Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Relapse continues to be a problem after bone marrow transplantation (BMT) for hematologic malignancies, particularly in recipients of autologous or T-cell-depleted allogeneic grafts and in patients with advanced disease. Interferon (IFN) has shown antiproliferative activity in several malignant hematologic diseases and potentially may be of benefit when administered early after BMT when the number of residual cells is minimal. We tested in a phase I study the maximum tolerated daily dose of recombinant IFN alpha-2b in patients who had received a transplant for a disease at high risk for relapse (acute myeloid leukemia or non-Hodgkin's lymphoma beyond first remission, advanced myelodysplastic syndrome, acute lymphoblastic leukemia at any stage, chronic myeloid leukemia in accelerated or blast phase. Recombinant IFN alpha-2b was started at a dose of 0.5 x 10(6) IU/m2 and escalated by 0.5 x 10(6) IU/m2 in groups of three or four patients. The intention was to administer IFN as soon as stable engraftment after BMT was achieved (defined as an absolute neutrophil count of greater than 2.0 x 10(9)/L and platelet count greater than 100 x 10(9)/L for 5 consecutive days) and continued for 2 months. A total of 14 patients were enrolled after autologous (n = 3) or allogeneic (n = 11) BMT. Dose-limiting toxicity was myelosuppression. Significant (grade 2 to 4) neutropenia and thrombocytopenia led to discontinuation or dose reduction in five of eight patients receiving 1.5 x 10(6) or 2 x 10(6) IU/m2 IFN. Mild to moderate (grade 1 or 2) anorexia, weight loss, and fatigue occurred in the majority of patients independent of the IFN dose. De novo acute GVHD responsive to steroid treatment developed in 3 of 11 allograft recipients. Natural killer (NK) cell function was low before IFN treatment and was not improved with the cytokine. Conversely, interleukin-2-activated NK cells showed normal function even before starting IFN and no change was seen during IFN treatment. Clonogenic hematopoietic progenitor studies showed depression of all progenitor lines (colony-forming unit [CFU]-granulocyte, erythroid, monocyte, megakaryocyte, CFU granulocyte-macrophage, burst-forming unit-erythroid) by IFN at all dose levels except at 0.5 x 10(6) IU/m2. Considering this result and the incidence and severity of marrow depression seen at doses greater than 1.0 x 10(6) IU/m2, we would consider this the maximum dose safely tolerated if IFN alpha-2b is administered in this setting for a prolonged course on a daily basis.
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PMID:Treatment with recombinant interferon (alpha-2b) early after bone marrow transplantation in patients at high risk for relapse [corrected]. 174 91

Pentostatin, a novel inhibitor of adenosine deaminase, has shown activity in various lymphoid malignancies of both the T and B cell lineage. This agent has unique side effects and in general myelosuppression has been mild. Interferon has both antiviral and antineoplastic properties. This agent has shown activity in hairy cell leukemia, chronic granulocytic leukemia, low grade lymphoma, and myeloma. Side effects from interferon are in general dissimilar to those that have been seen with pentostatin and in particular myelosuppression has not been a major toxicity with low doses of interferon. This current trial explored the combination of pentostatin and interferon in hematologic malignancies. Fifteen patients were enrolled in this phase I trial at a fixed dose of pentostatin of 4 mg/m2 biweekly and interferon at doses of 0.5, 1, 2, or 4 million units/m2 of interferon. At the first three dose levels of interferon nausea and vomiting were the predominant toxicity and appeared to worsen with time on study. Fatigue also was seen at the lowest level of interferon and was severe enough to cause two individuals to discontinue the study medications. At higher dose levels of interferon, myelosuppression, nausea and vomiting, and fatigue were the predominant toxicities. One patient with hairy cell leukemia had a complete response and a second patient with T cell cutaneous lymphoma had a partial response which lasted for 6 to 7 weeks. The maximum tolerated dose of interferon with pentostatin in this patient population was four million units/m2.
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PMID:A phase I trial of alpha-interferon in combination with pentostatin in hematologic malignancies. 205 72

Recombinant interferon alfa-2a (Roferon-A, Hoffmann-La Roche Inc., Nutley, NJ) has been evaluated in clinical trials of more than 1300 patients with a broad spectrum of oncologic disease. Patients with either solid tumors or hematologic malignancies were treated with daily or three-times-weekly intramuscular injections for induction periods ranging from 8 to 16 weeks. Doses ranged from 1 X 10(6) units to 124 X 10(6) units per injection. When administered in low daily doses (approximately 3 X 10(6) units), Roferon-A was well tolerated, and dose attenuation was rarely required. Change to three-times-weekly treatment regimen at the same dose was usually sufficient to control toxicity when it occurred in this group of low-dose patients. Those patients receiving higher doses frequently required dose attenuation to 50% of the starting dose to improve clinical tolerance. Virtually all patients treated with Roferon-A experienced some degree of acute toxicity manifested as fever, chills, myalgia, and/or headache. These reactions usually occurred with initial dosing and frequently improved spontaneously with continued administration of the drug. Acetaminophen pretreatment was generally useful in ameliorating these symptoms. Common adverse experiences occurring after repeated dosing included fatigue, anorexia, and weight loss. Serious adverse reactions including cardiovascular and neurologic toxicity have occurred infrequently, primarily at higher doses. Hematologic toxicity and elevations in liver function parameters were also observed, but rarely required dose attenuation. Adverse effects were usually reversible after dose reduction or discontinuation of therapy. Approximately 27% of all patients developed antibodies to rHuIFN-alpha 2A during treatment. No adverse clinical sequelae have been associated with antibody development to date.
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PMID:Safety and tolerance of recombinant interferon alfa-2a (Roferon-A) in cancer patients. 394 43

Results of an ongoing clinical study of a mismatched double-stranded (ds) RNA, termed Ampligen, in patients with metastatic cancer are described. In a pilot study of Ampligen (lot 1) involving mostly hematologic malignancies, patients received cumulative doses up to approximately 450 mg without untoward effects. Evidence of biologic/antitumor effects was observed (3/5 patients) by monitoring tumor-specific markers or tumor cell morphology. In patients with solid tumors receiving lot 2, Ampligen cumulative doses over 4 g were well tolerated. The drug was given by intravenous infusion (10-80 mg/infusion, twice weekly), in some instances for more than 1 year, without clinically significant side effects. Specifically, no evidence of hematologic, liver, or renal toxicity, which was previously noted with other dsRNAs, was observed. Side effects consisted of occasional mild fatigue or flu-like symptoms. Fever, when encountered, was transient and low grade (less than 100.5 degrees F). Importantly, an analysis of patient sera for dsRNA antibodies revealed that no patient had evidence of specific antibodies directed against Ampligen. Other dsRNAs cause up to a 60% incidence of antibody formation. Additionally, a novel method was developed to monitor Ampligen blood levels. In a survey of seven patients, Ampligen had a mean plasma half-life of 23 min. Ampligen administration can also result in activation of both natural killer (NK) cells and a lymphocyte, interferon-associated, intracellular enzyme. Dose-dependent antitumor effects were seen in several solid tumors; in doses of 10-40 mg, 3/9 patients showed stable disease for up to 1 year. At the 80-mg dose level, 2/5 patients showed tumor regressions (mixed and partial responses).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical studies with ampligen (mismatched double-stranded RNA). 408 35

A 66-year-old Japanese man was admitted to Hitachi General Hospital because of fatigue, fever, edema, and icterus. A blood examination showed anemia, leukocytosis, and hyperbilirubinemia. Antibiotics did not alleviate the inflammatory symptoms. On the 13th hospital day, the patient demonstrated mental confusion, with progressive anemia and thrombocytopenia. Bone marrow aspiration revealed an increase of macrophages showing erythrophagocytosis. A diagnosis of hemophagocytic syndrome was made, but no viral infection or hematological malignancy could be detected. The patient was treated with gamma-globulin and methylprednisolone for hemophagocytic syndrome, but died of respiratory insufficiency with progressive hyperbilirubinemia and trombocytopenia on the 29th hospital day, A postmortem examination showed proliferation of lymphoma cells within the small blood vessels of the brain, lungs, liver, and many other organs, but the bone marrow was not involved. An immunohistochemical examination resulted in a diagnosis of intravascular malignant lymphomatosis (IML) of B cell origin. No viral infection was detected with in situ hybridization methods. Although IML occasionally accompanies thrombocytopenia, infiltration of lymphoma cells in the bone marrow is rare. Lymphoma associated hemophagocytic syndrome may cause cytopenia in some patients with IML, as indicated in this case.
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PMID:[An autopsy case of intravascular malignant lymphomatosis with hemophagocytic syndrome, mental confusion and liver dysfunction]. 978 77

Anemia is common in patients with hematological malignancy. Most patients will have their anemia attributed to the anemia of chronic disease. The anemia of chronic disease is caused by cytokine mediated suppression of erythropoiesis and low serum erythropoietin levels are found in the majority of patients with cancer. Many of these anemic patients will be symptomatic with fatigue. Data from many studies indicates that treatment of anemic patients with erythropoietin will increase their hemoglobin concentration, decrease transfusion need and also improve their quality of life. A recent study also suggests that improving the hemoglobin level may improve the patients' prognosis but this finding needs to be confirmed.
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PMID:Erythropoietin for the treatment of anemia associated with hematological malignancy. 1127 43

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

Anemia is a common cause of cancer-related fatigue. A systematic review of the literature was performed to establish guidelines on the use of epoetin alfa for the treatment of anemia. The evidence in support of these guidelines was selected, reviewed, and summarized by the members of the Canadian Cancer and Anemia Guidelines Development Group. The effects of epoetin alfa on quality of life (QOL) in patients with cancer were examined in 5 randomized, placebo-controlled trials and 2 large, open-label, nonrandomized, community-based studies. The effects of epoetin alfa on red blood cell transfusion requirements were examined in 19 randomized controlled trials (RCTs) with 21 comparisons. All trials compared epoetin alfa to a suitable control group, examined specified outcome measures that could be analyzed, and studied patients with cancer who were receiving chemotherapy. Trials involving patients with hematologic malignancies originating in the bone marrow were excluded. Outcome measures included 1) quality of life (QOL) (as measured by scales including the Linear Analogue Self-Assessment [LASA] and the Functional Assessment of Cancer Therapy [FACT] subscales), and 2) transfusion requirements (as measured by the proportion of patients requiring transfusion and amount of transfusion). The analysis confirmed that epoetin alfa produced statistically significant and clinically relevant improvements in QOL in patients with cancer. The overall relative risk ratio for transfusion among patients receiving epoetin alfa was calculated to be 0.60 (95% Cl, 0.53-0.69; P < 0.00001), representing a 40% reduction in the proportion of patients requiring transfusion. These results support recommendations for the use of epoetin alfa in patients with cancer-related anemia.
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PMID:Epoetin alfa in cancer patients: evidence-based guidelines. 1172 99

Anemia is a common complication in patients with hematologic malignancies, and is caused by a variety of mechanisms, including neoplastic cell infiltration into the bone marrow, hemolysis, nutritional deficiencies, and defects in erythropoiesis as a result of the disease itself or cytotoxic therapy. The anemia associated with multiple myeloma is caused by inadequate erythropoietin levels consequent to renal impairment and the effect of inflammatory cytokines. The degree of anemia can have prognostic importance, as is the case with multiple myeloma, or be a significant indicator of disease stage, as noted with chronic lymphocytic leukemia. Anemia results in fatigue, exhaustion, dizziness, headache, dyspnea, and decreased motivation, seriously affecting a patient's quality of life. Since anemia is so prevalent in hematologic malignancy patients, its treatment must be an integral part of disease management, to improve quality of life and to possibly increase potential survival. Clinical studies have shown that effectively treating anemia and increasing hemoglobin levels using recombinant human erythropoietin (rHuEPO, epoetin alfa) has a significant effect on transfusion requirements and quality of life.
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PMID:The effects of anemia in hematologic malignancies: more than a symptom. 1208 53

Anemia is a common complication in patients with hematologic malignancies, with incidence rates ranging up to 63%. In myelodysplastic syndromes, anemia is an essential feature of the disease. The decrease in hemoglobin may lead to several symptoms such as fatigue, exhaustion, and impaired quality of life, and it may worsen prognosis. Before the introduction of recombinant human erythropoietin (rHuEPO, epoetin alfa), red blood cell transfusions were the traditional treatment for improvement of Hb levels. Transfusions, however, are associated with several adverse events and risks, have only transient effects, and have a limited capacity to ameliorate the symptoms of anemia. Epoetin alfa represents a physiologic treatment option, especially in the long-term treatment of cancer- and cancer treatment-associated anemia, and is well tolerated, with response rates as high as 80%. Epoetin alfa is less effective in the treatment of the anemia of myelodysplastic syndrome, but appears to be synergistic with granulocyte-colony stimulating factor. However, not every patient responds to epoetin alfa; to avoid unnecessary interventions and costs, predictors of response have been proposed. This article outlines the advantages and disadvantages of the two major treatment forms of anemia: transfusions and epoetin alfa. Representative studies on the efficacy of epoetin alfa in anemic patients with hematologic malignancies as well as models to predict response to epoetin alfa treatment are summarized.
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PMID:Anemia of hematologic malignancies: what are the treatment options? 1208 54


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