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

Conventional allogeneic stem cell transplantation (SCT) for myelodysplastic syndrome (MDS) is associated with excessive procedure-related mortality. The outcome following volunteer-unrelated donor (VUD) or sibling allogeneic SCT was therefore evaluated in 23 MDS patients conditioned with reduced-intensity regimens (fludarabine/busulphan/Campath-1H) because of advanced age (48 vs 37 years, P = 0.002) and/or co-morbidity (19 vs 3, P < 0.0001) which precluded conventional transplantation, and compared with 29 treated with standard protocols [busulphan/cyclophosphamide (Bu/Cy); Bu/Cy/total-body irradiation/Campath-1G]. Graft-versus-host disease (GVHD) prophylaxis comprised of cyclosporine/methotrexate. One hundred per cent donor engraftment (variable number tandem repeat analysis/cytogenetics/fluorescence in situ hybridization) was achieved in 18/19 (95%) evaluable patients receiving reduced-intensity regimens, although six (32%) have subsequently shown mixed chimaerism. Reduced-intensity conditioning was associated with significantly reduced duration of aplasia, less mucositis, fever, antibiotic, analgesia, parenteral nutrition use, less acute and chronic GVHD, and lower early procedure-related mortality [two (9%) vs nine (31%), P < 0.05]. Six patients relapsed (two standard, four reduced-intensity) and two (reduced-intensity) experienced late graft failure. The 2 year actuarial overall/disease-free survival (OS/DFS) was 48/39% in the reduced-intensity arm and 44/44% in the standard group. The 2 year non-relapse mortality was 31% and 50% respectively. In VUD recipients, OS was superior in the reduced-intensity arm (49%vs 34%). Predictors of DFS included good/intermediate-risk karyotype, low/intermediate-1 International Prognostic Scoring system score, human leucocyte antigen compatibility and attainment of complete remission. Our data demonstrates that VUD or sibling allogeneic SCT following reduced-intensity conditioning is feasible in high-risk MDS patients considered unsuitable for standard transplantation and is associated with comparable 3.5 year DFS to those receiving conventional regimens.
 ...
PMID:Allogeneic stem cell transplantation in the myelodysplastic syndromes: interim results of outcome following reduced-intensity conditioning compared with standard preparative regimens. 1235 19

Significant advances have been made in the development of targeted interventions for hematologic malignancies. Progress has been made in defining the molecular pathogenesis of human leukemias. Data indicate that nonrandom, somatically acquired translocations, inversions, and other abnormalities occur in many acute leukemias. In the treatment of acute promyelocytic leukemia (APL), targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy leads to dramatic improvements in disease-free survival. Imatinib mesylate, a signal transduction inhibitor that inhibits tyrosine kinase activity, the protein product of the ABL proto-oncogene, has remarkable activity in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). Farnesyltransferase inhibitors (FTIs), a promising class of agents that target multiple pathways including Ras proteins, are potential anticancer therapy for a wide range of malignancies, including leukemias and myelodysplastic syndromes (MDS). There also is evidence that recombinant human erythropoietin therapy (r-HuEPO) can benefit patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. This supplement will discuss advances in our understanding of human leukemias, including the use of unconjugated monoclonal antibodies such as Campath-1H (Wellcome, Beckenham, UK, and Ilex Oncology, San Antonio, TX) and rituximab and immunoconjugates such as gemtuzumab ozogamicin and BL-22. Although these novel therapies are beginning to fulfill their promise, continued research efforts are needed to determine the optimal role of targeted therapy in acute and chronic leukemias.
 ...
PMID:Advancing the treatment of hematologic malignancies through the development of targeted interventions. 1244 45

Allogeneic haemopoietic stem cell transplantation (SCT) is the only curative option for severe bone marrow (BM) failure in patients with Fanconi anaemia (FA). We have developed a non total body irradiation (TBI) conditioning protocol consisting of fludarabine (120-150 mg/m(2)), low dose of cyclophosphamide (40 mg/kg) and antilymphocyte globulin (45 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin alone for sibling allografts but also included Campath-1 H (days 1-5 post SCT) for the unrelated allografts. We have performed two sibling and two unrelated BM transplants with a follow-up of 11-51 months. All patients experienced minimal toxicity and were discharged from hospital 28-32 days post SCT. Neutrophil and platelet engraftment occurred from days 11 to 19 and 15 to 34, respectively. All patients achieved stable full donor haemopoiesis with normalisation of the peripheral blood count despite one of them having myelodysplasia (MDS) with 8% blasts prior to the SCT. The only site of acute GVHD was in the skin (grade I-II) and only one patient progressed to limited chronic GVHD. This protocol is associated with reduced toxicity and prompt engraftment in FA patients with AA and/or MDS undergoing SCT using sibling or unrelated donors.
 ...
PMID:Non-TBI stem cell transplantation protocol for Fanconi anaemia using HLA-compatible sibling and unrelated donors. 1313 Mar 11

Malignant diseases (MD) occurring after stem cell transplantation (SCT) are of particular concern as increasing number of patients survive and remain free of their original disease. The cumulative incidence at 15 years is 10-12%. The B-cell proliferative disorders (BCLP) are the most common MD in the first year after SCT; the incidence probability is 1% in allogeneic transplants but is much higher (until 14%) after HLA-identical, T-cell-depleted SCT in which Campath 1G or ATG are given. BCLP develop because of reactivation of the EBV and a depressed cellular immunity. Prediction of risk of BCLP can be made by frequent monitoring of EBV load in patients with risk factors. The most effective therapies are the early administration of anti-CD20 monoclonal antibody and adoptive immunotherapy with in vitro generated EBV-specific cytotoxic T cells. Myelodysplasia and acute myeloid leukemia with very poor prognosis have been described in 4-18% of patients with non-Hodgkin lymphoma and Hodgkin disease, 12-24 months after autologous SCT. The risk of development of solid tumors increases over time and the cumulative incidence among children who underwent an SCT at less than 10 years of age is 6-11% at 15 years. There are few studies evaluating quality of life (QOL) in children and adolescents who had received an SCT. The findings of these studies can be summarized as follows: (a) The majority of long survivors enjoy good QOL and return successfully to school or work. (b) A minority (10-15%) complain of physical problems or present moderate cognitive or psychological dysfunctions. (c) The importance of family, other social support and psychological adjustments is generally recognized. More extensive, longitudinal and comparative studies with other alternative therapies are required.
 ...
PMID:Secondary malignancies and quality of life after stem cell transplantation. 1581 38

Alemtuzumab is effective therapy for B- and T-cell lymphoproliferative disorders (LPD) but is associated with prolonged lymphopenia. Myeloid haematological toxicities are less well described, especially in T-cell disorders, and are usually transient. We report myeloid toxicities in a phase II trial of alemtuzumab for T-cell LPD. Five of 11 patients treated developed severe neutropenia and thrombocytopenia. Three cases had prolonged cytopenias (32-88+ weeks), including two with severe marrow hypoplasia. We observed three incidences of trilineage morphological myelodysplasia, two with new clonal cytogenetic abnormalities. Alemtuzumab can be associated with prolonged severe multilineage cytopenias, marrow hypoplasia and myelodysplasia in T-cell LPD.
 ...
PMID:Severe and prolonged myeloid haematopoietic toxicity with myelodysplastic features following alemtuzumab therapy in patients with peripheral T-cell lymphoproliferative disorders. 1598 49

Graft failure is associated with a high mortality rate. To date, regimens invoked for second transplants have resulted in inconsistent engraftment with high transplant-related mortality (TRM). We here report 16 consecutive patients, aged 4-59 years, who received second HSCT (HSCT-2) at a median of 45 days following primary or secondary failure of an initial unmodified (N = 3) or T cell-depleted (TCD) (N = 13) HSCT (HSCT-1). HSCT-1 was administered after myeloablative total body irradiation (TBI)- or alkylator-based conditioning for acute leukemias (N = 7), MDS (N = 6), CML (N = 2), and Fanconi anemia (N = 1). All patients experienced 1 or more infectious complications between HSCT-1 and HSCT-2, and 10 patients had active infections at the time of HSCT-2. Cytoreduction regimens used for HSCT-2 included fludarabine (Flu) in combination with cyclophosphamide (CTX) (N = 9), or thiotepa (Thio) (N = 5). In addition, 1 patient received Flu alone and 1 patient Thio combined with CTX. Antithymocyte globulin (ATG) (N = 11) or Alemtuzumab (N = 3) was added pretransplant to prevent rejection. For HSCT-2, donors included HLA-matched (N = 3) or mismatched (N = 8) related, or matched (N = 2) or mismatched (N = 3) unrelated donors. The primary graft donor was used in 6 of 16 cases. The grafts administered were unmodified peripheral blood stem cell transplantation (PBSCT) (N = 5) or bone marrow transplantation (BMT) (N = 3), TCD PBSCT (N = 8). All patients achieved engraftment at a median of 12 days and evaluable patients achieved complete donor chimerism. Six patients are alive with a median follow-up of 49 months, including 4/9 conditioned with Flu/CTX. In this series, outcome was statistically superior for younger patients (<or=20 years). In summary, second HSCT using the combination of a fludarabine- and ATG-based, nonmyeloablative regimen and higher numbers of CD34+ progenitor cells has been associated with acceptable toxicity and allowed consistent engraftment with hematopoietic reconstitution in patients with previous graft failure.
 ...
PMID:Fludarabine-based conditioning secures engraftment of second hematopoietic stem cell allografts (HSCT) in the treatment of initial graft failure. 1795 Sep 18

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for the BM dysfunction seen in patients with Shwachman-Diamond syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced-intensity-conditioning protocol in seven patients with SDS and BM aplasia or myelodysplastic syndrome/AML. The preparative regimen consisted of Campath-1H, fludarabine and melphalan. Four patients received matched related marrow and three received unrelated stem cells (two PBSCs and one marrow). All but one was 8 of 8 allele HLA matched. All patients established 100% donor-derived hematopoiesis. No patient in this cohort developed grades III-IV GVHD. One patient had grade II skin GVHD that responded to systemic corticosteroids and one had grade I skin GVHD, treated with topical corticosteroids. Two out of seven patients developed bacterial infections in the early post transplant period. Viral infections were seen in four out of seven patients and were successfully treated with appropriate antiviral therapy. All patients are currently alive. These data indicate that HSCT with reduced-intensity conditioning is feasible in patients with SDS and associated with excellent donor cell engraftment and modest morbidity.
 ...
PMID:Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome. 1850 Mar 73

Acquired bone marrow failure syndromes (BMFS) are a heterogeneous group of hematological disorders characterized by impaired bone marrow function and subsequent cytopenia of one or more blood cell lineages [1,2]. The well-accepted pathogenic mechanism of the typical bone marrow failure - aplastic anemia (AA)- is a T cell mediated immune attack targeting the hematopoietic tissue [3]. This pathogenic mechanism is at least partially shared by other bone marrow failure syndromes, such as lineage-restricted aplasias and some myelodysplastic syndromes. Thus, for these disorders immunosuppression (IS) is the pivotal etiologic treatment. While the standard IS regimen include the heterologous anti-thymocyte globulin [4], here we review the recent data on the anti-CD52 monoclonal antibody alemtuzumab as a novel IS agent for marrow failures. Alemtuzumab led to objective responses in aplastic anemia patients in 3 recent prospective studies, with overall response rates ranging between 37% and 72%. Adverse events were irrelevant, ruling out even the concerns about the risk of infectious complications. Alemtuzumab was effective even for the treatment of lineage-restricted marrow failure, with very acceptable toxicity and excellent response rates (as high as 80%). More recently, even patients suffering from myelodysplastic syndromes showed a remarkable hematological response to alemtuzumab-based IS treatment. Thus, alemtuzumab is a novel IS agent representing an excellent alternative to ATG for all immune-mediated marrow failure syndromes. Even if the dose and the schedule may still require further refining, the available data support the need of large prospective trials comparing alemtuzumab to current standard IS regimens.
 ...
PMID:Novel immunosuppressive strategies for bone marrow failure syndromes: a focus on alemtuzumab. 2156 2

Immunosuppressive therapy is a therapeutic option for selected low-risk myelodysplastic syndromes (MDS) patients. Besides standard treatment protocols that include ATG and CSA, the humanized CD52 antibody alemtuzumab has been shown to have efficacy in MDS treatment. We report our experience with alemtuzumab in nine MDS RCMD patients. All patients had a hypocellular bone marrow with a blast count <5 % and were classified as intermediate-1 according to the IPSS. We found a response in five patients (60 %); three patients achieved a complete remission 3 and 6 months after the treatment with alemtuzumab, and two patients showed a haematological improvement. Alemtuzumab was administered in a 10-mg dosage for 10 days. Treatment was well tolerated, and no severe side effects were observed. We could confirm the finding that the alemtuzumab is effective and save selected MDS patients. Due to the promising results, further studies, especially with regard to long-term survival and risk of leucemic progression should be initiated.
 ...
PMID:Real life experience with alemtuzumab treatment of patients with lower-risk MDS and a hypocellular bone marrow. 2393 99