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)

CPT-11 is an antineoplastic agent which acts as a specific inhibitor of DNA topisomerase 1 and has a broad spectrum of activity in solid tumors. Very few studies have evaluated the activity of CPT-11 in hematological malignancies. We conducted a phase II trial of CPT-11 in 26 patients with high-risk MDS (RAEB 1: n = 4; RAEB 2: n = 9; MDS having progressed to AML: n = 10; CMML: n = 3) who could not receive anthracycline/cytarabine intensive chemotherapy. Induction therapy consisted of four courses of CPT-11 given intravenously at 200 mg/m(2) every 2 weeks. Patient characteristics were: median age, 71 (range 51-77); sex, (M/F), 21/5, median % marrow blasts cells, 13.5 (range 7-52). Cytogenetics according to IPSS were: low-risk n = 13, intermediate-risk n = 6, high-risk n = 3, failure or not done n = 4. Six patients stopped treatment after only one or two courses of CPT-11 due to severe infection (n = 2), progressive disease (n = 3), acute lysis syndrome with renal failure (n = 1). In the 20 patients who received at least three cycles of CPT-11, complete remission was achieved in one case, partial remission in four cases, and hematological improvement in three cases with an overall response rate of 33% in the 26 patients. Duration of response was short (median 4 months, range 1-6 months) and median survival was 8 months (range 1-23 months). Digestive toxicity (diarrhea) occurred in 26/89 (29%) courses, but was mild (grade 1, 20% courses; grade 2 or 3, 9% courses). Hematological toxicity was difficult to assess in non-responders because of initial pancytopenia, but all the patients who responded had grade 3/4 hematological toxicity associated with grade >/=2 infection requiring hospitalization in 18% of the courses. No other major toxicity was observed. Thus CPT-11 has an interesting activity in MDS with excess of blasts; toxicity is easily managed and most patients can be treated in the out-clinic setting. These results suggest that further evaluation of CPT-11 in MDS is warranted.
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PMID:Phase II trial of CPT-11 in myelodysplastic syndromes with excess of marrow blasts. 1259 29

Thrombotic microangiopathy (TMA) is a microvascular disorder characterized by platelet aggregation and hemolytic anemia. In the setting of bone marrow transplantation (BMT), ischemic colitis due to TMA is difficult to differentiate from acute graft-versus-host disease. We report a 32-year-old man who presented ischemic colitis due to TMA after unrelated BMT for myelodysplastic syndrome. He suffered from treatment-resistant bloody diarrhea, and died of renal failure and Aspergillus pleuritis on day 253 post-BMT. Autopsy revealed endothelial injuries of arterioles and ischemic changes in the intestines and kidneys. Clinical and pathological characteristics of ischemic colitis due to BMT-associated TMA are described.
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PMID:Ischemic colitis as a manifestation of thrombotic microangiopathy following bone marrow transplantation. 1471 65

Autologous peripheral blood stem cell transplantation (APBSCT) after intensifying conditioning is one of the post-remission therapeutic options in childhood acute myeloid leukemia (AML) patients without a matched family donor, but the optimal conditioning regimen has not been defined. This study was performed to evaluate the efficacy of a novel conditioning regimen without busulfan or total body irradiation. In total, 28 children with AML underwent APBSCT with BCVAC (BCNU, etoposide, cytosine arabinoside and cyclophosphamide) conditioning regimen during first remission. The event-free survival rate was 71.43% for all patients and the only cause of treatment failure was relapse. Eight male patients recurred at 1-11 months (median 5 months) after APBSCT. One patient remains alive with salvage therapy after relapse. With the exception of fever, mucositis and diarrhea, no serious complications occurred during APBSCT, including veno-occlusive disease (VOD), and there was no transplantation-related mortality. One patient developed secondary MDS after APBSCT but recovered hematologically on medication. APBSCT with BCVAC conditioning was found to be a safe and effective alternative option for patients with childhood AML in first remission, without a matched family donor.
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PMID:Autologous peripheral blood stem cell transplantation with BCVAC conditioning in childhood acute myeloid leukemia. 1471 39

Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic peripheral blood stem cell transplantation (PBSCT). Patients with severe aGVHD not responding to treatment with steroids have a poor prognosis. We treated three patients with severe aGVHD refractory to steroids with infliximab. Patients (MDS 1, NHL 1, ALL 1) developed grade II-IV GVHD at a median of 13 days (range 9-17) after non-myeloablative PBSCT (HLA mismatched). All patients had received treatment with high-dose steroids for a median of 7 days (range 7-10) in addition to mycophenolate mofetil (MMF) (one). Infliximab was given in 3 weekly doses of 5 mg/kg. In one of three patients a partial resolution of diarrhea and minor improvement of skin were observed. One patient died with refractory GVHD. Infliximab is apparently an effective drug for the treatment of aGVHD, but can be more effective at doses of 5 mg/kg or higher and/or by administering it repeatedly every week.
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PMID:Infliximab for the treatment of severe steroid refractory acute graft-versus-host disease in three patients after allogeneic hematopoietic transplantation. 1495 53

Clofarabine (2-chloro-2'-fluoro-deoxy-9-beta-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).(1) Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m(2) per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m(2) per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.
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PMID:Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. 1548 72

JM-216 is an orally bioavailable platinum compound with activity against many tumor models. The objective of this study was to determine the safety profile and anti-tumor activity of JM-216 in patients with hormone refractory prostate cancer (HRPC) when given orally daily x 5 days. In this open label phase II study JM-216 was administered orally at the dose of 120 mg/m2/d for 5 days every 4 weeks. Patients continued on the therapy until evidence of disease progression or intolerable toxicity developed. Dose escalation and de-escalation were allowed according to patient's tolerance. Thirty-nine patients were enrolled onto the study and received a total of 155 courses (median 2, range 1-16) of JM-216. Dose delays (77% of courses) and dose reductions (31% of courses) were common and were mainly due to myelosupression. Treatment was discontinued in 5 patients due to treatment related toxicities. One patient developed myelodysplastic syndrome 11 months after the start of treatment. The most frequent grade III or higher adverse events included thrombocytopenia (54%), neutropenia (52%), anemia (24%) nausea (13%), vomiting (16%) and diarrhea (28%). PSA response was assessed in 32 patients, 10 (26%) had partial response, 14 (36%) had stable disease while PSA progression was seen in 8 (21%) patients. Of 20 (54%) patients with measurable disease two patients had a documented partial response. Although JM-216 had moderate activity in HRPC when given on daily basis for 5 days, it is associated with significant treatment related toxicities in this patient population.
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PMID:Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC). 1552 84

We conducted a phase II study to evaluate the efficacy and safety of cladribine (2-chlorodeoxyadenosine [2-CdA]) for patients with refractory or relapsed indolent B-cell lymphoma or mycosis fungoides. Forty-five patients were enrolled, and 43 patients, including 34 with follicular lymphoma, were eligible. 2-CdA was given by continuous intravenous infusion at a dose of 0.09 mg/kg daily for 7 consecutive days, and this schedule was repeated every 4 weeks up to a maximum of 6 cycles. The overall and complete response rates were 58.1% (25/43; 90% confidence interval, 44.5%-70.9%) and 14.0% (6/43), respectively. The disease progression-free proportions of all 43 eligible and all 25 responding patients at 2 years were 30.3% and 48.1%, respectively. Neutropenia and thrombocytopenia of grade 3 or 4 were observed in 53.3% and 37.8% of patients, respectively, with prolonged cytopenia observed in patients with increased numbers of treatment cycles. Nonhematologic toxicities of grade 3 or greater included diarrhea, arrhythmia, malaise, and gastrointestinal bleeding in 1 patient each, an increase in glutamic-pyruvic transaminase level in 2 patients, and infection in 5 patients. Two treatment-related deaths were observed. Four patients developed myelodysplastic syndrome (MDS) at 13 months to 2 years after completion of the 2-CdA treatments. 2-CdA is an active agent with acceptable toxicity for refractory or relapsed indolent lymphoma; however, prolonged myelosuppression and the potential development of MDS should be carefully monitored.
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PMID:Durable response but prolonged cytopenia after cladribine treatment in relapsed patients with indolent non-Hodgkin's lymphomas: results of a Japanese phase II study. 1554 Sep 3

On May 19, 2004, azacitidine (5-azacytidine; Vidaza(trade mark); Pharmion Corporation, Boulder, CO, http://www.pharmion.com) for injectable suspension received regular approval by the U.S. Food and Drug Administration (FDA) for the treatment of all subtypes of myelodysplastic syndrome (MDS). This report summarizes the basis for this approval. Effectiveness was demonstrated in one randomized, controlled trial comparing azacitidine administered s.c. with best supportive care (observation group) and in two single-arm studies, one in which azacitidine was administered s.c. and in the other in which it was administered i.v. The dose of azacitidine, 75 mg/m2/day for 7 days every 28 days, was the same in all three studies. In the randomized trial, study participants were well matched with respect to age, sex, race, performance status, MDS subtype, and use of transfusion during the 3 months before study entry. Patients in the observation arm were permitted by protocol to cross over to azacitidine treatment if their disease progressed according to prespecified criteria. During the course of the study, more than half of the patients in the observation arm did cross over to the azacitidine treatment arm. The primary efficacy end point was the overall response rate. Response consisted of complete or partial normalization of blood cell counts and of bone marrow morphology. The response rate in the azacitidine arm was about 16%; there were no responses in the observation arm. The response rates in the two single-arm studies were similar (13% and 19%). The responses were sustained, with median durations of 11 months and 17 months respectively. Responding patients who were transfusion dependent at study entry lost the need for transfusions. In addition, about 19% of patients had less than partial responses (termed improvement), and two-thirds of them became transfusion independent. Common adverse events associated with azacitidine treatment were gastrointestinal (nausea, vomiting, diarrhea, constipation, and anorexia), hematologic (neutropenia, thrombocytopenia), fevers, rigors, ecchymoses, petechiae, injection site events, arthralgia, headache, and dizziness. Liver function abnormalities occurred in 16% of patients with intercurrent hepatobiliary disorders and in two patients with previously diagnosed liver cirrhosis. Renal failure occurred in patients during sepsis and hypotension. There were no deaths attributed to azacitidine. Azacitidine, the first drug approved by the U.S. FDA for MDS, has a favorable safety profile and provides a clinical benefit of eliminating transfusion dependence and complete or partial normalization of blood counts and bone marrow blast percentages in responding patients.
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PMID:FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. 1579 20

The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematological malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two non-peptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy with overall response rates of 30%, with complete remissions in about 15%. Dose-limiting side effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated with primarily diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this, significant clinical efficacy of the FTIs in MDS, on par with that of currently available chemotherapeutic agents, has been observed, leading to further development of this new class of drugs in MDS and AML.
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PMID:Farnesyltransferase inhibitors in myelodysplastic syndrome. 1586 70

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, leading to bone marrow failure and peripheral blood cytopenias. MDS is difficult to diagnose because of the absence of symptoms in the early stage of the disease; it often is discovered accidentally during routine physical examinations or blood tests. The U.S. Food and Drug Administration approved azacitidine (Vidaza, Pharmion Corporation, Boulder, CO) for the treatment of MDS. Prior to the approval of azacitidine, no approved therapies were available for the treatment of MDS. Azacitidine is believed to exert its anticancer effects by induction of hypomethylation and cytotoxicity. In clinical studies, the most common adverse events during treatment with azacitidine included nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection-site erythema, constipation, neutropenia, and ecchymosis. To ensure proper treatment with azacitidine, nurses should have an understanding of dosage and administration guidelines, commonly observed adverse events, monitoring and care of adverse events, and monitoring of laboratory tests. Having a comprehensive understanding of MDS, its underlying disease characteristics, and current treatments will enable oncology nurses to provide optimal patient care.
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PMID:Advances in myelodysplastic syndrome: nursing implications of azacitidine. 1611 8


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