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)

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.
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PMID:Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. 1661 23

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor active clinically in cutaneous T-cell lymphoma and preclinically in leukemia. A phase 1 study was conducted to evaluate the safety and activity of oral vorinostat 100 to 300 mg twice or thrice daily for 14 days followed by 1-week rest. Patients with relapsed or refractory leukemias or myelodysplastic syndromes (MDS) and untreated patients who were not candidates for chemotherapy were eligible. Of 41 patients, 31 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia, 3 MDS, 2 acute lymphoblastic leukemia, and 1 chronic myelocytic leukemia. The maximum tolerated dose (MTD) was 200 mg twice daily or 250 mg thrice daily. Dose-limiting toxicities were fatigue, nausea, vomiting, and diarrhea. Common drug-related adverse experiences were diarrhea, nausea, fatigue, and anorexia and were mild/moderate in severity. Grade 3/4 drug-related adverse experiences included fatigue (27%), thrombocytopenia (12%), and diarrhea (10%). There were no drug-related deaths; 7 patients had hematologic improvement response, including 2 complete responses and 2 complete responses with incomplete blood count recovery (all with AML treated at/below MTD). Increased histone acetylation was observed at all doses. Antioxidant gene expression may confer vorinostat resistance. Further evaluation of vorinostat in AML/MDS is warranted.
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PMID:Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. 1796 10

Lenalidomide is a novel thalidomide analogue with enhanced immunomodulatory and antiangiogenic action lacking most of the typical thalidomide-associated adverse events. In myelodysplastic syndromes (MDS), it has been used primarily in the IPSS low- and intermediate-1 risk setting. Several trials have demonstrated its potential to lead to both erythroid and cytogenetic responses in these disease groups. In a clinical trial of patients with a del(5q) chromosomal abnormality, lenalidomide treatment resulted in red blood cell (RBC) transfusion independence in 67% of patients. Moreover, 45% of patients achieved a complete cytogenetic remission, and 28% achieved a minor cytogenetic remission. This result was independent of karyotype complexity. Lenalidomide might also induce long-term remissions in del(5q) patients with an elevated medullary blast count. In non-del(5q) patients, 43% of patients with confirmed low- and intermediate-1 risk achieved transfusion independence or a reduction of at least 50% of pre-treatment RBC transfusion levels. Adverse events are common but manageable and include neutropenia and thrombocytopenia, pruritus, rash, diarrhea, and others. Lenalidomide will prove an essential part in the armamentarium of MDS therapeutics. Combination therapies with cytokines, demethylating agents, tyrosine kinase inhibitors, or chemotherapy are being investigated and may show additional benefit in both low- and high risk MDS.
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PMID:Lenalidomide: a brief review of its therapeutic potential in myelodysplastic syndromes. 1847 76

MGCD0103 is an isotype-selective inhibitor of histone deacetylases (HDACs) targeted to isoforms 1, 2, 3, and 11. In a phase 1 study in patients with leukemia or myelodysplastic syndromes (MDS), MGCD0103 was administered orally 3 times weekly without interruption. Twenty-nine patients with a median age of 62 years (range, 32-84 years) were enrolled at planned dose levels (20, 40, and 80 mg/m(2)). The majority of patients (76%) had acute myelogenous leukemia (AML). In all, 24 (83%) of 29 patients had received 1 or more prior chemotherapies (range, 0-5), and 18 (62%) of 29 patients had abnormal cytogenetics. The maximum tolerated dose was determined to be 60 mg/m(2), with dose-limiting toxicities (DLTs) of fatigue, nausea, vomiting, and diarrhea observed at higher doses. Three patients achieved a complete bone marrow response (blasts <or= 5%). Pharmacokinetic analyses indicated absorption of MGCD0103 within 1 hour and an elimination half-life in plasma of 9 (+/- 2) hours. Exposure to MGCD0103 was proportional to dose up to 60 mg/m(2). Analysis of peripheral white cells demonstrated induction of histone acetylation and dose-dependent inhibition of HDAC enzyme activity. In summary, MGCD0103 was safe and had antileukemia activity that was mechanism based in patients with advanced leukemia.
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PMID:Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. 1849 56

An 11-year-old female Dachshund was presented with depression, diarrhea, weight loss, and radiographic evidence of masses involving the liver, spleen, and cranial lobe of the right lung. Results of a CBC included severe nonregenerative anemia (HCT 14.2%, hemoglobin, 4.3 g/dL, reticulocytes 66,000/microL) with marked metarubricytosis (nucleated RBCs 6.39 x 10(3)/microL). Examination of the peripheral blood smear revealed marked erythroid dysplasia, including marked anisocytosis with a prevalence of macrocytes, Howell-Jolly bodies, diffuse basophilic stippling, and multinucleated and atypical nucleated RBCs. Neutrophil hypersegmentation and giant forms were also noted. Numerous erythrocytes, particularly polychromatophilic cells, contained inclusions consistent with Cabot rings, which appeared as delicate red-purple ellipsoid or figure 8 structures. Rarely, Cabot rings were observed extracellularly. The dog was treated symptomatically with blood transfusions, prednisone, erythropoietin, and vitamin supplementation, but the anemia progressively worsened. The dog was euthanized 2 months after presentation. Bone marrow aspirate and core biopsy specimens obtained at the time of euthanasia revealed marked dysplastic changes in all cell lines, especially dyserythropoiesis, along with infiltrating carcinoma cells. A necropsy was performed, and histologic examination revealed poorly differentiated adenocarcinoma of the lung with multiple metastases to the marrow, spleen, and liver. The final diagnosis was marked myelodysplasia secondary to metastatic adenocarcinoma. Cabot rings are found rarely in humans with myelodysplasia, but have not been described previously in dogs. Based on the findings in this case, Cabot rings may occur rarely in dogs with severe dyserythropoiesis.
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PMID:Cabot rings as a result of severe dyserythropoiesis in a dog. 1853 17

Lonafarnib is an orally bio-available farnesyltransferase inhibitor that prevents farnesylation of specific target proteins including Ras. In a multicenter study, 67 patients with advanced myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) were treated with a continuous oral dose of 200-300 mg of lonafarnib and were evaluated for hematologic, pathologic and pharmacodynamic response. The median age of patients was 70 years (range 44-86). There were 32 patients with MDS (RAEB-20 and RAEB-t-12) and 35 with CMML. Overall 16 (24%) of the patients responded with two patients achieving a complete remission and one a partial response. Responses were seen in 6/32 and 10/35 patients with MDS and CMML, respectively. Of the 19 patients who were platelet transfusion-dependent prior to treatment, 5 (26%) became transfusion-free for a median duration of 185 days. A decrease in the farnesylation of the HDJ-2 protein measured in patient-derived cells was observed in the majority of patients during treatment with lonafarnib, but no clear correlation between changes in farnesylation and clinical effect could be made. Gastrointestinal toxicity was significant with 19% of patients discontinuing therapy due to diarrhea, nausea and/or anorexia. Lonafarnib has demonstrable activity in patients with advanced MDS and CMML.
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PMID:On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia. 1854 95

Although an activating mutation of Ras is commonly observed in myelodysplastic syndrome (MDS), the role of Ras in the natural history of MDS remains largely unknown. We prospectively studied efficiency and tolerance of lonafarnib, a compound able to inhibit Ras signalling pathway through an inhibition of farnesyl transferase, in patients with MDS or secondary acute myeloid leukaemia (sAML). Lonafarnib was administered orally at a dose of 200 mg twice daily for three courses of 4 weeks (separated by 1 to 4 weeks without treatment). Sixteen patients were included: FAB/RAEB (n = 10), RAEB-T (n = 2), sAML (n = 2) and chronic myelomonocytic leukaemia (CMML; n = 2); WHO/RAEB-1 (n = 4), RAEB-2 (n = 5), AML (n = 5), CMML (n = 2). Median age was 70 (53-77) years. The karyotype was complex or intermediate in 11 patients, and the International Prognostic Scoring Systems (IPSS) risk groups were low in two patients, INT-1 in one patient, INT-2 in four patients and high in six patients (unknown or not applicable in three patients). Among the 14 patients tested, five had Ras mutations in codons 12, 13 or 61 of N-Ras, K-Ras or H-Ras. One patient was excluded of the analysis for protocol violation, and 15 patients were assessable for tolerance. Gastrointestinal toxicities (diarrhoea, nausea and anorexia) and myelosuppression were the major side effects. Other toxicities included infections, fatigue, increase of liver enzymes, arrhythmia and skin rash. One patient died of infection, and the treatment was stopped in one other who developed atrial fibrillation. Doses were reduced in all but one patient treated with more than one course of farnesyl transferase inhibitor. Responses were assessable in 12 patients. A partial response in one sAML patient and a very transient decrease of blast cell count with normalisation of karyotype in one MDS patient were observed. No relation between improvement of marrow parameters and detected Ras mutations was observed. Lonafarnib alone, administered following our schedule, has shown limited activity in patients with MDS or secondary AML. Gastrointestinal and haematological toxicities appear the limiting toxicity in this population of patients.
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PMID:Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study. 1864 85

Phase 1 testing of ezatiostat, a glutathione S-transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome was conducted in a multidose-escalation study. Patients received 10 dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000, and 6000 mg) of ezatiostat tablets in divided doses on days 1 to 7 of a 21-day cycle for a maximum of 8 cycles. The safety and pharmacokinetics of ezatiostat were evaluated. Forty-five patients with low to intermediate-2 International Prognostic Scoring System risk myelodysplastic syndrome were enrolled. No dose-limiting toxicities were observed. The most common grade 1 or 2, respectively, treatment-related adverse events were nonhematologic: nausea (56%, 9%), diarrhea (36%, 7%), vomiting (24%, 7%), abdominal pain (9%, 0%), constipation (4%, 9%), anorexia (3%, 7%), and dyspepsia (3%, 7%). Concentration of the primary active metabolite, TLK236, increased proportionate to ezatiostat dosage. Seventeen hematologic improvement (HI) responses by International Working Group criteria were observed at dose levels of 200 to 6000 mg/day with 11 HI responses at doses of 4000 to 6000 mg/day. HI responses occurred in all lineages including 3 bilineage and 1 complete cytogenetic response. Decreased number of red blood cell and platelet transfusions and in some cases transfusion independence were attained. Extended dose schedules of ezatiostat tablets are under investigation.
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PMID:Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome. 1939 16

Vorinostat (Zolinza), a histone deacetylase inhibitor, was approved by the US Food and Drug Administration in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. This review summarizes evidence on the use of vorinostat in solid and hematologic malignancies and collated tolerability data from the vorinostat clinical trial program. Pooled vorinostat clinical trial data from 498 patients with solid or hematologic malignancies show that vorinostat was well tolerated as monotherapy or combination therapy. The most commonly reported drug-related adverse events (AEs) associated with monotherapy (n = 341) were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%), and Grade 3/4 drug-related AEs included fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.3%), and decreased platelet count (5.3%). The most common drug-related AEs observed with vorinostat in combination therapy (n = 157, most of whom received vorinostat 400 mg qd for 14 days) were nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), vomiting (31.2%), and anorexia (20.4%), with the majority of AEs being Grade 2 or less. In Phase I trials, combinations with vorinostat were generally well tolerated and preliminary evidence of anticancer activity as monotherapy or in combination with other systemic therapies has been observed across a range of malignancies. Ongoing and planned studies will further evaluate the potential of vorinostat in combination therapy, including combinations with radiation, in patients with diverse malignancy types, including non-small-cell lung cancer, glioblastoma multiforme, multiple myeloma, and myelodysplastic syndrome.
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PMID:Vorinostat in solid and hematologic malignancies. 1963 46

Fanconi anemia is a congenital syndrome characterized by hypoplasia of bone marrow and the development of aplastic anemia in childhood, followed by myelodysplastic syndrome and acute myelogenous leukemia in later life. We report here a patient first diagnosed with Fanconi anemia at age 10. Bone marrow transplantation was performed at age 23 and repeated after an episode of rejection at age 25. Hematologic findings returned to normal, but chronic graft-versus-host disease persisted. Esophageal cancer developed at age 35. Invasion of the bronchus and aorta by the tumor was suspected on computed tomography. Chemoradiotherapy was administered to down-stage the tumor, using low-dose cisplatin and 5-fluorouracil. After two courses of chemotherapy with cisplatin (total dose, 100 mg) and 5-fluorouracil (5000 mg) plus radiotherapy (30 Gy), Grade 3 diarrhea and bone marrow suppression developed, and treatment was discontinued. After resolution of toxicity, a good response to the neoadjuvant therapy was seen on computed tomography scan, and a subtotal esophagectomy was performed which demonstrated a complete response in the resected specimen. However, tongue cancer developed at age 40 years, and hemiglossectomy was performed. Patients with Fanconi anemia have a high risk of developing esophageal cancer while they are still young. Reduced doses of alkylating agents and radiotherapy are used in patients with Fanconi anemia. However, the optimal dosage of chemoradiotherapy and the treatment strategy for esophageal cancer in patients with Fanconi anemia remain unclear, and outcomes are generally extremely poor. In this patient, esophageal cancer associated with Fanconi anemia responded well to multidisciplinary therapy.
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PMID:Successful treatment of esophageal squamous cell carcinoma in a patient with Fanconi anemia. 2041 55


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