading factors to influence the course of the post-transplant period, the frequency and severity of graft-versus-host disease (GVHD), and the rate of relapse. However, the most important contribution of the chimeric state is the development of graft versus leukemia (GVL) effect. A new conditioning protocol (DBM/Ara-C/Cy) for allogeneic BMT in CML patients and its consequence on chimera state and GVL effect is demonstrated.
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PMID:[Clinical and immunopathological significance of chimerism in bone marrow and organ transplantations] 1205 Jul 23

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

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

To investigate the properties of haploidentical donor-derived bone marrow engraftment and hematopoietic reconstitution in patients received bone marrow transplantation, 15 patients with leukemia received bone marrow grafts without T cell depletion from their family donors of those with 2-3 mismatched loci of HLA antigens. The donors were given G-CSF 250 micro g/day for 7 days prior to marrow harvest. All patients were treated with conditioning regimens consisting of high-dose of Ara-C, cyclophosphamide, and total body irradiation. A four-agent based GVHD prophylaxis was used as cyclosporine A, MTX, ATG and mycophenolate mofetile (MMF). Donor engraftment was evaluated as identification of HLA locus, chromosome karyotype, DNA fingerprinting, blood type and other parameters such as occurrence of GVHD, recovery of peripheral blood cell counts as well as normal myelogram. The results showed that successful and stable engraftment was established in all patients. The median time of granulocyte counts > 0.5 x 10(9)/L and platelet > 20 x 10(9)/L was 18 (13-23) and 22 (16-32) days, respectively. One of the patients relapsed despite the bone marrow chimerism appearing after transplantation. The grade I acute GVHD occurred in 8 and grade II-IV in 5 of the 15 patients. Of the patients, 7 received marrow grafts from donors of opposite sex were identified for donor engraftment by chromosome analysis, 4 by blood typing, 7 with HLA locus analysis and 1 with DNA fingerprinting. In conclusion, HLA haploidentical bone marrow transplantation is feasible with a series of management including mobilization with G-CSF in donors, intensive conditioning and proper immunosuppressants, which enable the allo-transplants to stride across the immunological barrier.
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PMID:[Clinical study on hematopoietic reconstitution in patients with leukemia by haploidentical bone marrow transplantation]. 1296 74

A 1-year-old girl with juvenile myelomonocytic leukemia (JMML) underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. A few months after BMT she experienced a bone marrow relapse that did not respond to withdrawal of immunosuppression. To enhance the graft-versus-leukemia (GVL) effect, she underwent peripheral stem cell transplantation (PSCT) from the same donor, using a nonmyeloablative conditioning regimen. She achieved clinical remission and developed chronic graft-versus-host disease (GVHD), which was treated with prednisone and cyclosporine A. One year after PSCT she experienced an isolated central nervous system (CNS) relapse. She was treated with intrathecal Ara-C followed by craniospinal irradiation and achieved a third clinical remission. While extramedullary relapses have been described in JMML, this is the first report of a CNS relapse. Based on this case and others in the literature, the authors suggest that newer therapies are changing the natural history of JMML. By manipulating the GVL effect it is possible to achieve a prolonged bone marrow remission, but only at the expense of unmasking the risk of late extramedullary relapse.
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PMID:Isolated CNS relapse following stem cell transplantation for juvenile myelomonocytic leukemia. 1460 4

To explore feasibility and efficacy of unrelated HLA matched donor marrow transplantation in treatment of myelodysplastic syndrome, one case (male, 31 years old) of myelodysplastic syndrome-refractory cytopenia with multilineage dysplasia (MDS-RCMD) has been received unrelated HLA-matched donor transplantation. Busulfan, cyclophosphamide, Ara-C, MeCCNU and antithymocyte globulin (ATG) were used for preparative regimen. Mycophenolate mofetile, cyclosporin A and short-term methotrexate were used for graft-versus-host disease prophylaxis. The results showed that neutrophil of > 0.5 x 10(9)/L, platelet of 58 x 10(9)/L and hemoglobin of 114 g/L were observed at 10, 20 days and 3 months respectively post transplantation. Disease-free survival without GVHD was 9 months. In conclusion, unrelated HLA matched donor marrow transplantation is an effective approach for treatment of patients with MDS.
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PMID:[Unrelated HLA-matched donor marrow transplantation for one case of myelodysplastic syndrome]. 1522 72

To explore the feasibility of nonmyeloablative conditioning regimens, hematopoietic reconstitution, chimera level and the occurrence of GVHD after nonmyeloablative allogeneic stem cell transplantation in H-2 haploidentical mice, CB6F1 mice were used as the recipient and were divided into 3 groups, mice were pretreated five days before transplantation. Group A was pretreated with myeloablative conditioning regimens (TBI with 10.5 Gy), group B was pretreated by TBI (2 Gy) + Ara-C + Cy and group C-TBI (2 Gy) + Ara-C + CY + Flu, respectively. For all recipient mice, the prevention of GVHD was not given, and 2 x 10(7) bone marrow cells mixed 1 x 10(7) spleen cells from C57BL/6 mice were injected through tail vein on day 0, and then hematopoietic recovery, engraftment and GVHD of recipients were observed. The results of chimera detection after transplantation showed that the engraftment of group A remained full donor chimerism, and engraftments of group B and group C were associated with mixed chimerism or full donor chimerism, but the chimerism of group B remained below 80% and tended to decrease after 50 days whereas chimerism of group C was above 80% (chimerism close to or being full donor type) and preserved even after 50 days. GVHD occurred in all the recipient mice due to that prevention was not given, wherein the occurrence and death rate of GVHD in group A was obviously higher than that of group B and group C (P <0.01), but there was no statistical difference between group B and group C. In conclusion, the nonmyeloablative conditioning regimens mainly based on fludarabine can form stable and lasting engraftment in the body of recipients. The mixed chimerism established in recipients induce tolerance of transplantation and decrease or avoid the occurrence of GVHD.
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PMID:[Establishment of nonmyeloablative allogeneic stem cell transplantation model in H-2 haploidentical mice and its related study]. 1549 29

To explore the effects of ABO incompatibility between recipient and donor on HLA-matched nonmyeloablative allogeneic peripheral blood stem cell transplantation (NAST), a retrospective, cohort study was performed. Among 24 HLA-matched NAST, 15 were major ABO-incompatible and 9 minor. Control group included 24 HLA-matched NAST with ABO-compatible grafts. Nonmyeloablative conditioning regimens consisted of CTX, Ara-C and ATG. The patients were given cyclosporine A and mycophenolate mofetile for prophylaxis of acute GVHD. The ABO-incompatible patients received grafts depleted erythrocytes by hydroxyethyl starch (HES) sedimentation. The results showed that successful and stable engraftment was established in 23 patients. No recipient developed clinically immediate hemolysis during graft infusion, but 2 recipients experienced delayed hemolysis attributable to the ABO incompatibility. The median time of granulocyte counts >0.5 x 10(9)/L and platelet >30 x 10(9)/L was 11 and 14.9 days, respectively. In ABO major incompatible group, the onset of erythropoiesis after NAST was delayed. One out of 10 recipients with blood group "O" in this group developed pure red cell aplasia (PRCA), lasting 5 months. The acute GVHD occurred in 7 out of the 24 patients. The chronic GVHD occurred in 5 of 21 cases. Relapse was observed in 2 patients with acute leukemia. The actuarial probability of disease-free survival at 2 years was 63.3%. In conclusion, ABO-incompatible grafts for NAST have no adverse effect on engraftment, recovery of platelets, incidence of GVHD, relapse rate or survival. ABO-incompatible NAST is fairly safe if there is indication, however, the onset of erythropoiesis is delayed when major ABO mismatched.
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PMID:[ABO-incompatible nonmyeloablative allogeneic peripheral blood stem cell transplantation]. 1574 33

A 34-year-old female was referred to our hospital for the evaluation of atypical lymphocytosis. Leukocyte count at diagnosis was 17,900/microl with 58% atypical lymphocytes having a convoluted nucleus and prominent nucleoli. Because the leukocyte count increased to 43,600/microl, the patient was treated with 2'deoxycoformycin followed by CHOP combination chemotherapy. However, both treatments failed to achieve remission. We planned an allogeneic bone marrow transplantation from an HLA-matched unrelated donor. The patient was treated with Ara-C and etoposide before conditioning to decrease the high leukemia burden. After administration of total body irradiation (12 Gy in six fractions) and cyclophosphamide (total dose of 120 mg/kg) unmanipulated marrow cells were infused. Under prevention of GVHD by CsA and short-term MTX, leukocyte engraft was prompt at day 16, and acute GVHD grade II was observed. Because 9.4% of residual recipient type T-cells was seen with STR analysis on day 22, we decreased the dose of Cs'A. After the occurrence of mild acute GVHD, the residual T-cell number decreased. The patient is still in complete remission for up to 22 months after BMT. We conclude that allogeneic SCT is effective for the treatment of T-PLL.
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PMID:[Allogeneic bone marrow transplantation for chemotherapy-resistant T-prolymphocytic leukemia]. 1644 Jul 47


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