piperidines and Bone-Marrow-Diseases

Increasing the intensity of induction chemotherapy has generated considerable recent interest in the treatment of acute myeloid leukemia. Achieving complete remission is a sine qua non condition for prolonged disease-free survival and may affect long-term outcome. In this setting, administering a repeat course of induction shortly after completion of the first course, known as timed-sequential chemotherapy (TSC), has been tested and may lead to an improved long-term outcome. Whether these results are due to the biologic recruitment of cell cycle-specific agents is unknown. However, this strategy to intensify induction may lead to more profound myelosuppression and to potential toxicities. Here we review the results of timed-sequential chemotherapy, used as induction regimen in de novo, relapsed or refractory AML or used as post-remission therapy, and compare them with those from other types of regimens.

Topics: Acute Disease; Adolescent; Adult; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Cell Cycle; Child; Cytarabine; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Flavonoids; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Middle Aged; Piperidines; Premedication; Prognosis; Rats; Remission Induction; Retrospective Studies; Salvage Therapy; Treatment Outcome

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 hematologic malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two nonpeptidomimetic 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% and complete remissions in about 15%. Dose-limiting adverse 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 primarily with 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 lack of evidence, significant clinical efficacy of the FTIs has been observed in MDS, on a par with the efficacy of currently available chemotherapeutic agents, leading to further development of this new class of drugs in MDS and AML.

Topics: Adult; Aged; Antineoplastic Agents; Bone Marrow Diseases; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Progression; Farnesyltranstransferase; Gastrointestinal Diseases; Genes, ras; Hematologic Neoplasms; Humans; Middle Aged; Myelodysplastic Syndromes; Piperidines; Prenylation; Protein Processing, Post-Translational; Pyridines; Quinolones; Treatment Outcome

To explore the effects of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)-with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand.. In this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures. Treatment differences with p<0.05 (vs MTX monotherapy) were considered significant.. In total, 109 patients were randomised and treated. Treatment differences in RAMRIS bone marrow oedema (BME) at month 6 were -1.55 (90% CI -2.52 to -0.58) for tofacitinib + MTX and -1.74 (-2.72 to -0.76) for tofacitinib monotherapy (both p<0.01 vs MTX monotherapy). Numerical improvements in RAMRIS synovitis at month 3 were -0.63 (-1.58 to 0.31) for tofacitinib + MTX and -0.52 (-1.46 to 0.41) for tofacitinib monotherapy (both p>0.05 vs MTX monotherapy). Treatment differences in RAMRIQ synovitis were statistically significant at month 3, consistent with DCE MRI findings. Less deterioration of RAMRIS and RAMRIQ erosive damage was seen at months 6 and 12 in both tofacitinib groups versus MTX monotherapy.. These results provide consistent evidence using three different MRI technologies that tofacitinib treatment leads to early reduction of inflammation and inhibits progression of structural damage.. NCT01164579.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Bone Density; Bone Marrow; Bone Marrow Diseases; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Edema; Female; Hand; Humans; Magnetic Resonance Imaging; Male; Methotrexate; Middle Aged; Piperidines; Pyrimidines; Pyrroles; Synovitis; Treatment Outcome; Wrist Joint