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)

Forty-five patients with myeloproliferative or myelodysplastic syndromes, treated with recombinant interferon-alpha (rIFN-alpha) for a minimum of 1 up to 4 years, were examined for the occurrence of thyroid autoimmunity. During treatment, the rate of thyroid autoimmunity rose to more than 20%. The decrease in severity and frequency of thyroid autoimmunity after withdrawal of IFN shows that this is a potentially reversible side effect. The key determinant for the manifestation of this IFN-related autoimmune phenomenon seems to be a predisposition for autoimmunity, since patients with initially detectable thyroid antibodies are prone to exacerbations of thyroid autoimmunity. Concurrent with thyroid autoimmunity, hypothyroidism occurred but did not correlate with the levels of thyroid antibodies, although severe hypothyroidism in two patients was accompanied by increased levels of thyroid antibodies. This investigation shows that thyroid autoimmunity and consecutively hypothyroidism must be expected in certain patients treated with rIFN-alpha during long periods. Furthermore, it may be assumed that IFN-alpha does not induce the development of autoimmunity, but rather enhances the levels of pre-existent thyroid antibodies.
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PMID:Thyroid autoimmunity and hypothyroidism during long-term treatment with recombinant interferon-alpha. 145 73

We examined the efficacy and toxicity of recombinant interferon-alpha 2b (rIFN-alpha 2b) in 10 previously untreated patients with advanced myelodysplastic syndromes. Morphological subtypes were refractory anaemia with excess of blasts (RAEB) in 4, RAEB in transformation (RAEB/T) in 3 and chronic myelomonocytic leukaemia (CMML) in 3 cases. IFN was administered subcutaneously at increasing doses of 1 to 3 x 10(6) IU per day. The median duration of therapy was 6 months (range, 3 to 14). 2 patients, both with a diagnosis of CMML, achieved a complete and partial remission, respectively. In the complete responder, remission could be maintained for 9.5 months by daily administration of 1 x 10(6) IU IFN. The other patients were classified as failures, although in 4 cases a decrease of bone marrow blasts was noted and none of the patients progressed to overt leukaemia while being treated with IFN. During the study, all patients with RAEB and RAEB/T showed a moderate to severe reduction in peripheral leukocyte and platelet counts, requiring premature termination of IFN therapy in 5 cases. Despite adequate supportive measures, 2 patients died of pneumococcal pneumonia and gastrointestinal bleeding, respectively. In 1 patient, IFN therapy had to be stopped because of neurologic toxicity (polyneuropathy). From these data we conclude that rIFN-alpha 2b at the doses and schedule tried is not a useful treatment for advanced myelodysplastic syndromes. Patients with CMML, however, may be an exception and should further be considered as candidates for therapeutic trials with rIFN-alpha 2b.
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PMID:Treatment of advanced myelodysplastic syndromes with recombinant interferon-alpha 2b. 198 3

We measured superoxide scavenging activity (SSA) of erythrocytes with the recently developed chemiluminescence method by Nakano et al in Down syndrome and various hematological diseases. Hematological disorders were aplastic anemia, myelodysplastic syndrome, multiple myeloma, malignant lymphoma and chronic myelogenous leukemia. The SSA of erythrocytes was 1.7 times higher in Down syndrome, which was consistent with values reported in the previous publications. The erythrocyte SSA in patients of multiple myeloma treated with interferon-alpha was higher than that in healthy volunteers. The erythrocyte SSA in myelodysplastic syndrome, malignant lymphoma and chronic myelogenous leukemia did not differ from that in healthy volunteers. The mean value of erythrocyte SSA in aplastic anemia also remained within normal range. However, when an individual's hemoglobin concentration was compared with his or her own erythrocyte SSA, there was a clear correlation between them. Namely erythrocyte SSA increased when anemia was severe. There was no correlation between erythrocyte SOD activity and ageing.
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PMID:Erythrocyte superoxide dismutase in various hematological diseases. 215 34

The ability of human alveolar macrophages to support colony formation of precursor blast cells of the myeloid lineage was investigated. Myeloid blast cells were collected from patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and from the livers of fetuses aborted in the second trimester of gestation. It was found that the alveolar macrophages (AM) produced sufficient amount of colony-stimulating activity which culminated in the fourth week of in vitro cultivation. Conditioned media from AM supported the growth of multipotential blast cell colonies (GEMM-CFU) in AML and MDS, while in fetal hemopoiesis macrophage colonies preponderated. Preincubation with human interferon-alpha (IFN-alpha) can abrogate the production of the granulocyte-macrophage colony stimulating factor (GM-CSF) by AM. Media conditioned by AM were not able to compensate for cell-to-cell contact in long-term cultures of AML blast cells but CSFs released from AM in vivo can contribute to aggravation of the disease.
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PMID:Release of granulocyte-macrophage colony-stimulating activity from human alveolar macrophages and its support of human myeloid blast cell proliferation. 227 85

Metaphase DNA fluorescence in situ hybridization (metaphase-FISH) was performed on follow-up samples from 60 patients suffering from haemopoietic malignancies (acute and chronic myeloid leukaemia, acute lymphoblastic leukaemia, non-Hodgkin's lymphoma and myelodysplastic syndrome). All patients had clonal chromosomal trisomies or translocations at diagnosis, and were treated by bone marrow transplantation (BMT), chemotherapy (CT) or interferon-alpha therapy. Metaphase-FISH was performed during therapy-induced complete haematological remission (CR) (BMT and CT patients) using biotin-labelled whole chromosome paint probes. 28% of all patients in CR were shown by FISH to have abnormal metaphase cells, and 62% of this group suffered a clinical relapse. Of those with negative FISH results (72%), 12% relapsed. In three CML patients treated with BMT a small population of t(9;22)-positive cells was demonstrated. These cells disappeared during follow-up without causing a relapse. One ALL patient had abnormal cells a short time after start of therapy but was also later found FISH-negative. Furthermore, we demonstrated that metaphase-FISH is a suitable method for quantifying the proportion of abnormal cells in CML patients during interferon-alpha therapy. Metaphase-FISH was also employed to detect a local relapse in an ALL patient. Thus, metaphase-FISH was found reliable and sensitive for detection of minimal residual disease in patients with haemopoietic malignancies.
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PMID:Metaphase fluorescence in situ hybridization (FISH) in the follow-up of 60 patients with haemopoietic malignancies. 781 2

Interferon-alpha has been used as a differentiating agent in the treatment of patients with myelodysplastic syndrome with conflicting results and often significant toxicity. In order to maximize the differentiating effects of this agent and minimize the myelosuppressive effects, a prospective pilot study was initiated utilizing interferon alpha-2a (Roferon A, Roche Laboratories) in the treatment of complicated or poor prognosis myelodysplasia. The study regimen utilized 'mini-dose' interferon alpha-2a at 1 x 10(6) units subcutaneously three-times per week for 16 weeks followed by an 8 week observation period. Nine patients were enrolled between May 1990 and June 1991, of which seven are evaluable. Forty-three percent (3/7) had a partial or clinical response as defined by normalization of one or more of the hemoglobin concentration, white blood cell count, or platelet count, or a decrease in transfusion requirement by > or = 50%. Only one patient was removed from study for interferon-associated toxicity. Mini-dose interferon alpha-2a appears to be an effective regimen for some patients with myelodysplasia which can be administered with minimal toxicity. Further investigation with interferon-alpha for the treatment of myelodysplastic syndrome, at the dosage utilized in this study, is warranted.
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PMID:Mini-dose interferon alpha-2a in the treatment of myelodysplasia. 842 72

In polycythemia vera (PV), treatment with chlorambucil and radioactive phosphorus (p32) increases the risk of leukemic transformation from 1% to 13-14%. This risk has been estimated to be 1-5.9% with hydroxyurea (HU) therapy. When compared with historical controls, the risk with use of HU does not appear to be statistically significant. The leukemogenic risk of HU therapy in essential thrombocytosis (ET) and in myelofibrosis with myeloid metaplasia (MMM) is unknown. HU remains the main myelotoxic agent in the treatment of PV, ET, and MMM. We studied 64 patients with these three disorders, seen at our institution during 1993-1995. The patients were studied for their clinical characteristics at diagnosis, therapies received, and development of myelodysplasia or acute leukemia (MDS/AL). Forty-two had PV, 15 ET, and 6 MMM, and 1 had an unclassified myeloproliferative disorder. Of the 42 patients with PV, 18 were treated with phlebotomy alone, 16 with HU alone, 2 with p32, 2 with multiple myelotoxic agents, and 2 with interferon-alpha (IFN-alpha). Two patients from the phlebotomy-treated group, one from the HU-treated group, and 1 from the multiple myelotoxic agent-treated group developed MDS/AL. In the larger group, 11 received no treatment or aspirin alone, 18 were treated with phlebotomy alone, 25 with HU, 5 with multiple myelotoxic agents, 2 with p32, 2 with IFN-alpha, and 1 with melphalan. Study of the entire group of 64 patients showed that only one additional patient (total of 5 out of 64) developed MDS/AL. This patient had been treated with HU alone. Statistical analysis did not show any association between clinical characteristics at diagnosis, or HU therapy, and development of MDS/AL (P=0.5). Thus, our data provide no evidence suggestive of increased risk of transformation to MDS/AL with HU therapy in PV, ET, and MMM. Larger, prospective studies are needed to study this issue further.
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PMID:Leukemogenic risk of hydroxyurea therapy in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. 863 10

The present study describes clinicopathological criteria to distinguish the 5 sequential stages proposed by Wasserman et al in the natural history of newly diagnosed PV patients. The European Working Group on MPD (EWG.MPD) extended and modified the PVSG diagnostic criteria of PV by including bone marrow histopathology. From the results of prospective randomized studies in PV it became evident that new clinical trials in previously untreated PV patients should focus on comparing interferon-alpha, a non-leukemogenic approach, versus a potential leukemogenic myelosuppressive treatment modality. Hydroxyurea appears to be the least leukemogenic myelosuppressive agent in long-term prospective clinical PV-studies extending observation periods of more than 10 years. The rational for using IFN-alpha as a first-line treatment option in newly diagnosed PV-patient include its effectiveness to abate constitutional symptoms and to induce a complete remission thereby avoiding phlebotomy, iron deficiency, and macrocytosis associated with hydroxyurea. Moreover IFN-alpha may prevent or delay the development of postpolycythemic myelofibrosis if used early in the course of the disease. Clinicians will be reluctant to postpone the use of hydroxyurea in early stage PV as long as a conservative approach using phlebotomy aiming at a hematocrit below 0.45, plus low-dose aspirin for the control platelet function or anagrelide for the control platelet number is used to keep the patient healthy. Low-dose aspirin will prevent the microvascular thrombotic complications of thrombocythemia associated with PV in remission after phlebotomy, but lacks myelosuppressive activity. Control of megakaryocyte maturation and reduction of platelet production to normal (<400 x 10(9)/l) by relatively low doses of anagrelide will predict a significant reduction of vascular complications in the early stages of PV, may prevent progression to myelofibrosis during follow-up of PV and very probable will postpone the use of hydroxyurea treatment for controlling the platelet count in PV. Large scale randomized clinical trials in PV are proposed, which should aim not only for clinical and hematological response, safety, efficacy, but should also assess toxicity, the need for phlebotomy and whether the development of progressive disease such as splenomegaly, pruritus, myelofibrotic myeloid metaplasia, spent phase, myelodysplasia and acute leukemia can be delayed or prevented by IFN-alpha as compared to a conservative approach of phlebotomy plus low-dose aspirin or anagrelide followed by hydroxyurea when signs of myeloproliferative activity became evident.
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PMID:Diagnosis and treatment of polycythemia vera and possible future study designs of the PVSG. 1067 96

Chronic myeloid leukemia (CML) is genetically characterized by the presence of the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22 called the Philadelphia (Ph) chromosome. In 2-10% of the cases, this chimeric gene is generated by variant rearrangements, involving 9q34, 22q11, and one or several other genomic regions. All chromosomes have been described as participating in these variants, but there is a marked breakpoint clustering to chromosome bands 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13. Despite their genetically complex nature, available data indicate that variant rearrangements do not confer any specific phenotypic or prognostic impact as compared to CML with a standard Ph chromosome. In most instances, the t(9;22), or a variant thereof, is the sole chromosomal anomaly during the chronic phase (CP) of the disease, whereas additional genetic changes are demonstrable in 60-80% of cases in blast crisis (BC). The secondary chromosomal aberrations are clearly nonrandom, with the most common chromosomal abnormalities being +8 (34% of cases with additional changes), +Ph (30%), i(17q) (20%), +19 (13%), -Y (8% of males), +21 (7%), +17 (5%), and monosomy 7 (5%). We suggest that all these aberrations, occurring in >5% of CML with secondary changes, should be denoted major route abnormalities. Chromosome segments often involved in structural rearrangements include 1q, 3q21, 3q26, 7p, 9p, 11q23, 12p13, 13q11-14, 17p11, 17q10, 21q22, and 22q10. No clear-cut differences as regards type and prevalence of additional aberrations seem to exist between CML with standard t(9;22) and CML with variants, except for slightly lower frequencies of the most common changes in the latter group. The temporal order of the secondary changes varies, but the preferred pathway appears to start with i(17q), followed by +8 and +Ph, and then +19. Molecular genetic abnormalities preceding, or occurring during, BC include overexpression of the BCR/ABL transcript, upregulation of the EVI1 gene, increased telomerase activity, and mutations of the tumor suppressor genes RB1, TP53, and CDKN2A. The cytogenetic evolution patterns vary significantly in relation to treatment given during CP. For example, +8 is more common after busulfan than hydroxyurea therapy, and the secondary changes seen after interferon-alpha treatment or bone marrow transplantation are often unusual, seemingly random, and occasionally transient. Apart from the strong phenotypic impact of addition of acute myeloid leukemia/myelodysplasia-associated translocations and inversions, such as inv(3)(q21q26), t(3;21)(q26;q22), and t(15;17)(q22;q12-21), in CML BC, only a few significant differences between myeloid and lymphoid BC are discerned, with i(17q) and TP53 mutations being more common in myeloid BC and monosomy 7, hypodiploidy, and CDKN2A deletions being more frequent in lymphoid BC. The prognostic significance of the secondary genetic changes is not uniform, although abnormalities involving chromosome 17, e.g., i(17q), have repeatedly been shown to be ominous. However, the clinical impact of additional cytogenetic and molecular genetic aberrations is most likely modified by the treatment modalities used.
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PMID:Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. 1191 88

High-dose melphalan has been commonly used as conditioning for amyloidosis with considerable toxicity. We hypothesized that the novel conditioning regimen of 550 cGy total body irradiation (TBI) alone for autologous peripheral blood stem cell transplantation would have reduced organ toxicity and thus permit safer transplantation of primary amyloidosis patients, even those with poor risk disease. The comprehensive regimen included pretransplantation chemotherapy, single-dose TBI alone (550 cGy at 30 cGy/min) conditioning, and post-transplantation interferon-alpha maintenance. Thirteen patients were enrolled in this feasibility study. Patients with multiorgan involvement were included; 10 patients had poor or intermediate risk disease. Cardiac toxicity was significant. Treatment-related mortality through 100 days post-transplantation was 15% and was caused by cardiac mortality. One patient died from arrhythmia after receiving TBI; 2 patients had grade IV cardiac toxicity (with subsequent complete recovery). One patient died 1 month after mobilization from progressive cardiomyopathy and never received conditioning. However, noncardiac organ toxicity was mild. No patient required parenteral nutrition support; no patient developed mucositis; and no patient experienced gastrointestinal bleeding following transplantation. The complete hematologic remission rate was 45%, with pretransplantation chemotherapy being the most active part of the regimen. Survival estimates from enrollment to 1 and 2 years post-transplantation were 66% and 47%, respectively. Causes of death were disease progression (6), myelodysplasia (1), arrhythmia following TBI (1), and congestive heart failure after mobilization (1). In this cohort of primary amyloidosis patients, the transplantation regimen of 550 cGy TBI was feasible and associated with modest treatment-related mortality. Efficacy with TBI conditioning may be reduced compared with high-dose melphalan, but this should be explored in a future trial with a larger cohort of patients.
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PMID:Primary amyloidosis patients with significant organ dysfunction tolerate autologous transplantation after conditioning with single-dose total body irradiation alone: a feasibility study. 1281 48


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