UMLS:C0026986 - FACTA Search

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Query: UMLS:C0026986 (myelodysplastic syndrome)
14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed the prognostic value of p53 mutations for response to chemotherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations were detected by single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing. A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS, and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated cases and 66 of 81 (81%) nonmutated cases treated with intensive chemotherapy achieved complete remission (CR) (P = .005) and none of five mutated cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial survival was 2.5 months in mutated cases, and 15 months in nonmutated cases (P < 10(-5)). In the MDS patients who received chemotherapy (intensive chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P = .004), and median actuarial survival was 2.5 and 13.5 months, respectively (P < 10(-5)). In all MDS cases (treated and untreated), the survival difference between mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambucil and/or CHOP and/or fludarabine) responded, as compared with 29 of 36 (80%) nonmutated cases (P = .02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < 10(-5)). In 35 of the 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our findings show that p53 mutations are a strong prognostic indicator of response to chemotherapy and survival in AML, MDS, and CLL. The usual association of p53 mutations to loss of the nonmutated P53 allele, in those disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells.
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PMID:p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. 794 87

A 68 year old woman was hospitalized because of cervical lymphadenopathy. Hematological data on admission showed anemia, leukopenia with a normal platelet count. Serum serological studies revealed polyclonal hypergammaglobulinemia, a positive microsome and thyroid test, and positive reaction to antithyroglobulin antibody. Microscopic examination of a cervical lymph node revealed malignant lymphoma, diffuse large cells of B cell phenotype. The bone marrow smears revealed hypercellularity with dysplastic features including pseudo-Pelger and other nuclear abnormalities of neutrophils, micromegakaryocytes, dyserythropoiesis with megalobastic changes, 60% ring sideroblast and with no increase in proportion of blast cells (3.6%). A diagnosis of myelodysplastic syndrome (MDS, refractory anemia with ring sideroblast (RARS)) was made. Remission of ML obtained with radiation and subsequent systemic chemotherapy with CHOP-Bleo regimen, although she died 2.5 yr after the diagnosis due to relapse of ML without leukemic transformation of MDS. Although basic disturbances in these three conditions are not clear, it is evident that treatment was not concerned with the pathogenesis in this case, because the three conditions existed without treatment. It may be hypothesized that an initial event which selects a clone of stem cells that retains the capacity to differentiate into myeloid and lymphoid line would manifest with the features of RARS in the myeloid line and with the sort of immunological abnormalities reported in this case. Subsequent events select subclones and these progressively lose terminal differentiation, culminating as B-cell lymphoma.
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PMID:[Malignant lymphoma complicating myelodysplastic syndrome with autoantibody for the thyroid gland]. 926 63

A retrospective analysis was performed on 76 consecutive elderly patients with acute leukemia aged 60 years or more (48 men, 28 women). Forty patients were 60-69 years old, 28 were 70-79 years old and 8 were > or = 80 years old. There were 55 patients with acute myelogenous leukemia (AML), 13 acute lymphoblastic leukemia (ALL) and 8 AML from myelodysplastic syndrome (MDS/AML). Patients were treated with the JALSG protocol, CAG regimen, or low-dose Ara-C regimen for AML, and DVP/M-CHOP protocol for ALL. The complete remission (CR) rates were 52.7% (29 of 55) in AML, 61.5% (8 of 13) in ALL, and 0% in MDS/AML. The median CR durations were 226, 85, 0 days, and the median survivals were 204, 177, 99 days, respectively. CR rates were 65.3% for the JALSG protocol, 62.5% for the CAG regimen and 25.0% for low-dose Ara-C regimen. According to age, CR was obtained 62.5% in patients aged 60-69 years and 33.3% in patients over 70 years old. Our results indicated that patients aged 60-69 years should be treated with intensive chemotherapy.
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PMID:[Retrospective analysis of elderly patients > or = 60 years of age with acute leukemia]. 957 40

We diagnosed a probable fludarabine-induced secondary MDS approximately 18 months after treatment of a low grade non-Hodgkin's lymphoma. After diagnosis of a B-cell lymphoma composed of relatively small cells, fludarabine was administered between May and October, 1997, to a 64-year-old female patient. In December 1998, a mild bicytopenia was present with a leukocyte count of 3800/microl and platelets of 142000/microl. The white cell differential count was normal. The hemoglobin level was normal, but MCV was elevated. Bone marrow cytology revealed normal cellularity with dyserythropoiesis and dysmegakaryocytopoiesis. PAS staining showed scattered positivity in early erythroid cells. In 12 of 20 mitoses, the karyotype showed complex rearrangements, described as 46,XX,t(4;11)(q23?24;q13),del(5q),del(7)(q22),+mar[8]/45,-3. A diagnosis of treatment-related MDS was made. While there was no evidence of bone marrow infiltration by the lymphoma, CT scans demonstrated paraaortic lymph nodes up to 10 cm in diameter. After one course of CHOP chemotherapy, prolonged bone marrow aplasia and septic complications occurred. Chemotherapy was abandoned and Rituximab was administered. In July and November, 1999, bilateral pneumonia and urinary tract infection, respectively, were treated with antibiotics. NHL was in complete remission, but peripheral blood counts deteriorated markedly, and transfusions of packed red cells had to be started in November, 1999. The suspicion of leukemic transformation could not be confirmed because the patient declined further bone marrow biopsies. In December, 1999, the patient died from pneumonia.
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PMID:Secondary myelodysplastic syndrome after fludarabine therapy of a low-grade non-Hodgkin's lymphoma. 1113 66

In a patient with recently diagnosed chronic myelomonocytic leukemia features, the biopsy of a peripheral lymphadenopathy seven months later revealed disorganised lymphoid tissue with a few large EBER (+) LMP1 (+) B-lymphocytes before any treatment was given. At this time, a clonal TCR gamma rearrangement and very faint clonal IgH rearrangement were demonstrated, and the diagnosis of angioimmunoblastic T-cell lymphoma was made. Treatment with MOPP was started, followed by Hydroxycarbamide and CHOP but the outcome was fatal. During the evolution, there was no blastic transformation of the chronic myelomonocytic leukemia. The T-cell lymphoma extended to abdominal lymph nodes, Waldeyer ring and bone marrow and the percentage of large LMPI EBER (+) B-cells increased in the lymph nodes. These findings do not support a common stem cell abnormality leading to myelodysplasia in the bone marrow and lymphoma in peripheral lymph nodes. The lack of a clearcut light chain restriction in the EBV infected B-cell is suggestive of a persistant EBV infection in polyclonal or oligoclonal activated B-cells as described in immunodepressed patients. The association of CMML features and an angioimmunoblastic T-cell lymphoma is discussed.
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PMID:Occurrence of angioimmunoblastic T cell lymphoma in a patient with chronic myelomonocytic leukemia features. 1142 21

We report a case of therapy-related myelodysplastic syndrome (t-MDS) in adult T-cell lymphoma. A 69-year-old man suffered from cutaneous adult T-cell lymphoma, which was treated with radiation to the skin and combination chemotherapy of CHOP-V-MMV and VEPA-B. After 14 months of these therapies, anemia and thrombocytopenia appeared, and bone marrow aspiration smears showed immature myeloblasts, dysplastic erythroblasts, and micromegakaryocytes. Therapy-related MDS of refractory anemia with an excess of blasts was diagnosed. Cytogenetic study of the bone marrow cells showed 5q- and additional abnormalities. Rearrangement of the MLL gene was observed in the bone marrow cells. Mutations of N-ras codons at 12,13, and 61, p53 tumor suppressor gene, and monoclonal integration of human T-lymphotrophic virus -1 provirus DNA were not observed in the bone marrow cells. The patient died of pneumonia 21 months after diagnosis of cutaneous adult T-cell lymphoma.
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PMID:Therapy-related myelodysplastic syndrome in a case of cutaneous adult T-cell lymphoma. 1184 94

Hematopoietic reconstitution could be associated with premature ageing of the transplanted cells and a high frequency of myelodysplastic syndrome and secondary leukaemia. Telomere length decreases with cell divisions and age, and at a crucial length it is associated with chromosomal instability and cell senescence. Telomerase is a reverse transcriptase enzyme that adds nucleotides to chromosomal ends. Most somatic cells lack telomerase activity yet haematopoietic stem cells retain low levels of telomerase. Some studies have found that chemotherapy and stem cell transplantation lead to the accelerated shortening of telomere length. As granulocyte colony-stimulating factor (G-CSF) is routinely used in the mobilization of stem cells for transplantation, we evaluated its effects on telomerase activity and regulation, and on telomere dynamics, in normal donors and selected lymphoma patients. Administration of G-CSF increased telomerase activity in CD34+ haematopoietic cells compared with controls. In marrow-derived CD34+ cells, telomerase activity increased sevenfold, compared with a 14-fold increase in peripheral-blood-mobilized CD34+ cells. A parallel increase in the expression of human telomerase enzyme reverse transcriptase RNA and protein kinase C alpha occurred. In addition, G-CSF administration to five lymphoma patients after consecutive courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, resulted in telomere length preservation or elongation, as opposed to marked attrition in patients who did not receive growth factors. We conclude that the in vivo administration of G-CSF prevents or attenuates telomere attrition associated with chemotherapy administration. This attenuation may contribute to the preservation of telomere integrity inG-CSF-primed transplanted stem cells.
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PMID:Granulocyte colony-stimulating factor administration upregulates telomerase activity in CD34+ haematopoietic cells and may prevent telomere attrition after chemotherapy. 1254 95

A 62-year-old woman was diagnosed as having malignant lymphoma, diffuse large B-cell type. She underwent chemotherapy with the standard dose of CHOP and MINE regimens, resulting in complete remission. Four months later, the myelodysplastic syndrome of RA (refractory anemia) with pancytopenia developed and rapidly progressed to acute myelogenous leukemia (AML-M6) in 4 months. Cytogenetic analysis for the bone marrow specimens of both periods of MDS and AML-M6 revealed complex karyotypic abnormalities involving chromosome 5, 7, 11q23 and 20q11.2. Neither rearrangement of the MLL gene by Southern blot analysis nor tandem duplication of MLL gene by RT-PCR technique was detected. The patient was died from progression of leukemia and pneumonia. The autopsy showed no residual disease of lymphoma-related disease.
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PMID:[Therapy-related acute myelogenous leukemia (AML-M6) with add(11) (q23) and del(20) (q11.2) developing via myelodysplastic syndrome after chemotherapy for malignant lymphoma]. 1272 43

The role of high dose therapy, including autologous stem cell transplantation (ASCT) in indolent non-Hodgkin's lymphomas remains controversial. We evaluated a dose intense regimen of CHOP induction followed by high dose cyclophosphamide consolidation (CHOP-HC) versus CHOP alone in a prospective comparison to assess intensified therapy without ASCT. Twenty-five patients with previously untreated advanced stage indolent NHL were enrolled: follicular lymphoma, grade 1 (11 patients) and grade 2 (8 patients); small lymphocytic lymphoma (5 patients); and lymphoplasmacytic lymphoma (1 patient). All patients were treated as clinically indicated. The median age was 47 years (21-70). There were 15 males, and 10 females. Three patients had intra-abdominal stage II, 2 patients with stage III, and 20 patients with stage IV disease. All patients received induction with CHOP for 4 cycles (weeks 1, 4, 7, 10): cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., vincristine 1.4 mg/m2 i.v. (2 mg capped dose) and prednisone 100 mg p.o. x 5 days. Following induction, responding patients were given consolidation with either high dose cyclophosphamide @ 3 gm/m2 i.v. for 3 doses with G-CSF (weeks 13, 15, 17) or 2 additional cycles of CHOP (weeks 13, 16), stratified by stage and bulk of disease. The overall response rate to CHOP was 92% (3 CR, 8 PR) and to CHOP-HC was 93% (4 CR, 8 PR). The overall response, complete response and partial response rates were comparable in both arms. Median progression free survival for CHOP was 15.9 and 23.0 months for CHOP-HC. At 74.3 months median follow-up, all patients in the CHOP arm have recurred; 3 patients in the CHOP-HC arm (3 CR) have not recurred. The median overall survival has not been reached (at 5 years, 77% OS for CHOP-HC versus 83% OS for CHOP alone]. Greater hematologic toxicity was observed with CHOP-HC resulting in an increased number of hospitalizations for sepsis. There were no treatment-related deaths. No myelodysplasia or acute leukemia has been seen to date. With no obvious improvement in CR and with greater hematologic toxicity than CHOP, CHOP-HC is not recommended for treatment of indolent non-Hodgkin's lymphomas.
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PMID:CHOP with high dose cyclophosphamide consolidation versus CHOP alone as initial therapy for advanced stage, indolent non-Hodgkin's lymphomas. 1285 95

Iodine-131 tositumomab [B1, Bexxar , iodine-131 anti-B1 antibody] is a murine antibody conjugated to iodine 131 that recognises and binds to the B1 (CD20) antigen which is found specifically on B lymphocytes. Iodine-131 tositumomab has a dual mechanism of action. It is capable of initiating a host immune response to those B cells to which it is attached, and it also triggers apoptosis in a significant proportion of the cells to which it binds. The product was first discovered by Coulter Corporation, Miami, in collaboration with the Dana-Farber Cancer Institute and the University of Michigan. The spin-off company Coulter Pharmaceutical, upon its formation, obtained worldwide rights to iodine-131 tositumomab. (Coulter Corporation was acquired subsequently by Beckman Instruments in October 1997. The union of the two companies produced Beckman Coulter.) In December 2000, Coulter Pharmaceutical was acquired by, and merged into, Corixa Corporation.Iodine-131 tositumomab is available for licencing in Japan. Corixa Corporation and GlaxoSmithKline signed an agreement to jointly develop and commercialise iodine-131 tositumomab. The total agreement has a potential value of up to $US132 million, plus shared profits and royalties. The two companies will jointly market the antibody in the US following regulatory approval. Corixa Corporation has announced it expects iodine-131 tositumomab to be approved in the US for non-Hodgkin's lymphoma (NHL). Under the terms of the original agreement, GlaxoSmithKline will receive exclusive marketing rights outside the US, excluding Japan. However, an amended agreement between the two companies will allow Corixa Corporation to also market the product outside the US. In February 2003, the European Commission granted iodine-131 tositumomab orphan-drug designation. Corixa Corporation and GlaxoSmithKline also intend to jointly investigate the use of the product in other indications. GlaxoSmithKline may also receive access to second generation anti-CD20 compounds under its agreement with Corixa Corporation. In May 2003, Corixa Corporation entered into an agreement that will see GlaxoSmithKline market Bexxar in Canada. Under the terms of the agreement, Corixa Corporation will manufacture and supply the product to GlaxoSmithKline, who will register, market and sell it in Canada. In October 2001, Amersham PLC, a supplier of medical equipment, announced that its Amersham Health unit had signed a marketing agreement with Corixa Corporation. The agreement allows Amersham Health to market iodine-131 tositumomab in Europe. Corixa Corporation formed agreements with Boehringer Ingelheim Pharma KG and Lonza Biologics to produce the B1 antibody and radiolabelling of the antibody has been contracted out to MDS Nordion.Iodine-131 tositumomab has received orphan drug and fast track designation for the treatment of NHL. Corixa Corporation submitted a Biologics Licence Application (BLA) to the US FDA in 1999, seeking permission to market Bexxar in the US for the treatment of relapsed or refractory, low grade or transformed low grade B-cell NHL. Following a priority review, the US FDA requested that Corixa Corporation reformat certain sections and perform additional analyses of existing data in its BLA. Corixa Corporation and GlaxoSmithKline resubmitted their BLA to the US FDA in September 2000. The BLA was subsequently accepted by the US FDA in November 2000. However, in March 2001, the US FDA requested additional information in its complete review letter to Corixa Corporation and marketing partner GlaxoSmithKline. The two companies submitted data pertaining to the chemistry, manufacturing and controls section of the BLA, and to the majority of the questions regarding the clinical section of the BLA in August 2001. Corixa Corporation and GlaxoSmithKline submitted the remainder of the response to the US FDA in September 2001, following an independent review of clinical trial data. In March 2002, Corixa Corporation received another complete review letter from the US FDA, which stated that additional clinical trials would have to be conducted in order to provide adequate evidence of the safety and clinical benefit of Bexxa. The US FDA also denied Corixa Corporation's request for accelerated approval, stating that the data provided was inadequate to show that Bexxar filled an unmet medical need. Corixa Corporation has met formally with the US FDA but the two were unable to resolve their differences. Corixa Corporation will now file a formal request for dispute resolution under the Food and Drug Administration Modernisation Act. Corixa Corporation also requested a presentation of Bexxa data to the US FDA's scientific advisors. In June 2002, the US FDA granted the company's appeal for additional regulatory review. In December 2002, the US FDA's Oncologic Drugs Advisory Committee agreed that Bexxar has clinical benefit for patients with NHL. In May 2003, Corixa Corporation and GlaxoSmithKline announced that they had fulfilled many of the steps required for US FDA approval, however the US FDA has extended its review of the application for another 3 months. This extension will allow for further refinement of post marketing commitments and package insert language, and to ensure they are consistent with an updated safety database requested by the US FDA and submitted by Corixa Corporation in early April. GlaxoSmithKline was waiting for the outcome of the situation before deciding on marketing plans for Bexxar. Corixa Corporation and GlaxoSmithKline will conduct a head-to-head study of Bexxar and Idec's Zevalin, planned for mid-2003. The trial will likely be one of three phase IV studies that the US FDA requires for accelerated approval of Bexxar. Corixa Corporation initiated its Expanded Access Program for Bexxar in response to requests from physicians and patients for continued access to Bexxar during the period prior to potential US FDA marketing approval.A phase II multicentre trial of Bexxar in combination with CHOP chemotherapy is underway in the US as first-line therapy in patients with intermediate-grade NHL. Corixa Corporation has initiated a phase II trial of iodine-131 tositumomab in combination with cyclophosphamide, vincristine and prednisone for the treatment of previously untreated low-grade NHL. The trial was initiated while the company was preparing its BLA for Bexxar for use as a single agent for relapsed or refractory NHL. Corixa Corporation intends to pursue additional trials to expand the potential use of iodine-131 tositumomab to other indications, including chronic lymphocytic leukaemia. The agent is also in a clinical trial for preparation in autologous bone marrow transplant patients. The trial is designed to test the combination of iodine-131 tositumomab and chemotherapy. The trial began in 1995 and has so far enrolled 40 patients. In addition, a phase II dose-escalation trial has begun at the University of Nebraska for the combined use of iodine-131 tositumomab and chemotherapy as preparation for autologous bone marrow transplant. Corixa Corporation has received an issued US patent covering methods for administering and dosing radioimmunotherapy for the treatment of B-cell lymphomas. The patent covers iodine-131 tositumomab and other anti-CD20 antibodies used to aid in selective tumour targeting. Corixa Corporation has exclusive rights to the patent.A February 2000 media release from GlaxoSmithKline and Corixa Corporation stated that they had been issued a composition patent relating to radiolabelled monoclonal antibodies (including Bexxar) for the treatment of B-cell lymphomas. On 11 September 2001, IDEC announced that it had filed two separate lawsuits. The first lawsuit is against Corixa Corporation and the University of Michigan on six patents pertaining to products and processes related to radioimmunotherapy. They seek a declaration that Zevalin does not infringe Corixa Corporation's issued US patents. The second lawsuit involves two patents relating to cell culture media, and is against GlaxoSmithKline. IDEC's lawsuit in this case, seeks a declaration that its manufacture of Zevalin does not infringe GlaxoSmithKline's issued US patents. Corixa Corporation and GlaxoSmithKline have also filed a complaint for patent infringement against IDEC. These actions however, should have no effect on the regulatory process that Zevalin is completing, or prevent IDEC from launching the drug before iodine-131 tositumomab.A year earlier, in March 2001, the Financial Times reported that Bexxar could reach peak sales of $US120 million. In 1998, Coulter Pharmaceutical received a licencee fee payment of $US34 million from SmithKline Beecham (now GSK) in the fourth quarter of the year, as part of the joint development and commercialisation agreement for Bexxar.
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PMID:Iodine-131 Tositumomab: (131)I-anti-B1 antibody, (131)I-tositumomab, anti-CD20 murine monoclonal antibody-I-131, B1, Bexxar, (131)I-anti-B1 antibody, iodine-131 tositumomab, iodine-131 anti-B1 antibody, tositumomab. 1289 47

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