Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Therapy-related myelodysplasia (MDS) is a fatal marrow disorder distinct from primary MDS. We examined the efficacy of bone marrow transplantation (BMT) as a treatment for patients with therapy-related MDS. Eighteen patients with therapy-related MDS and twenty-five patients with primary MDS received an allogeneic, syngeneic, or unrelated donor BMT. Graft-versus-host disease prophylaxis included methotrexate, methotrexate plus cyclosporine, FK-506, or T cell depletion. Conditioning regimens consisted of cyclophosphamide/total body irradiation, with and without cytosine arabinoside, busulfan/cyclophosphamide, and cyclophosphamide/etoposide/carmustine. For patients with therapy-related MDS, the median age was 32 years and the actuarial disease-free survival was 24% (95% confidence interval 6, 42%) with a median follow-up of 3 years. For patients with primary MDS, the median age was 36 years and the actuarial disease-free survival at 3 years was 43% (95% confidence interval 22, 64%). Four of the therapy-related patients and two of the primary patients have relapsed. Three patients experienced graft failure; all three had received T cell-depleted marrow and two had marrow fibrosis. Our results suggest that patients with therapy-related MDS can be successfully transplanted. Transplantation should be considered early in the disease, since long-term disease-free survival is achievable.
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PMID:Bone marrow transplantation for therapy-related myelodysplasia: comparison with primary myelodysplasia. 938 75

Today more than 80000 allogeneic bone marrow transplantations (BMT) have been performed worldwide. The major indications are hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and myelodysplastic syndromes. Unrelated donors are increasingly used and there are around 4 million volunteer donors available in different registers, the largest being the National Marrow Donor Program. Molecular typing has improved the typing technique which has resulted in a decreased risk of graft-versus-host disease (GVHD), lower transplant-related mortality (TRM) and improved leukemia-free survival (LFS). Using HLA-identical siblings, patients with AML in first complete remission (1 CR) and high-risk ALL in 1 CR are clear indications for BMT. However, if an HLA-identical sibling is not available, it is not known today if an unrelated bone marrow or autografting is the best option for all patients with acute leukemia in 1 CR. Because BMT is the only curable treatment for CML, a search for an unrelated donor should start as soon as it is evident that an HLA-identical sibling is not available. BMT within a year from diagnosis is of major importance for outcome. Allogeneic peripheral blood progenitor cells (PBPC) have been used as an alternative to bone marrow. Preliminary studies indicate a faster engraftment, but prospective randomized trials are necessary to establish the role of allogeneic PBPC. Umbilical cord blood has also been used as a source of allogeneic hematopoietic stem cells. Using cord blood from HLA-identical siblings, engraftment seems to be delayed, but the probability of GVHD is low. Preliminary data using unrelated cord blood cells are encouraging. GVHD has an important antileukemic effect. Recently, a graft-versus-myeloma and a graft-versus-breast-cancer effect has been demonstrated. In patients who relapse after BMT, donor lymphocytes can induce remission, especially in patients with CML. With molecular techniques it is possible to detect relapse at an early stage, so called minimal residual disease. Liposomal amphotericin B has few side-effects and decreased the death rate by invasive fungal infection in BMT recipients. Early diagnosis and treatment of cytomegalovirus (CMV) infection with new antiviral drugs have dramatically reduced the incidence and mortality in CMV disease. Cyclosporine combined with methotrexate is today the most widely used immunosuppressive regimen and has decreased GVHD and improved survival. However, several new immunosuppressive drugs need to be explored in clinical BMT. Immune modulation by for instance cytokines and cytokine inhibititors is a new exciting development.
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PMID:Allogeneic bone marrow transplantation for hematological malignancies--controversies and recent advances. 940 43

The immune reactivity of allogeneic lymphocytes plays a major role in control of leukemia after bone marrow transplantation. We studies the efficacy of donor leukocyte transfusion (DLT) on acute and chronic leukemia in relapse after bone marrow transplantation in Japan. Sixty nine patients with chronic myelocytic leukemia (N = 17), acute lymphoblastic leukemia (N = 25), acute myelocytic leukemia (N = 26), myelodysplastic syndrome (N = 5), non-Hodgkin lymphoma (N = 2) and rhabdomyosarcoma (N = 1) were treated with transfusions of donor lymphocytes. Therapeutic effects were induced by donor leukocyte transfusion in 20 patients (29%) including 3 patients out of 4 (75%) with CML in cytogenetic and chronic phase relapse, 4 out of 5 (80%) patients with myelodysplastic syndrome, 3 out of 13 (23%) patients with CML in transformed phase, 5 out of 25 (20%) patients with acute myelocytic leukemia, and 4 out of 20 (20%) patients with acute lymphoblasic leukemia. Twenty two patients (30%) developed acute GVHD (> or = 2) and 6 out of 73 (8.2%) patients developed fatal GVHD after donor leukocyte transfusion. Patients relapsed within 6 months after marrow transplantation had a probability of having severe acute GVHD (> or = 2) after DLT. Fourteen out of 24 (58%) patients with GVL response were re-relapsed thereafter. Minimal dose of donor leukocytes infused in successfully treated 9 patients without cytoreductive therapy was 2 x 10(7)/kg in total and minimal dose of that in 6 patients with fatal GVHD was 7 x 10(7)/kg in total. The anti-leukemia effect of donor leukocyte transfusion was strongest against CML in cytogenetic and chronic phase and induce a durable complete remission.
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PMID:[Therapeutic effect of donor leukocyte transfusion in relapsing marrow transplants in Japan]. 942 32

Of 229 consecutive patients receiving allogeneic blood or bone marrow stem cell transplants for acute myeloid leukemia, chronic myeloid leukemia, or myelodysplastic syndrome between 1974 and 1996, 52 patients relapsed. The original tumor recurred as granulocytic sarcoma (chloroma) in three patients (1.3%). Chloroma was found in the ovary in two patients and in the central nervous system in one patient. None of these three patients had experienced > or = grade II acute or more than limited chronic graft-versus-host disease. The intervals between transplantation and recurrence with chloroma were 2, 6, and 13 years. Two patients received a second transplant, and all three died of treatment sequelae.
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PMID:Myeloid leukemia and myelodysplastic syndrome relapsing as granulocytic sarcoma (chloroma) after allogeneic bone marrow transplantation. 943 83

Myeloablative conditioning associated with hazardous immediate and late complications is considered as a mandatory first step in preparation for allogeneic blood or marrow transplantation (allogeneic BMT) for the treatment of malignant hematologic disorders and genetic diseases. Immune-mediated graft-versus-leukemia (GVL) effects constitute the major benefit of allogeneic BMT. Therefore, we have introduced the use of relatively nonmyeloablative conditioning before allogeneic BMT aiming for establishing host-versus-graft tolerance for engraftment of donor immunohematopoietic cells for induction of GVL effects to displace residual malignant or genetically abnormal host cells. Our preliminary data in 26 patients with standard indications for allogeneic BMT, including acute leukemia (n = 10); chronic leukemia (n = 8), non-Hodgkin's lymphoma (n = 2), myelodysplastic syndrome (n = 1), multiple myeloma (n = 1), and genetic diseases (n = 4) suggest that nonmyeloablative conditioning including fludarabine, anti-T-lymphocyte globulin, and low-dose busulfan (8 mg/kg) is extremely well tolerated, with no severe procedure-related toxicity. Granulocyte colony-stimulating factor mobilized blood stem cell transplantation with standard dose of cyclosporin A as the sole anti-graft-versus-host disease (GVHD) prophylaxis resulted in stable partial (n = 9) or complete (n = 17) chimerism. In 9 patients absolute neutrophil count (ANC) did not decrease to below 0.1 x 10(9)/L whereas 2 patients never experienced ANC < 0.5 x 10(9)/L. ANC > or = 0.5 x 10(9)/L was accomplished within 10 to 32 (median, 15) days. Platelet counts did not decrease to below 20 x 10(9)/L in 4 patients requiring no platelet support at all; overall platelet counts > 20 x 10(9)/L were achieved within 0 to 35 (median 12) days. Fourteen patients experienced no GVHD at all; severe GVHD (grades 3 and 4) was the single major complication and the cause of death in 4 patients, occurring after early discontinuation of cyclosporine A. Relapse was reversed by allogeneic cell therapy in 2/3 cases, currently with no residual host DNA (male) by cytogenetic analysis and polymerase chain reaction. To date, with an observation period extending over 1 year (median 8 months), 22 of 26 patients (85%) treated by allogeneic nonmyeloablative stem cell transplantation are alive, and 21 (81%) are disease-free. The actuarial probability of disease-free survival at 14 months is 77.5% (95% confidence interval, 53% to 90%). Successful eradication of malignant and genetically abnormal host hematopoietic cells by allogeneic nonmyeloablative stem cell transplantation represents a potential new approach for safer treatment of a large variety of clinical syndromes with an indication for allogeneic BMT. Transient mixed chimerism which may protect the host from severe acute GVHD may be successfully reversed postallogeneic BMT with graded increments of donor lymphocyte infusions, thus resulting in eradication of malignant or genetically abnormal progenitor cells of host origin.
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PMID:Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. 944 33

Allogeneic bone marrow transplantation (BMT) offers a potential cure for younger patients with myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (sAML). More than 600 patients from 50 European centers have now been reported to the European Group for Blood and Marrow Transplantation (EBMT). We retrospectively analyzed 131 patients reported to the Chronic Leukemia Working Party of the EBMT who underwent BMT from HLA-identical siblings without prior remission induction chemotherapy. At the time of BMT 46 patients had refractory anemia (RA) or RA with ringed sideroblasts, 67 patients had more advanced MDS subtypes and 18 patients had progressed to sAML. The 5-year disease-free (DFS) and overall survival (OS) for the entire group of patients was 34 and 41%, respectively. Fifty patients died from transplant-related complications, most commonly graft-versus-host disease and/or infections. Relapse occurred in 28 patients between 1 and 33 months after BMT, resulting in an actuarial probability of relapse of 39% at 5 years. DFS and OS were dependent on pretransplant bone marrow blast counts. Patients with RA/RARS, RAEB, RAEB/T and sAML had a 5-year DFS of 52, 34, 19 and 26%, respectively. The 5-year OS for the respective patient groups was 57, 42, 24 and 28%. In a multivariate analysis, younger age, shorter disease duration, and absence of excess of blasts were associated with improved outcome. From these data we conclude that patients with myelodysplasia who have appropriate marrow donors, especially those aged less than 40 years and those with low medullary blast cell count should be treated with BMT as the primary treatment early in the course of their disease. Transplantation early after establishing the diagnosis of MDS may improve prognosis due to a lower treatment-related mortality and a lower relapse risk.
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PMID:Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. 948 48

A 37-year-old female highly alloimmunized by multiple transfusions received a sex matched HLA-identical unrelated bone marrow transplant for hypoplastic MDS-RA with moderate myelofibrosis. Conditioning consisted of total body irradiation, cyclophosphamide and ATG, GVHD prophylaxis consisted of CsA, MTX and prednisolone. The CD34+ stem cell content of the first graft was relatively low due to an inadequate harvest. The patient appeared not to have engrafted by day 23 post-BMT. She therefore received a second sex mismatched HLA-identical unrelated bone marrow graft on day 25 after two days of 3.5 mg/kg methylprednisolone from a different donor. Over the ensuing days, the first marrow showed slow engraftment followed by engraftment of the second graft. The first graft was then rejected, as monitored by peripheral blood studies of chimerism. No signs of acute GVHD were observed. Despite successful trilineage engraftment and complete second donor chimerism, the patient died from disseminated toxoplasmosis encephalitis and pneumonia on day +104.
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PMID:Second unrelated bone marrow transplantation without additional conditioning therapy after engraftment failure. 948 60

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular marrow. Drugs, chemical exposure, radiation, and viruses are implicated as etiologic agents, although the majority of community-acquired SAA is idiopathic. Regardless of the inciting event, most cases of SAA result from immune-mediated destruction of bone marrow progenitor cells, which spares pluripotent hematopoietic stem cells. SAA is treated by either allogeneic bone marrow transplantation (BMT) or immunosuppressive therapy. BMT restores normal hematopoiesis and cures the disease in 60% to 80% cases, with the major causes of failure being graft rejection and graft-versus-host disease. Most patients treated with immunosuppressive therapy recover hematopoiesis sufficiently to not require transfusions and are free of infection, although in many, recovery is incomplete. Moreover, up to 50% of SAA patients successfully treated with immunosuppressive therapy relapse or develop a secondary clonal disorder, such as paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome, or leukemia. High-dose cyclophosphamide without BMT is capable of restoring normal hematopoiesis with little or no risk of relapse or secondary clonal disorders. A number of effective treatment options for the treatment of SAA are now available. The optimal approach for definitive management of SAA continues to evolve.
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PMID:Biology and management of acquired severe aplastic anemia. 955 29

To explore the feasibility and potential advantages of PBSC in allogeneic transplantation, we grafted 24 patients (age 16-57, median 37) with different hematologic diseases (ALL = 10, AML = 5, MM = 4, NHL = 2, CML = 1, MDS = 1, AA = 1), 23 HLA-identical to their siblings and 1 partially matched. Cells were collected from donors by apheresis after G-CSF 10 to 16 mg/kg/day for 4 to 5 days, and stored at 4 degrees C until infusion. The patients were conditioned with chemotherapy regimens including busulfan and cyclophosphamide in the majority of cases and received GVHD prophylaxis with CSA-MTX in all but two. The graft consisted of PBSC alone, with a median of 143.5 (range 18.1-358.9) x 10(4)/kg CFU-GM, 9.0 (range 3.3-18.0) x 10(6)/kg CD34+ cells and 2.8 (range 1.2 to 8.6) x 10(8)/kg CD3+ and cells. An ANC >0.0.5 x 10(9)/L was recovered on (median) day 13 (range 11-17), and a platelet count >50 x 10(9)/L on (median) day 13 (range 12-55) post graft. There was no correlation between CD34+ cells or CFU-GM number in the inoculum and time to hematologic reconstitution. Acute GVHD (grade II-IV) occurred in 10 out of 22 (45%), chronic GVHD in 10 out of 18 evaluable (55%) patients. We found no relationship between occurrence of acute or chronic GVHD and number of CD3+ cells in the graft. Four patients relapsed and 7 died after transplantation. Fifteen patients are currently alive and disease-free 67 to 710 (median 286) days from the graft. Allogeneic transplantation with unmanipulated PBSC ensures a fast and stable engraftment. Acute GVHD incidence and severity seems comparable to that of bone marrow transplantation, but there may be an increase in chronic GVHD, mainly of the extensive form.
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PMID:Transplantation of unmanipulated allogeneic PBSC: preliminary report on 24 patients. 957 Jun 80

Donor lymphocyte infusions (DLI) can induce remissions in patients who have relapsed after allogeneic bone marrow transplantation (BMT). However, DLI frequently also result in significant acute and/or chronic graft-versus-host disease (GVHD). Several clinical and experimental lines of evidence have suggested that CD8(+) T cells play a critical role in the pathogenesis of GVHD. To develop methods to reduce the incidence of GVHD associated with DLI, we administered defined numbers of CD4(+) donor T cells after ex vivo depletion of CD8(+) lymphocytes to 40 patients with relapsed hematologic malignancies after allogeneic BMT. Cohorts of patients received 0.3, 1.0, or 1.5 x 10(8) CD4(+) cells/kg. Overall, 12 of 38 patients (32%) evaluable for toxicity developed acute or chronic GVHD. However, 6 of 27 patients (22%) receiving 0.3 x 10(8) CD4 cells/kg developed GVHD compared with 6 of 11 patients (55%) who received >/=1.0 x 10(8) CD4 cells/kg (P = .07). Treatment-related mortality was low (3%), with 1 death related to infection in the setting of immunosuppression for GVHD. Disease responses after CD4(+) DLI were documented in 15 of 19 patients (79%) with early-phase chronic myelogenous leukemia (CML) relapse, 5 of 6 patients (83%) with relapsed multiple myeloma, and 1 patient with myelodysplasia. For patients with early-phase CML relapse, the Kaplan-Meier probability of achieving complete cytogenetic remission was 87% and the probability of complete molecular response was 78% at 1 year after DLI. The median time to complete cytogenetic response and molecular response in patients with CML was 13 weeks (range, 9 to 30 weeks) and 34 weeks (range, 10 to 56 weeks), respectively. The median time to response in patients with multiple myeloma was 26 weeks (range, 15 to 62 weeks). All patients in this trial who developed GVHD demonstrated tumor regression, but the presence of GVHD was not required for patients to achieve a response, because 48% of responding patients never developed evidence of GVHD. Two patients with CML who did not respond at dose level 1 subsequently achieved complete cytogenetic remission after a second infusion of CD8-depleted cells at dose level 2. In patients with evidence of mixed hematopoietic chimerism who achieved a complete remission after DLI, cytogenetic analysis of marrow cells also demonstrated conversion to complete donor hematopoiesis in all evaluable patients. These studies suggest that relatively low numbers of CD8-depleted donor lymphocytes are effective in inducing complete remissions in patients with stable-phase CML and multiple myeloma who have relapsed after allogeneic BMT. Because of the relatively low risk of toxicity associated with the infusion of defined numbers of CD4(+) donor cells, further studies can be undertaken in the setting of persistent minimal residual disease to prevent relapse after allogeneic BMT.
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PMID:Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. 957 3


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