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)

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

R115777 (Tipifarnib, Zarnestra)-farnesyl transferase inhibitor belongs to the new class of signal transduction inhibitors which seems to be yielding results in the treatment of patients with solid tumors. Recently it has also been considered as a drug of promise in hematologic malignancies such as acute myeloid leukemia (AML), especially in older patients, in chronic myelogenous leukemia (CML) as well as myelodysplastic syndromes (MDS). The aim of our study was to evaluate the influence of R115777 used alone or with purine nucleoside analogs (PNA): cladribine (2-CdA) and fludarabine (F-ara-A) on leukemic progenitors [colony-forming unit-leukemia (CFU)-L] from AML patients. Our studies were based on the methods of semisolid leukemic CFU-L and normal granulocyte-macrophage progenitor (CFU-GM) cultures in vitro. R115777 was added to the culture alone or in combinations with PNA. We showed that R115777 used alone or together with PNA at all combinations significantly inhibited the colony growth of AML CFU-L, when compared with normal CFU-GM (P < 0.01). In addition, the drugs used in combinations of two higher concentrations in significantly higher degree inhibited CFU-L colony growth, when compared either with R115777 or with any of PNA used alone (P < 0.04). IC(50) for R115777 were 67.1 and 121.9 nm for AML CFU-L and normal CFU-GM, respectively. Furthermore, in the case of AML the combination index was 0.89 and 1.16, respectively, for the combination of R115777 with 2-CdA and R115777 with F-ara-A. An additive effect on AML CFU-L cells and subadditive effect on normal CFU-GM were seen. To assess a proapoptotic effect, the drugs were added to the liquid cultures at the same concentrations as for clonogenic assays. A significant increase in the rate of apoptosis induced by combinations of drugs in comparison with single agents was observed. In conclusion, the combination of R115777 with both PNA could be more effective than the drugs used alone. However, further experimental studies on the usefulness of these combinations in the treatment of myeloid leukemia patients are warranted.
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PMID:The influence of farnesyl protein transferase inhibitor R115777 (Zarnestra) alone and in combination with purine nucleoside analogs on acute myeloid leukemia progenitors in vitro. 1552 64

A 77-year-old man was diagnosed as having essential thrombocythemia (ET) in 1994. He had been treated with hydroxyurea (HU) for six years, and 9 years after the diagnosis of ET, he then developed acute myelomonocytic leukemia (AMMoL) following myelodysplastic syndrome (MDS). Since he suffered from ischemic heart disease, we chose the ara-C+VP-16 therapy. Two courses of the ara-C+VP-16 therapy resulted in partial remission in the bone marrow and a prolonged hematological response. This case seemed rare, since in previous reports, prognosis of ET patients developing MDS and AML was very poor and most of the patients expired within six months.
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PMID:[Successful treatment of acute myelomonocytic leukemia developed from essential thrombocythemia with cytarabine plus etoposide]. 1560 90

Triapine, an iron chelator and a potent inhibitor of ribonucleotide reductase, has significant anti-leukemia activity. A phase I study of Triapine in combination with ara-C was conducted in 32 patients with refractory acute leukemia and high-risk MDS. Triapine (105 mg/m2/day 6-h infusion) was followed immediately by ara-C [100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8)mg/m2/day] as an 18-h infusion for 5 consecutive days. Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (one patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/day, no DLTs occurred in seven patients treated at this dose level. Mean Triapine C(max) and AUC were 1.13 microg/mL and 251.5 minmicrog/mL. Of 31 evaluable patients, 4 (13%) (3 AML, 1 Ph+ALL) achieved a CR (1 at a dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200mg/m2). The recommended phase II regimen is Triapine 105 mg/m2/day followed by ara-C 600 mg/m2/day for 5 consecutive days every 3-6 weeks.
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PMID:Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome. 1647 31

The association between Down syndrome and acute myelogenous leukemia (AML) has been well documented. AML in Down syndrome is usually a specific type of megakaryoblastic leukemia (M7, AMKL). A myelodysplastic syndrome generally precedes this malignancy. Down syndrome patients with AMKL have a much better prognosis than other children with AML. A case study of a 22-month-old female with Down syndrome and myelodysplastic syndrome of a megakaryoblastic lineage is presented here. Upon admission to a pediatric hematology/oncology clinic, flow cytometry results reported a distinct population of phenotypically abnormal myeloblasts expressing myeloid antigens and the immature cell markers. The patient was placed on a national research group study and began chemotherapy treatment. To date she has received two courses of cytarabine (ara-c) and daunorubicin therapy, which were tolerated well, and is awaiting her third course. Her blood counts stabilize for a while after treatments and her prognosis is good.
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PMID:Down syndrome with myelodysplasia of megakaryoblastic lineage. 1691 Feb 32

We analyzed cytosolic high-Km 5'-nucleotidase (cN-II) and deoxycytidine kinase (dCK) mRNA expression in bone marrow mononuclear cells (BMMNC) of patients with high-risk myelodysplastic syndrome (MDS) using quantitative real-time polymerase chain reaction (rt-PCR). At diagnosis, the cN-II mRNA expression of patients was higher than that of healthy volunteers, but the dCK mRNA expression showed no significant difference. Patients with ara-C-containing chemotherapies whose BMMNC showed a high level of cN-II expression (greater than the median value) had shorter median overall survival (15 months versus 22 months, p<0.01) and shorter median post-chemotherapy survival (10 months versus 16 months, p=0.012). These data suggest that the expression level of cN-II mRNA might be a prognostic factor of high-risk MDS.
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PMID:Clinical significance of high-Km 5'-nucleotidase (cN-II) mRNA expression in high-risk myelodysplastic syndrome. 1743 83

Twenty-one acute myeloid leukemia (AML) patients were enrolled and received oral induction therapy with cytarabine ocfosfate (SPAC) and etoposide (EP). The median age was 69 years (range: 33-86). There were 11 patients with de novo AML and 10 AML cases that had evolved from myelodysplastic syndromes. Seventeen patients had abnormal karyotypes including eight complex abnormalities, various complications, and 7 of 21 had a poor performance status (PS) with Eastern Cooperative Oncology Group (ECOG) scores of 3-4. All patients completed induction therapy without severe adverse events. Seven achieved complete remission (CR), and two achieved partial remission (PR). Uni- and multivariate analyses demonstrated a positive and significant correlation between the results of therapy (CR +/- PR) and overall survival. The plasma concentrations of cytosine arabinoside (ara-C) in some cases were higher than those previously reported, indicating the accumulation of ara-C with increasing numbers of days of SPAC administration. We conclude that this therapy is well tolerated and useful for refractory and elderly AML patients.
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PMID:The value of oral cytarabine ocfosfate and etoposide in the treatment of refractory and elderly AML patients. 1822 14

Arsenic has been used for more than 2,000 years in the treatment of a variety of medical conditions, including plague, hysteria, syphilis, and cancer. Numerous potential mechanisms of action have been identified. Arsenic trioxide has remarkable efficacy in acute promyelocytic leukemia and is approved by the US Food and Drug Administration for this indication. It has also been studied in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma and has limited single-agent efficacy in these diseases. We have completed a phase I/II trial of arsenic trioxide combined with low-dose ara-C (LDAC) in 49 patients with Int-2/high-risk MDS and 64 patients age 60 years and older with untreated AML. The regimen was generally well tolerated and complete remissions were observed in both MDS and AML patients, including in patients with poor baseline performance status and unfavorable cytogenetics. Manuscript has been accepted for publication.
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PMID:Arsenic and old lace: novel approaches in elderly patients with acute myeloid leukemia. 1876 Jul 7

Myelodysplastic syndrome (MDS) is not a single disease, but a collection of hematopoietic disorders that require newer strategies. Currently, azacitidine, decitabine, and lenalidomide are approved by the US Food and Drug Administration for the treatment of MDS. A recent study demonstrated an improved overall survival (24.4 months vs 15 months) in high-risk MDS patients receiving azacitidine plus best supportive care vs conventional care which has resulted in an updated label for this product. Conventional care consisted of supportive care alone or either low-dose ara-C or standard chemotherapy plus best supportive care. While these data are encouraging, newer agents such as vorinostat, MGCD0103, MS-275, and tipifarnib are currently being studied as monotherapy or in combinations with approved treatments for MDS. The goal of combining pharmacotherapy, such as the combination of DNA methylation inhibitors and histone deacetylase inhibitors, in the management of MDS is to increase the response rates and decrease the toxicities associated with treatment. Clinical experience in the use of combination products has given practitioners the empirical knowledge necessary to better treat patients with MDS. Utilizing convergent or complementary molecular mechanisms with in vitro or in vivo evidence of synergy is a fresher and maybe a more efficacious approach to combination therapy.
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PMID:Future directions in myelodysplastic syndrome: newer agents and the role of combination approaches. 1881 8

The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G-CSF mobilized PBSC (n=26) or bone marrow cells (n=1) were transplanted from unrelated (n=21) or matched related (n=6) donors. Non-hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse-free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara-C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high-risk AML or MDS, with engraftment and GvHD-incidence comparable to other RIC regimens.
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PMID:Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome. 2188 83


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