Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methotrexate, a mainstay treatment for children with acute lymphoblastic leukaemia, can cause neurotoxicity, with paralysis, seizures, somnolence, anorexia, and headaches. The pathophysiology of this reaction is unknown. It has been suggested that the anti-inflammatory effect of methotrexate in patients with arthritis is due to adenosine release brought on by inhibition of purine synthesis. Since adenosine is a central nervous system depressant, we wondered whether adenosine release in the central nervous system could account for some of the neurotoxicity due to methotrexate, and whether that toxicity could be lessened by displacement of adenosine from its receptor by aminophylline. 6 patients (age 3-16 years) who had methotrexate-induced neurotoxicity unresponsive to standard treatment received 2.5 mg/kg aminophylline. In addition, the concentration of adenosine in the cerebrospinal fluid (CSF) from 11 children completing a 24-h systemic methotrexate protocol was compared with that in 8 newly diagnosed patients and 12 who had not received any treatment for at least a week. 4 of 6 patients with toxic signs and symptoms attributed to methotrexate and unrelieved by steroids, epidural blood patch, promethazine, 5-hydroytryptamine antagonists, paracetamol, and narcotics, had complete resolution of neurotoxicity after or during a 1-h infusion of aminophylline; 2 others had a pronounced improvement but persistent nausea. CSF adenosine concentrations of patients receiving methotrexate, even when there was very slight or no toxicity, were greatly increased compared with control subjects (mean values of 217 and 51 nmol/L, median 175 and 52 nmol/L). Subacute methotrexate neurotoxicity may be mediated by adenosine and relieved by aminophylline.
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PMID:Aminophylline for methotrexate-induced neurotoxicity. 777 73

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.
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PMID:Phase I study of NKT-01. 778 Nov 37

A late phase II study of a new camptothecin analogue, irinotecan hydrochloride (CPT-11), was conducted to evaluate the anti-tumour effect and toxicity in patients with refractory leukaemia and lymphoma including adult T-cell leukaemia (ATL)-lymphoma, in a multi-institutional cooperative study. All the patients with ATL had been previously treated with various conventional combination chemotherapies and were refractory to these therapies or had relapsed. CPT-11 was administered at a dose of 40 mg m-2 day-1 for three consecutive days repeated weekly until evidence of disease progression. One complete remission and four partial remissions were achieved in 13 assessable patients with ATL. The median total dose to achieve remission was 240 mg m-2 and the median duration of response was 31 days. The major toxicities were leucopenia (83%), diarrhoea (62%) and nausea/vomiting (69%). These were relatively severe, but they were generally tolerable and reversible. However, one patient died probably as a result of this therapy. No effective chemotherapy for adult T-cell leukaemia-lymphoma has yet been established, and the prognosis for patients with this disease is very poor. Our results suggest that CPT-11 may be a promising agent for this disease. Further combination therapy with CPT-11 is needed to improve the therapy for ATL.
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PMID:Treatment of adult T-cell leukaemia-lymphoma with irinotecan hydrochloride (CPT-11). CPT-11 Study Group on Hematological Malignancy. 791 38

A nationwide multi-center cooperative phase II clinical study of irinotecan hydrochloride (CPT-11) was conducted to evaluate its efficacy in intractable malignant lymphoma and acute leukemia. In malignant lymphoma, one course of CPT-11 consisted of intravenous drip infusion at a dose of 40 mg/m2 once daily for 3 consecutive days, performed once a week. In acute leukemia, one course of CPT-11 consisted of intravenous drip infusion at a dose of 15 to 20 mg/m2 a day twice daily for 7 consecutive days (1 cycle), performed every 2 to 4 weeks. Among the 79 patients with malignant lymphoma and 50 patients with acute leukemia enrolled in the study, 66 and 41 patients, respectively, completed treatment. These patients had all undergone chemotherapy prior to treatment. Among the malignant lymphomas, the response rate in non-Hodgkin's lymphoma (NHL), including 9 CRs, was 42% (26/62, 95% CI: 30-54%); of these there was a response rate of 39% (5/13), including 1 CR, in adult T-cell leukemia (ATL) as well. In Hodgkin's disease (HD), on the other hand, there were no cases in which efficacy was demonstrated (0/4). The overall response rate in malignant lymphoma was 39% (26/66), and the response rate even among the recurrent intransigent cases was 42% (16/38). The 50% survival time (MST) in the 74 eligible cases of malignant lymphoma was 153 days. In acute leukemia, on the other hand, partial remission was observed in 2 of 17 cases (12%) of acute lymphocytic leukemia (ALL), but no cases of remission were observed in the 24 patients with acute myelogenous leukemia (AML). The overall remission rate in acute leukemia was 5% (2/41, 95% CI: 1-14%). The principal adverse effects were myelosuppression in malignant lymphoma and gastrointestinal symptoms, including diarrhea, nausea/vomiting, anorexia and abdominal pain, in both malignant lymphoma and acute leukemia, and there was little organ damage to the heart, liver or kidney. Myelosuppression and gastrointestinal adverse effects were severe in some of the patients, so caution is required. Based on the above findings, CPT-11 appears to be efficacious in the treatment of non-Hodgkin's lymphoma.
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PMID:[Late phase II clinical study of irinotecan hydrochloride (CPT-11) in the treatment of malignant lymphoma and acute leukemia. The CPT-11 Research Group for Hematological Malignancies]. 821 Feb 56

The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to-moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.
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PMID:Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia. 838 70

Ninety-seven patients with refractory or relapsed acute myelogenous leukemia (AML), median age 37 years, received as salvage therapy a single course of idarubicin 6 mg/m2 as an intravenous (i.v.) bolus daily for 5 days, cytarabine (Ara-C) 600 mg/m2 i.v. for a period of 2 hours daily for 5 days and etoposide (VP-16) 150 mg/m2 for a period of 2 hours daily for 3 days (ICE protocol). Thirty-six patients were primarily resistant to standard inductive therapy with daunorubicin and Ara-C; 50 patients were in first relapse, three patients in second or third relapse, and eight patients in relapse after transplants. Forty-two (43%) out of 97 patients achieved complete remission, 11 patients died of infection or hemorrhage during induction, and 44 patients (45%) had resistant disease. Of the various variables examined, only disease status (i.e. refractory versus relapsed AML) was predictive for a significantly lower response rate. The median remission duration was 16 weeks; the overall median survival was 10 weeks. Nausea, vomiting, and oral mucositis were common but were rarely severe. No patient experienced treatment-related cardiac toxicity. In conclusion, the ICE protocol is a tolerable regimen providing effective antileukemic activity in patients with advanced AML. The evolution of this protocol in previously untreated patients with AML appears indicated.
Leukemia 1993 Feb
PMID:Idarubicin in combination with intermediate-dose cytarabine and VP-16 in the treatment of refractory or rapidly relapsed patients with acute myeloid leukemia. The GIMEMA Cooperative Group. 842 73

18 consecutive patients with acute myeloid leukaemia (AML) treated with 34 cycles of intensive chemotherapy received ondansetron as antiemetic treatment. 14 patients were chemotherapy-naive, while 4 patients were treated for relapsed leukaemia. All patients received at least one cycle of chemotherapy, 11 patients (61%) received two cycles and 5 patients (28%) received three cycles. The remission induction regimen consisted of cytarabine 200 mg/m2 daily from day 1 to day 7, in combination with an anthracycline or amsacrine on 3 days. During the second and third cycle the dose of cytarabine was increased. Ondansetron was administered as follows: 8 mg intravenously before the start of chemotherapy, followed by 8 mg orally three times daily for 10 days. 50% of patients had no episodes of vomiting during the first cycle of chemotherapy and 78% had less than five episodes of vomiting over 10 days. 72% of patients had no or only mild nausea. These high response rates were maintained during the subsequent cycles. No side-effects due to ondansetron were registered. These data indicate that ondansetron is efficacious in preventing nausea and vomiting in patients with AML treated with intensive chemotherapy.
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PMID:Control of nausea and vomiting with ondansetron in patients treated with intensive non-cisplatin chemotherapy for acute myeloid leukaemia. 843 1

Thirty patients with chronic myeloid leukemia in chronic phase and less than 1 year from diagnosis were treated with a combination of interferon alfa-2a (IFN) 9 million units daily continuously and intermittent low-dose cytosine arabinoside (Ara-C) 20 mg/m2 daily for 21 days every 42 days. The leukemia was controlled initially with hydroxyurea prior to commencing IFN and Ara-C. The treatment was continued for at least 12 months after which time nonresponders were withdrawn from the trial and responders continued on IFN alone. The median duration of follow-up is 14 months (range 10-53 months). Hematological response was assessed by clinical and laboratory parameters and cytogenetic response was assessed by regular bone marrow chromosome analysis. A complete hematological response occurred in 28/30 patients (93%). A complete cytogenetic response (no detectable Philadelphia chromosome-positive metaphases) was present on at least one occasion in 9/30 (30%), a partial cytogenetic response (between 1 and 34% Philadelphia chromosome-positive metaphases) in 7/30 (23%) and a minor response in 4/30 (13%), giving an overall cytogenetic response rate of 67%. Significant side effects included mucositis, nausea, cytopenia and depression. Side effects could be managed by dose reduction or temporary cessation and were tolerable in most patients, but in 1 patient this led to withdrawal from the trial due to severe depression. Two patients have transformed, 1 to acute lymphoblastic leukemia and 1 to accelerated phase. Two patients have died after exiting the study, both from complications of allogeneic bone marrow transplantation. In conclusion, these results are superior to the results using IFN alone and indicate the need for a randomized study.
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PMID:Combined interferon alfa-2a and cytosine arabinoside as first-line treatment for chronic myeloid leukemia. 847 67

Patients with AML who relapse after an initial remission, have a poor prognosis. Administration of hemopoietic growth factors (HGFs) such as interleukin-3 (IL-3) during chemotherapy may result in an increased cell kill by cytotoxic agents. In addition, administration of IL-3 following chemotherapy may potentially accelerate hemopoietic recovery from chemotherapy-induced bone marrow hypoplasia. We performed an open labelled, phase I/II study in which patients received IL-3 by continuous infusion from 24 h before the beginning of chemotherapy until day 28. Chemotherapy included daunorubicin or mitoxantrone days 1-3 and cytarabine 200 mg/m2 days 1-7. IL-3 was given at a dose of 5 microgram(s)/kg/day in 10 patients, 7.5 microgram(s)/kg /day in six patients and 10 microgram(s)/kg/day in four patients. Complete remissions (CR) after one cycle of this treatment were obtained in 5/10 patients and 5 microgram(s)/ kg group, 2/6 in the 7.5 microgram(s)/kg group and 3/4 in the 10 microgram(s)/kg group). Thus, 50% (10/20) of all individuals and 45% (5/11) of the elderly patients attained CR. Eight of 20 patients entered PR, and 2/20 patients died during the hypoplastic phase from infectious complications. Neutrophils and platelets recovered to 0.5 x 10(9)/l at day 25 (median) and to 50 x 10(9)/l at day 32, respectively. Adverse events during IL-3 and concomitant chemotherapy were fluid retention (4/20), rash (14/20), bone pain (2/20), headache (10/20), chest pain (1/20), arthritis (1/20), fever and nausea. IL-3 (at the dose of 10 microgram(s)/kg) was discontinued in two patients because of side-effects (fluid retention, fever, rash and chest pain), and in two other patients the high IL-3 dose was tolerated with no problems for 29 days. Thus, IL-3 applied to patients with high-risk AML at dosages of 5-10 microgram(s)/kg is tolerated with acceptable toxicity and results in a satisfactory frequency of complete responses following a single treatment cycle.
Leukemia 1996 Jan
PMID:Recombinant human interleukin-3 (rH IL-3) in combination with remission induction chemotherapy in patients with relapsed acute myelogenous leukemia (AML): a phase I/II study. 855 36

FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activation of antigen-specific T lymphocytes, a major component in the pathogenesis of graft-versus-host disease (GVHD). This study was designed to obtain first estimates of the safety and efficacy of FK506 monotherapy in the prevention of GVHD following HLA-identical sibling marrow transplantation. Additionally, a subset of patients was studied to define the pharmacokinetic profile of FK506. Twenty-seven adult patients with leukemia or myelodysplasia received FK506 starting the day before transplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion. When clinically possible, FK506 was given orally in two divided doses starting at five times the daily intravenous dose. FK506 doses were adjusted to target a steady state or trough blood level between 10 to 30 ng/mL. These patients were followed for 6 months posttransplant. All patients had sustained marrow engraftment. Frequently noted adverse events included reversible renal dysfunction, diarrhea, fever, nausea, vomiting, and headache. Most patients required FK506 dose reductions associated with elevated serum creatinine. Two (7%) patients relapsed, one of whom died of the disease within the 6-month study period. A second patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of distribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and bioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed grade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indicate that FK506 monotherapy has activity in preventing GVHD. Further studies of FK506 with lower doses to improve tolerability and in combination with other immunosuppressants to augment efficacy are warranted.
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PMID:FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation. 860 72


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