Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite progress in leukemia therapy, only 20-30% of patients with acute myelogenous leukemia (AML) are cured. 1-beta-D-arabinofuranosylcytosine- and topoisomerase II-reactive drugs are the primary therapeutic agents used. The aim of this study was to evaluate the potential activity of tallimustine in leukemia. In this study, we first investigated the efficacy and toxic effects of tallimustine, a distamycin-A derivative, in a human leukemia model in severe combined immunodeficient (SCID) mice. On the basis of its dramatic activity in this preclinical study, a Phase I study of tallimustine at a starting dose of 300 microgram/m2/day for 3 days every 3-4 weeks was conducted in patients with refractory or relapsed leukemia. In SCID mice grafted with a human myelomonocytic leukemia cell line, tallimustine resulted in complete remission of disease in most mice at tolerable dosages ranging from 0.86 to 3.0 mg/kg/day for 3 days and was combined effectively and safely with a 2-day schedule of high-dose ara-C. In the Phase I study, 26 patients with refractory or relapsed leukemia were treated. The maximum tolerated dose was 900 microgram/m2/day for 3 days every 3-4 weeks. This dose was 3 times higher than the maximum tolerated dose in solid tumors and was limited by severe mucositis. Magnesium and potassium wasting were also observed, but other side effects (fatigue and gastrointestinal) were minor. Two (8%) patients with AML achieved complete remission and two achieved hematological improvement with persistent thrombocytopenia. The results of this study indicate that tallimustine has promising activity in AML. Future studies may combine tallimustine with other agents known to be active against AML, and investigate its activity in other hematological malignancies. The recommended Phase II single-agent dose of tallimustine is 750-900 microgram/m2/day for 3 days, and combination studies may start at 50-66% of this dose schedule. The SCID mouse model of human leukemia may be promising in the preclinical evaluation and selection of potential antileukemic agents.
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PMID:Tallimustine, an effective antileukemic agent in a severe combined immunodeficient mouse model of adult myelogenous leukemia, induces remissions in a phase I study. 981 37

This report describes a case of diabetes insipidus associated with acute myelogenous leukemia. An 11-year-old boy presented with fatigue, polydipsia and polyuria. His evaluation revealed a diagnosis of acute myelogenous leukemia FAB-M2, and a water deprivation test confirmed the diagnosis of central diabetes insipidus. His brain magnetic resonance imaging (MRI) showed a thickened, enhancing pituitary stalk with absence of the normal hyperintense signal in the posterior pituitary. He was treated with systemic chemotherapy, intensive intrathecal therapy, and 1,000 cGy to the pituitary. The patient achieved a remission but continued to need desmopressin therapy to control his diabetes insipidus. Diabetes insipidus is a rare complication of acute myelogenous leukemia that can be caused by leukemic infiltration of the pituitary. The diabetes insipidus is irreversible despite intensive systemic and central nervous system chemotherapy and radiation.
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PMID:Diabetes insipidus as a presenting symptom of acute myelogenous leukemia. 1103 61

A 17-year-old male with AML FAB M4 relapsed 4 months after myeloablative conditioning and peripheral blood stem cell transplantation (PBSCT) from an HLA-identical unrelated donor. A second PBSC harvest was infused 2 days after completion of cytoreductive therapy with mitoxantrone 7 mg/m(2)/day i.v. for 3 days (total dose 21 mg/m(2)), fludarabine 30 mg/m(2)/day i.v. for 6 days (total dose 180 mg/m(2)) and Ara-C 125 mg/m(2)/day i.v. for 5 days (total dose 625 mg/m(2)). Neutrophil recovery occurred on day +10 and was associated with GVHD grade III of the skin which was treated with cyclosporin A (CsA) and prednisone. Because of fever of unknown origin and progressive fatigue combined with hypotension on day +15 after second PBSCT, echocardiography was performed which revealed a dramatic decrease in systolic function compared to the status pre-transplant. On the same day acute heart failure with consecutive ventricular fibrillation occurred. Although resuscitation was performed immediately the patient died. The autopsy revealed massive infiltration by donor CD8-positive lymphocytes with concomitant extensive damage of the heart tissue. Acute myocarditis of viral origin was excluded by in situ hybridization and nested PCR techniques. In this patient, myocardial involvement by acute GVHD seems to have triggered a fatal arrhythmia and heart failure.
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PMID:Acute heart failure after allogeneic blood stem cell transplantation due to massive myocardial infiltration by cytotoxic T cells of donor origin. 1124 47

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

Emerging data suggest an involvement of angiogenesis in the pathophysiology of acute myeloid leukemia (AML). Thus, antiangiogenic therapy could constitute a novel strategy for the treatment of AML. To test this hypothesis, a phase I/II dose-escalating trial was performed to study the safety and efficacy of thalidomide, a putative inhibitor of angiogenesis, in 20 patients with AML. Thirteen patients were assessable for both toxicity and response, tolerating a maximum dose of 200 to 400 mg daily for at least 1 month. Seven patients had to be prematurely withdrawn from drug administration owing to progressive disease and death (3 patients), personal decision (2 patients), or inability to tolerate thalidomide (2 patients). Overall, adverse events were fatigue, constipation, rash, and neuropathy (grade 1 to 2 in most patients). In 4 patients, a partial response, defined as reduction of at least 50% in the blast cell infiltration of the bone marrow accompanied by increases in platelet counts and hemoglobin values, was observed. One additional patient showed a hematologic improvement without fulfilling the criteria of a partial response. The responses lasted a median of 3 months (range, 1-8 months). In parallel, microvessel densities significantly decreased in these 5 patients during treatment with thalidomide (P <.05). This decrease was accompanied by declining plasma levels of basic fibroblast growth factor, one of the most potent angiogenic growth factors. In conclusion, single-agent thalidomide has antiangiogenic and antileukemic activity in AML, although a causal relationship between both effects has still to be proven.
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PMID:Efficacy and safety of thalidomide in patients with acute myeloid leukemia. 1180 84

Quality of life (QL) was evaluated in 101 patients with AML undergoing intensive and prolonged treatment at 12 sequential time points by using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C 30 questionnaire and the profile of mood states scale (POMS). For those patients having completed the course of inpatient treatment (n=37), QL improved from the beginning of chemotherapy to the end of inpatient treatment. Patients who subsequently went off protocol did not differ significantly in their self-assessed QL when compared with patients who completed therapy. Fatigue was more closely related to QL than nausea/emesis or appetite loss, but did not correlate with hemoglobin levels.
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PMID:Fatigue as an important aspect of quality of life in patients with acute myeloid leukemia. 1183 78

We examined the efficacy of thalidomide in 34 patients with myelodysplastic syndromes (MDS): five RAEB-T, four RAEB, three CMML, six RARS, and 16 RA. Patients belonged to the following cytogenetic groups: 15 complex abnormal karyotypes, 12 normal karyotypes, four cases with 5q- as sole anomaly and three single aberrations. The median thalidomide dose was 400 mg/day (25/34 patients). Four patients discontinued the study after less than 5 weeks, because of fatigue (three) or skin rash (one). One patient died of heart failure after 4 weeks. In the remaining 29 patients (median follow-up: 13 months), treatment responses were classified according to the IWG criteria. Six patients (four RA, two CMML) showed progressive disease (five with transformation into AML) and four patients showed stable disease. Hematological improvement (HI) was observed in 19 patients. Nine of the responders (three RA, one RARS, two RAEB, three RAEB-T) achieved partial remission with granulocytes > or = 1500/microl, Hb > 11 g/dl and platelets > or =100,000/microl. Four patients (one RARS, one CMML, one RAEB, one RAEB-T) had a major response, with platelet and RBC transfusion independence. Six patients (five RA, one RARS) showed minor responses (three HI-E, two HI-E+HI-P, one HI-E+HI-N). Hematological improvement occurred after a median of 2 months of thalidomide treatment. Two patients (RAEB-T) relapsed after a partial remission lasting 8 and 16 months, respectively. In summary, a therapeutic benefit was achieved in 19 of 34 study patients (56%).
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PMID:Thalidomide for the treatment of patients with myelodysplastic syndromes. 1184 Feb 56

We conducted a nonrandomized prospective phase II study of thalidomide in anemic patients with myelofibrosis with myeloid metaplasia (MMM), with or without preceding polycythemia vera or essential thrombocythemia, with a primary aim to improve anemia. Thalidomide was given in escalating doses with a target dose of 800 mg daily, but the median dose of thalidomide that was actually tolerated was 400 mg daily. Fifteen patients were entered into the study and 14 were evaluable for response. Five of 14 (36%) patients discontinued thalidomide before 3 mo because of side effects, and none of these five patients had a response at the time when thalidomide was stopped. When evaluated after 3 mo of therapy, none of the remaining nine patients exhibited a discernible clinical response. Three patients showed progressive disease defined as > 50% increase in the need for red cell transfusions. Treatment was poorly tolerated, with all patients reporting side effects of thalidomide, the most prominent being fatigue documented in 80% of patients. Two patients died while on study, one from acute myelogenous leukemia and one from pneumonia. We conclude that thalidomide given in doses employed in the treatment of multiple myeloma gives no clinically relevant hematological effects in advanced MMM and is hampered by a very high incidence of side effects.
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PMID:Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia. 1218 Apr 84

Bone marrow necrosis (BMN) is a relatively uncommon clinicopathologic entity. The etiology is diverse, and malignancy, especially hematopoietic in origin, is the most common underlying disease of BMN. In this retrospective analysis, cases with BMN were re-evaluated for etiology, histopathologic details, and clinical manifestations. In the last 8 years, 23 cases of BMN were detected among the 1,083 bone marrow (BM) biopsies, and the prevalence was found to be 2.2%. Three of these 23 cases with BMN were children, and 20 cases were in adults. Sixteen of these cases (80%) had underlying malignant disease, and four (20%) had nonmalignant disease. Among the malignant cases, three cases had acute myeloblastic leukemia (AML), four had relapsed Hodgkin's disease (R-HD), one had acute lymphoblastic leukemia (ALL), two had chronic myelocytic leukemia (CML), two had non-Hodgkin's lymphoma (NHL), three had disseminated intravascular coagulation (DIC) associated with metastatic solid tumor, and one had myelodysplastic syndrome/myeloproliferative syndrome (MDS/MPS). Among the nonmalignant cases, two had tuberculosis infection, one had anti-phospholipid syndrome (APS), and one had a history of drug ingestion. The most common symptoms were bone pain, fever, fatigue, and jaundice. The most common laboratory findings were variable and associated with underlying disease, but anemia, leukopenia, thrombocytopenia, and high LDH and alkaline phosphatase levels were detected in the majority of the cases, as was also seen in other series. BMN was graded according to the extent of necrosis in the BM biopsy, and necrosis was extensive in 12 cases, moderate in five cases, and mild in three cases. Increased reticulin was found in 16 cases; four cases had severe, eight had moderate, and four had mild fibrosis, and this was found to be an interesting accompanying finding in BMN. In conclusion malignancy is the most common cause of BMN but some nonmalignant conditions such as tuberculosis and APS may be the underlying cause of BMN.
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PMID:Bone marrow necrosis: clinicopathologic analysis of 20 cases and review of the literature. 1221 Aug 11

Treatment of healthy donors with recombinant human granulocyte colony-stimulating factor (rhG-CSF) allows the mobilization and peripheralization into circulating blood of an adequate number of CD34+ cells that can then be collected by leukapheresis (PBSC). This procedure avoids the invasiveness of bone marrow harvest and the risks related to general anesthesia. The main adverse effects of rhG-CSF are: bone pain, 84%, headache, 54%, fatigue, 31%, and nausea, 13%, which are usually scored by the donors as moderate to severe, resolving within 2-3 days after discontinuation of the cytokine. Analgesics, mainly acetaminophen, are sufficient to control the pain. Less than 5% of the donors experience non-cardiac chest pain, a local reaction at the injection site, insomnia, dizziness or a low-grade fever. Discontinuation of the PBSC procedure because of adverse effects of rhG-CSF or leukapheresis is rarely necessary (0.5%) but this good tolerability can be hampered by the need, in 5-20% of cases, for an adequate venous access that requires insertion of a central or venous catheter. There are no absolute contraindications to the stimulation of healthy donors with rhG-CSF but the description of cases of non-traumatic splenic rupture, iritis, cardiac ischemia, and gouty arthritis suggests that further precautionary restrictions are advisable when deciding eligibility for PBSC collection. The main advantages for patients receiving an allogeneic PBSC transplant are the faster hematologic and immunologic recovery and the potential for a greater efficacy in advanced disease by lowering the transplant-related mortality. One of the major concerns regarding the use of rhG-CSF in unrelated healthy donors is the uncertainty about its possible role in triggering malignancy, in particular myelodysplastic syndrome and acute myeloid leukemia. There are no studies with an adequate sample size and follow-up that can answer this question but two recent retrospective studies reported that in the medium term rhG-CSF is not associated with an excess of lymphoproliferative disorders. Currently, caution on the long-term safety of the use of rhG-CSF in healthy donor is still warranted but the data so far accumulated on allogeneic PBSC transplants are encouraging both as far as concerns the good short-medium tolerability profile of G-CSF-stimulation of the donor and the potential major efficacy in leukemia patients.
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PMID:The use of cytokine-stimulated healthy donors in allogeneic stem cell transplantation. 1241 88


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