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)

The relative benefit of allogeneic bone marrow transplantation (alloBMT) vs autologous BMT (autoBMT) for patients with relapsed or refractory Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) remains uncertain. Toxicity from graft-versus-host disease (GVHD) may diminish the potential benefits both of graft-versus-tumor activity and of receiving uncontaminated donor marrow stem cells. From 1987 to 1995, 27 adults (ages 18-60 years; median 36) underwent alloBMT for lymphoma after failure of standard chemotherapy. Twenty-one had NHL and six had HD (nodular sclerosis). Thirteen patients had primary refractory disease or chemotherapy-resistant relapses; two of these had relapsed after autoBMT. Three patients had untested relapses (one of them had relapsed after autoBMT), and 11 had chemotherapy-sensitive relapses. Twenty-four received HLA-matched bone marrow from a sibling (one twin); three received haploidentical marrow cells. Nine (33%) died from lymphoma. Eleven (41%) died of treatment-related causes. Opportunistic infections were a substantial problem leading to eight of these deaths (30%). Six patients (22%) survive free of lymphoma 17-70 months post-BMT (median, 56 months); four had had sensitive relapses, one had had a resistant relapse, and one had had nontested relapse. Three have chronic GVHD (limited in one; extensive in two). One HD patient who had relapsed after autoBMT remains in remission 19 months after alloBMT. No therapy-related myelodysplasia has been observed. We conclude that alloBMT has substantial morbidity in heavily pretreated lymphoma patients due to acute toxicity, infections and GVHD. However, 22% of our HD/NHL patients have had long-term disease-free survival.
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PMID:Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin's disease and non-Hodgkin's lymphoma. 933 51

We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy-related MDS and/or AML (t-MDS/t-AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t-MDS/t-AML were breast carcinoma and Hodgkin's disease in two patients each, and non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere-specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients.
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PMID:dic(5;17): a recurring abnormality in malignant myeloid disorders associated with mutations of TP53. 936 36

Although therapy-related (secondary) myelodysplastic syndromes and acute nonlymphocytic leukemias are most frequently observed following therapy of Hodgkin's disease and non-Hodgkin's lymphoma, the therapy of acute lymphocytic leukemia, multiple myeloma, polycythemia vera, cancers of breast, lung, ovary, gastrointestinal tract, testis, and soft tissues is also associated with subsequent development of leukemia. A preceding myelodysplastic syndrome is observed in over 70% of patients who develop therapy-related leukemia, in contrast to patients with de novo leukemia in whom approximately 20% of patients have similar prodromal syndromes. Chemotherapeutic drugs--including alkylating agents, platinum analogs, and epipodophyllotoxins--and ionizing radiation have both been implicated in the etiology of secondary tumors. The median duration from time of chemotherapy or radiation therapy, or both, to diagnosis of secondary leukemia is 3 to 4 years. The risk for development of secondary leukemia is highest between 24 and 72 months following cytotoxic therapy, with a steady decline in incidence thereafter. Of those people who will develop secondary leukemia, approximately 6% of patients do so within the 1st year, whereas 15% of patients will not do so until more than 7 years from commencement of mutagenic therapy. We review here selected recent publications on clinical and therapeutic data in therapy-induced myelodysplasia and acute leukemia.
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PMID:Secondary myelodysplastic syndromes and leukemias. 937 Dec 91

The incidence of non-Hodgkin's lymphoma continues to rise. Molecular events in lymphocytes from individuals without lymphoma are found with increasing age and may represent early changes toward malignant transformation. Molecular, immunophenotypic, and histologic data have been used to propose a new classification system and several new entities have been identified. Localized, low-grade non-Hodgkin's lymphoma can be cured by radiotherapy, whereas patients with extensive disease experience a continuous remitting course. The effect of high-dose regimens is yet to be determined. Current therapy cures less than 50% of patients with advanced aggressive lymphoma and randomized multi-institutional trials using several regimens have shown similar outcomes. The addition of high-dose therapy to patients in remission may offer a survival advantage to a high-risk subset. Late complications of myeloablative therapy, including myelodysplasia and leukemia, are being increasingly recognized. A significant advance in the treatment of posttransplantation lymphoproliferative disorders using donor T cells was made and future applications of this approach are anticipated.
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PMID:Non-Hodgkin's lymphoma. 937 5

Radioimmunotherapy offers an exciting new therapeutic modality for patients with recurrent hematologic malignancies and solid tumors resistant to conventional chemotherapy. In this review, a brief overview of tumor radiobiology as well as various obstacles to treatment is presented. Early radiolabeled antibody trials documented myelosuppression as the dose-limiting toxicity. Ongoing trials in solid tumors and hematologic malignancies are testing the hypothesis that myeloablative doses of radiation in conjunction with hematopoietic stem cell rescue will improve long-term survival. For solid tumors, there are many barriers to achieving this goal. The most encouraging trials in metastatic breast cancer have documented significant symptomatic relief and a 50% partial response in patients. In contrast, trials involving hematologic malignancies have produced more impressive results. With a median follow-up of 33 months, 67% of patients with recurrent acute myelogenous leukemia or myelodysplasia treated with radiolabeled antibodies, total-body irradiation, and high-dose chemotherapy remain disease free. Alone, myeloablative doses of radioimmunotherapy have documented a 41% complete response in patients with Hodgkin's disease. Seattle trials with recurrent non-Hodgkin's lymphoma have demonstrated objective responses in 90% of patients, complete responses in 85% of patients, a progression-free survival of 62%, and an overall survival of 93% with a median follow-up of 2 years.
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PMID:The role of radioimmunotherapy in bone marrow transplantation. 937 15

Myelodysplastic syndrome (MDS) is an uncommon but serious complication of patients who undergo autologous bone marrow transplantation (auto-BMT) for non-Hodgkin's lymphoma or Hodgkin's disease. Some patients exhibit an indolent course, but others succumb to aggressive disease. p53 overexpression is rare in de novo MDS but common in therapy-associated MDS. We used an immunostaining method to analyze expression of p53, the p53-associated tumor suppressor gene products, MDM2, p21waf1, retinoblastoma gene protein (pRB), and the antiapoptotic oncoprotein bcl-2 before and after BMT in BM specimens from eight patients with clonal karyotypic abnormalities characteristic of MDS. Staining was compared with findings in normal BM specimens and specimens from auto-BMT controls and patients with de novo MDS. p53 protein was found in three (75%) of four post-transplantation specimens from patients in whom a clinically aggressive form of MDS developed. In contrast, p53 was absent in all of the specimens from four patients with karyotypic evidence of MDS, but with indolent disease. bcl-2 protein was overexpressed by immature myeloid cells in seven of eight pre-BMT specimens. After BMT, it was predominantly found at low levels in cases positive for p53. MDM2 was present only after transplantation and was found with equal frequency in patients with indolent and aggressive MDS. We detected p21waf1 in only one aggressive post-BMT MDS specimen. pRB was normally expressed in all of the specimens. These data show that p53 and bcl-2 staining patterns in post-transplantation MDS are similar to those described in therapy-associated MDS. p53 positivity is associated with poor prognosis in auto-BMT patients with MDS. Expression of MDM2, p21waf1, and pRB in this group of patients is not helpful in predicting outcome.
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PMID:Expression of p53, MDM2, p21waf1, bcl-2, and retinoblastoma gene proteins in myelodysplastic syndrome after autologous bone marrow transplantation for lymphoma. 938 63

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

Forty of the 550 patients (7%) entered to the 11q23 Workshop had secondary (s) acute lymphoblastic leukemia (nine cases), s-acute myeloid leukemia (25 cases, predominantly of FAB type M5), s-acute leukemia unspecified (one case) or s-myelodysplastic syndrome (five cases) following treatment for a primary malignancy. Breast cancer (12 cases) and non-Hodgkin's lymphoma (eight cases) were the most frequent primaries. Twenty-three patients had been treated with either an epipodophyllotoxin (seven patients) or an anthracycline (10 cases) or both (four cases) frequently combined with alkylating agents (12 cases) and with radiotherapy (six cases). Two further patients had alkylating agents and two had radiotherapy alone. Time between diagnosis of the primary and secondary malignancy was between 10 months and 22 years (median 24 months). The incidence of secondary malignancies in 11q23 subgroups was: t(11;19)(q23;p13.1) (33%), t(9;11) (8%), t(4;11) (5.5%), t(10;11)(5%), t (6;11) (3%), del11q23(2%) and 10 patients had a rare 'other' abnormality. No associations were seen between type of prior malignancy and 11q23 subgroup, or between prior malignancy and leukemia subtype. Remission, when achieved (32 patients), was short (median 5 months). Two patients survived following a bone marrow transplant for s-leukemia and s-myelodysplastic syndrome.
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PMID:Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. EU Concerted Action 11q23 Workshop. 959 90

Recent studies have documented an increased risk of therapy-related myelodysplastic syndrome or acute myelogenous leukemia (t-MDS/AML) after autologous bone marrow transplant (ABMT) for non-Hodgkin's lymphoma (NHL). To develop methods to identify patients at risk for this complication, we have investigated the predictive value of clonal bone marrow (BM) hematopoiesis for the development of t-MDS/AML, as defined by an X-inactivation based clonality assay at the human androgen receptor locus (HUMARA), in a group of patients undergoing ABMT for NHL from a single institution (Dana-Farber Cancer Institute, Boston, MA). One hundred four female patients were analyzed. At the time of ABMT, the prevalence of polyclonal hematopoiesis was 77% (80/104), of skewed X-inactivation pattern (XIP) was 20% (21/104), and of clonal hematopoiesis was 3% (3/104). To determine the predictive value of clonality for the development of t-MDS/AML, a subgroup of 78 patients with at least 18 months follow-up was analyzed. As defined by the HUMARA assay, 53 of 78 patients had persistent polyclonal hematopoiesis, 15 of 78 had skewed XIP, and 10 of 78 (13.5%) either had clonal hematopoiesis at the time of ABMT or developed clonal hematopoiesis after ABMT. t-MDS/AML developed in 2 of 53 patients with polyclonal hematopoiesis and in 4 of 10 with clonal hematopoiesis. We conclude that a significant proportion of patients have clonal hematopoiesis at the time of ABMT and that clonal hematopoiesis, as detected by the HUMARA assay, is predictive of the development of t-MDS/AML (P = .004).
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PMID:Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: a single institution study. 961 44

Secondary acute myeloid leukemia (s-AML) and secondary myelodysplastic syndrome (s-MDS) probably represent the worst possible long-term complications of cancer therapy in patients originally cured of their primary malignancy. The frequency and type of s-AML and s-MDS are reviewed for patients treated with standard and/or high-dose chemotherapy for Hodgkin's disease, non-Hodgkin's lymphoma (NHL), and breast or testicular cancer. Patients treated for Hodgkin's disease, have a 20- to 40-fold increased risk of developing s-AML, this risk increasing with the number of mechlorethamine-containing cycles given as well as following splenectomy and in patients more than 40-50 years of age. Generally, patients with NHL, breast or testicular cancer experience a lower, 2- to 15-fold, risk of developing s-AML. Epipodophyllotoxins appear to be the most important factor for s-AML in patients treated for testicular cancer. Doses of 2g/m2 or more are associated with an increased risk of s-AML and, with these high doses, a cumulative incidence of 2% 3% at 5 years is observed. Adjuvant cyclophosphomide, methobrexate, 5-Fu therapy in breast cancer patients does not appear to increase risk significantly as compared to the general population. The extent of the leukemogenic potential of anthracyclines remains to be defined. NHL patients receiving mechlorethamine, prednimustine or long-term maintenance therapy are also at an increased risk of s-AML. A considerably increased risk of developing AML, with a cumulative incidence of approximately 9% at 5 years, has been observed following allogenic bone marrow transplantation (ABMT) or peripheral stem cell transplantation (PBSCT) in patients with NHL. It is likely that the increased risk of s-AML/s-MDS following high-dose chemotherapy with ABMT or PBSCT is related to prior treatment rather than to high-dose chemotherapy itself. However, this issue remains to be conclusively addressed. s-AML or s-MDS rarely develops after allogenic bone marrow transplantation. s-AML and s-MDS increasingly represent a problem in modern cancer therapy because of better treatment strategies, which result in improved cure rates. Patients who receive chemotherapy must be informed about the potential risk of developing s-AML or s-MDS. Future studies should include a follow-up long enough to record the occurrence of all s-AML/s-MDS and all potential influencing factors reliably. These data would enable risk factors to be defined and risk/benefit analyses to be carried out, allowing the correct assessment of current and future therapy strategies.
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PMID:Risk of secondary myeloid leukemia and myelodysplastic syndrome following standard-dose chemotherapy or high-dose chemotherapy with stem cell support in patients with potentially curable malignancies. 961 48


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