Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of the myeloid growth factor G-CSF after allogeneic hematopoietic stem cell transplantation is usually well tolerated, and associated with rapid hematopoietic engraftment. We report a high incidence (50%) of side-effects associated with post-transplant G-CSF in patients with chronic phase chronic myeloid leukemia undergoing allogeneic HLA-identical sibling peripheral blood stem cell transplantation. One or more of the following signs and symptoms were observed shortly after the subcutaneous injection of G-CSF: dyspnea, chest pain, nausea, hypoxemia, diaphoresis, anaphylaxis, syncope and flushing. These reactions led to discontinuation of G-CSF in the majority of patients. Predictive factors could not be identified, and the underlying mechanism leading to these reactions is unknown.
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PMID:Adverse side-effects associated with G-CSF in patients with chronic myeloid leukemia undergoing allogeneic peripheral blood stem cell transplantation. 1084 33

Farnesyl protein transferase inhibitors (FTIs) represent a new class of anticancer agents specifically targeting aberrant biologic processes involved with cellular transformation and malignancy. Originally developed to inhibit tumors by preventing activation of oncogenic ras genes via suppression of their posttranslational farnesylation, their anticancer activity appears to stem from their ability to inhibit farnesylation of various proteins that mediate signal transduction, growth, apoptosis, and angiogenesis. The safety, biologic activity, clinical response, and pharmacokinetics of R115777, a potent, orally active FTI, were recently investigated in a phase I dose-ranging study in patients with acute leukemias. Patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), or chronic myelogenous leukemia (CML) in blast crisis received R115777 100 mg, 300 mg, 600 mg, 900 mg, or 1,200 mg twice daily for 21 days. Cycles were repeated every 28 to 31 days for up to four cycles. An overall response rate of 29% (10/34 evaluable patients) was observed across all R115777 doses. R115777 was well tolerated; common adverse events included fatigue, increased creatinine, nausea, and neutropenia. Dose-limiting toxicity occurred at 1,200 mg twice daily. Farnesylation of lamin A and HDJ-2, examined as biologic end points, was inhibited by R115777 doses > or = 600 mg twice daily. Pharmacokinetic evaluation suggests that R115777 is concentrated in bone marrow at steady state. The biologic and antitumor activity and favorable tolerability of R115777 support further clinical evaluation alone and in combination therapy in hematologic malignancies.
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PMID:Farnesyl protein transferase inhibitors as targeted therapies for hematologic malignancies. 1152 24

Chronic myeloid leukaemia (CML) is characterised by the occurrence of the Philadelphia (Ph) chromosome (9/22 translocation) and the formation of a fusion protein--the BCR-ABL transcript with constitutive activation of the BCR-ABL tyrosine kinase and consequent changes in the intracellular signal transduction, which is responsible for the deregulated myeloid cell proliferation. STI571 (signal transduction inhibition number 571) is a potent and selective inhibitor of the BCR-ABL tyrosine kinase. In the chronic phase of the disease, normal peripheral blood values are achieved within the first month of treatment in the large majority of patients and in many patients also a cytogenic response within the following months. The results in the advanced phase are far less favourable, which is explained by the development of resistance owing to reactivation of the BCR-ABL signal transduction. Side effects are primarily nausea, vomiting, various rashes, oedema, most often in the periorbital region, and musculoskeletal symptoms, including muscle cramps. Perspectives for treatment with STI571 are described, as are combinations with alpha-interferon and other cytostatics with a synergistic profile.
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PMID:[STI571 (Glivec)--a new drug for the treatment of chronic myeloid leukemia]. 1208 21

We investigated the clinical activity of the farnesyl transferase inhibitor R115777 in 22 patients with chronic myelogenous leukemia (CML) in chronic, accelerated, or blastic phase and in 8 patients with myelofibrosis (MF) and 10 patients with multiple myeloma (MM). R115777 was administered at 600 mg orally twice daily for 4 weeks every 6 weeks. Seven patients with CML (6 in chronic phase, 1 in advanced phase) achieved complete or partial hematologic response. Four of them had a minor cytogenetic response. Responses were transient, with a median duration of 9 weeks (range, 3-23 weeks). Two patients discontinued therapy because of toxicity while in complete hematologic response. Two MF patients had a significant decrease in splenomegaly, one had normalization of white blood cell count and differential, and one became transfusion independent. One patient with MM had a reduction in monoclonal protein of 34%. Adverse events included nausea in 22 patients (55%; all grade 2 or lower) and fatigue in 19 (48%; grade 3 or higher in 1). Other grade 3 or 4 toxicities included skin rash (4 patients, 10%), peripheral neuropathy (2 patients, 5%), and liver toxicity (2 patients, 5%). Patients who responded to therapy had significantly higher plasma vascular endothelial growth factor (VEGF) concentrations prior to treatment than nonresponders. Plasma concentrations decreased significantly during therapy among responders. R115777 showed clinical activity in patients with CML and MF. The effect on VEGF needs to be further investigated to determine whether this might be a possible mechanism of action of R115777.
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PMID:Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. 1241

Farnesyltransferase inhibitors (FTIs) target multiple pathways including the Ras pathway implicated in the pathogenesis of some hematologic malignancies. R115777 and BMS-214662, selective FTIs in clinical development, exhibit preclinical activity against cell lines and tumor xenografts with or without ras mutations. Phase I dose-escalating trials at M.D. Anderson Cancer Center have explored the potential of these agents as monotherapy for leukemias and myelodysplastic syndrome (MDS). In 20 patients with MDS, two cycles of oral R115777 for 3 consecutive weeks followed by a 1-week rest produced an overall response rate of 30%, consistent with 29% reported in poor-prognosis acute leukemia or blast-phase chronic myelogenous leukemia (CML). Administration of BMS-214662 as a weekly intravenous infusion produced a decrease in bone marrow blasts of greater than 50% in 23% of patients with acute leukemia or MDS; 18% achieved normalization of blast counts to less than 5%. In both studies, most responding patients did not have ras mutations. The most common side effects at maximum tolerated doses of R115777 (400 mg twice daily) and BMS-214662 (118 mg/m(2) weekly) were myelosuppression and nausea, respectively. Further evaluation of FTIs for hematologic malignancies clearly is warranted. Future research should address whether molecular techniques can identify patients most likely to respond to an FTI, optimal administration schedules for these agents, and the value of incorporating an FTI into combination regimens for difficult-to-treat hematologic malignancies.
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PMID:Clinical development of farnesyltransferase inhibitors in leukemias and myelodysplastic syndrome. 1244 48

Despite nine studies reporting the results achieved when treating patients with chronic myeloid leukemia (CML) with interferon (rIFNalpha) and cytarabine (araC), the optimal doses and schedule for this combination remain to be determined. Results of imatinib mesylate (STI-571) in chronic phase CML are preliminary, thus, trials of rIFNalpha-2b/araC in CML are of continued interest. We report the results of CALGB study 9013, providing a 10-year follow-up on 88 evaluable previously untreated patients. Cycles of therapy with rIFNalpha-2b and araC sufficient to cause a decline in either the white blood cell (WBC) count to < 2000/microl or platelets to < 50,000/microl were given. The starting dose of rIFNalpha-2b was 5 million units (mu)/m2/day subcutaneously (s.c.) and of araC 10 mg/m2 twice daily s.c. Treatment was discontinued when cytopenia occurred and was restarted when both the WBC and platelet counts had recovered. Bone marrow was obtained regularly for morphologic, cytogenetic and molecular studies. Medians at entry included age 48 years, WBC = 89,900/microl and platelets = 345,000/microl. The performance status was 0 or 1 in 88%; splenomegaly was present in 46%. Fifty five (63%) patients had a complete hematologic response and 10 (11%) had a partial hematologic response for an overall response rate of 74%. Median time to best response was 5.3 months. Median survival for all patients from study entry was 81 months, the 5-year survival probability was 65%. When 28 patients were censored at the time of bone marrow transplantation the median survival was 82 months. Grade 3 anorexia, nausea, vomiting and diarrhea developed in 15, 27, 13 and 7%, respectively. Mild to moderate elevations of transaminases occurred in 42%, and were severe in 5%. Sixty-three patients had adequate follow-up cytogenetic studies: 10 had a complete cytogenetic response (CCyR), 23 partial (PCyR, 50-99% normal cells), 20 minor and 10 no response (CALGB criteria). Thus, the CCyR plus PCyR rate among these 63 patients was 52%. Assuming the 25 patients with no cytogenetic follow-up as non-responders, 38% of the 88 patients had at least a PCyR. The median time to CCyR or PCyR was 5.6 months. The median time to best response in these 33 patients was 10.0 months, and median duration of cytogenetic response was 28 months. Cytogenetic responders had significantly longer survival than non-responders (p = 0.01) using a landmark analysis at 18 months. This intermittent schedule of rIFNalpha-2b/ara-C has a high response rate in patients with CML with acceptable toxicity.
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PMID:Treatment of the chronic phase of chronic myeloid leukemia with an intermittent schedule of recombinant interferon alfa-2b and cytarabine: results from CALGB study 9013. 1269 Nov 41

Imatinib (Gleevec) (formerly STI571) has demonstrated high levels of efficacy in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST) and has been used in more than 12,000 patients participating in clinical trials. Experience from clinical trials with imatinib has largely demonstrated the drug to be well tolerated in humans. Common side effects, usually manageable, include nausea, rash, superficial edema, myelosuppression, muscle cramps, and elevated liver transaminases. With longer follow-up and with further experience with the treatment of patients outside of clinical trials, we are able to report on rarer toxicities, the identification of certain predictors of common toxicities, and the clinical experience with male fertility and pregnancy outcomes.
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PMID:Imatinib treatment: specific issues related to safety, fertility, and pregnancy. 1278 71

Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML), in advanced stage of disease, is resistant to standard chemotherapy. Imatinib was found to be effective in these patients. This paper shows our preliminary results. Imatinib mesylate was given to 15 patients during a 9-month period. Nine of them were in accelerated phase and 6 in blastic crisis of Ph+ CML. Patients were evaluated for hematologic and cytogenetic responses. Imatinib mesylate induced complete haematologic response in 12 patients (80% and cytogenetic response in 8 patients (53%). Six patients (40%) had a major cytogenetic response. After a 9-month follow up Ph+ CML progressed in 9 patients (60%) and 4 of them died. The most frequent adverse effects were edema, nausea, neutropenia and thrombocytopenia. Imatinib mesylate has a substantial, but short term activity in the accelerated phase and blastic crisis of the Ph+ CML.
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PMID:[Treatment of chronic myeloid leukemia with imatinib in the accelerated stage of the disease]. 1469 90

The purpose of this study was to determine dose-limiting toxicities and pharmacokinetics of imatinib in children with refractory or recurrent Philadelphia chromosome-positive (Ph(+)) leukemias. Oral imatinib was administered daily at dose levels ranging from 260 to 570 mg/m(2). Plasma pharmacokinetic studies were performed on days 1 and 8 of course 1. There were 31 children who received 479 courses of imatinib. The most common toxicities encountered, which occurred in less than 5% of courses, were grade 1 or 2 nausea, vomiting, fatigue, diarrhea, and reversible increases in serum transaminases. One patient at the 440-mg/m(2) dose level had dose-limiting weight gain. There were no other first-course dose-limiting toxicities. A maximum tolerated dosage was not defined. Among 12 chronic myeloid leukemia (CML) patients evaluable for cytogenetic response, 10 had a complete response and 1 had a partial response. Among 10 acute lymphoblastic leukemia (ALL) patients evaluable for morphologic response, 7 achieved an M1 and 1 achieved an M2 bone marrow. We observed marked interpatient variability in the pharmacokinetic parameters. In conclusion, we found that daily oral imatinib is well tolerated in children at doses ranging from 260 to 570 mg/m(2). Doses of 260 and 340 mg/m(2) provide systemic exposures similar to those of adults who are treated with daily doses of 400 and 600 mg, respectively.
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PMID:Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study. 1523 74

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


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