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

Twenty-nine patients were conditioned for allogeneic marrow transplant with cytarabine (ara-C) (3 g/m2 every 12 hours for 12 doses) and total body irradiation (TBI) (200 cGy daily for six days) with or without cyclophosphamide (CY) (60 mg/kg) to determine toxicity and efficacy. Four patients had chronic myelogenous leukemia (CML) in accelerated phase or blast crisis, and 25 patients had acute leukemia, 24 at stages later than first remission. Three patients (10%) had fatal regimen-related toxicity and another 10% experienced severe toxicity in at least one organ system. The addition of CY to the ara-C and TBI regimen was not associated with an increase in the frequency of severe toxicity. Twenty-five of 29 patients engrafted eight to 33 days posttransplant: three died early before engraftment, and one patient failed to engraft. Ten of 29 patients are alive without disease, and the actuarial probability of disease-free survival for the entire group at 3 years is 33%. Three of ten patients with acute nonlymphocytic leukemia (ANL), six of 15 with acute lymphocytic leukemia (ALL), and one of four with CML are alive and disease free 25 to 42 months (median, 30 months) after transplant. High-dose ara-C (HDara-C) and TBI with or without CY can be administered with approximately the same toxicity as CY plus TBI. Phase III studies appear warranted to determine if these newer regimens provide improved results compared with currently used regimens.
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PMID:High-dose cytarabine and total body irradiation with or without cyclophosphamide as a preparative regimen for marrow transplantation for acute leukemia. 328 31

High doses of cytosine arabinoside (ara-C) were administered by continuous infusion to 24 patients with acute leukemia in relapse or blast phase of chronic myelogenous leukemia (CML). Ara-C was infused at a dose rate of 250 mg/M2/hr for 36 to 72 hr. The major toxicities were myelosuppression, diarrhea, and abdominal pain. Other toxicities included pulmonary edema, neurotoxicity, and liver function abnormalities. The gastrointestinal toxicity was dose-limiting and a phase II dose was established at 250 mg/M2/hr for 60-72 hr. Four patients treated with this dose schedule had objective responses. Two patients with CML in blast phase returned to chronic phase and have remained stable without maintenance therapy for 12 and 18 months. Two patients with acute myelogenous leukemia in relapse entered complete remissions which continued unmaintained for 4 and 6 months. Steady-state plasma ara-C levels ranged between 7 and 24 x 10(-6) M, while ara-U levels were as high as 4.5 x 10(-4) M. There was no detectable accumulation of ara-C or ara-U during the infusion period. These findings would suggest that the continuous infusion of high dose ara-C may be useful in the treatment of acute leukemia and CML in blast crisis.
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PMID:Prolonged high dose ARA-C infusions in acute leukemia. 328 17

We tested the value of early intensification of chemotherapy in 68 consecutive children with acute nonlymphocytic leukemia (ANLL) who were admitted to St. Jude Children's Research Hospital from November 1983 through March 1987. Fifty-eight patients (85%) entered complete remission after treatment with etoposide (VP-16)/cytarabine (ara-C) (A), followed by daunorubicin (Dauno)/ara-C/thioguanine (6-TG) (B) and then VP-16/azacytidine (5-AZ) (C). Thirty percent of the complete responders, mainly those with an M4 or M5 leukemia subtype, attained M1 marrow status after component A, 60% after A + B, and 10% after A + B + C. Induction failures resulted primarily from absolute or relative drug resistance; there was only one death during this phase of therapy. Postremission treatment consisted of three pairs of drugs (vincristine [VCR]/amsacrine [m-AMSA], or doxorubicin [Doxo]/6-TG/ara-C, and VP-16/cyclophosphamide [CTX]) administered sequentially in 6-week cycles for 22 months. Despite the high rate of remission induction, only 33% +/- 7% SE of the patients are expected to be failure-free survivors at 2 years. Remission durations were not significantly affected by the majority of factors examined in this study, with the exception of marrow cellularity after VP-16/ara-C induction therapy. Patients with less than or equal to 5% leukemic cells survived relapse-free for a median of 36.1 months, compared with 11.3 months for the group with a larger infiltrate (P = .01). Although postremission therapy did not improve the percentage of long-term failure-free survivors, the induction regimen we used appears highly effective, and its components should be considered for inclusion in other treatment programs.
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PMID:Early intensification of chemotherapy for childhood acute nonlymphoblastic leukemia: improved remission induction with a five-drug regimen including etoposide. 329 13

It has been proposed that intensive chemotherapy ror RAEB is dangerous, and a small dose of ara-C therapy is recommended in many institutes for its ability to differentiate leukemic cells. Combination chemotherapy for RAEB, however, has not been completely evaluated. We introduced B-DOMP therapy, which is used in our hospital, for RAEB. B-DOMP therapy includes Behenoyl ara-C, daunomycin, oncovin, 6-MP and prednisolone, which achieved approximately 80% of complete remission of ANLL for adults. Five males and one female of RAEB, aged 40-74 (median 70), were treated by B-DOMP regimen. Two cases achieved complete remission, 2 remained in partial remission and 2 cases died within one month. In three cases, the cause of death was fungal pneumonia. It must be stressed that life-threatening pneumonia was common after chemo therapy for RAEB, and careful protection against fungal infection using laminarair flow is required.
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PMID:[Intensive chemotherapy of refractory anemia with excess of blasts]. 338 97

Thirty-four patients with acute promyelocytic leukemia (APL) (median age 37 years, range 20 to 69 years) received induction treatment between 1974 and 1985 with cytosine arabinoside (ara-C) and an anthracycline. Bone marrow hypercellularity was present at the time of diagnosis in all patients, although the median peripheral leukocyte count was 2,600/microL. A second course of induction therapy consisting of further ara-C and anthracycline was initiated 15 days after the start of treatment if bone marrow hypocellularity could not be documented. Karyotypic analysis of bone marrow blasts was performed on 15 of 34 patients; 11 of 15 had abnormalities in chromosomes 15 and/or 17. Twenty-nine of 34 (85%) patients had laboratory evidence of disseminated intravascular coagulopathy. Of the 29 patients surviving 14 days, 24 (83%) received a second course of induction therapy. Complete remission was achieved in 25 of 34 (74%) patients, with four of 25 (16%) requiring one course of induction chemotherapy and 21 of 25 (84%) receiving two courses. Bone marrow specimens obtained 15 days after the start of therapy from the 25 patients who eventually attained complete remission showed the continued presence of dysplastic promyelocytes in 21 cases; three specimens were technically inadequate and only one was truly devoid of promyelocytes. Seventeen of 25 (68%) patients still had persistence of abnormal bone marrow promyelocytes seven or more days after the second course of therapy. Patients in complete remission received various forms of postremission therapy. Ten of the 25 (40%) completely responding patients remain alive in continuous complete remission. Neither the absence of bone marrow hypocellularity nor the persistence of dysplastic promyelocytes during induction exerted any influence on the probability for survival. These findings confirm and extend prior reports that complete remission in APL, in contrast to other subtypes of acute nonlymphocytic leukemia (ANLL), can frequently be achieved without bone marrow aplasia. Whether this observation signifies that complete remission in APL is due to leukemic cell differentiation or selective cytotoxicity is unknown. The absence of therapy-induced bone marrow hypoplasia in APL is not an absolute indication of induction failure or a poor ultimate prognosis.
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PMID:Complete remission in acute promyelocytic leukemia despite persistence of abnormal bone marrow promyelocytes during induction therapy: experience in 34 patients. 342 28

Four cases of hypoplastic leukemia, one of acute myelocytic leukemia (M2) and one of RAEB-t were treated with a low-dose 4N-behenoyl-1-beta-D-arabinofuranosylcytosine (LD-BHAC) regimen, in which 50 mg BHAC was administered daily intravenously by one-hour drip infusion for 14 days. Among the 6 cases, three (2 hypoplastic leukemia and one M2) obtained complete remission and one (hypoplastic leukemia), partial remission. Response rates were 66.6% of all cases, and 75% of cases of hypoplastic leukemia. During treatment, cytopenia was observed in all cases and a decrease in bone marrow nucleated cell counts was recognized in the aged M2 patient with remission. Although side effects of the drug on the digestive system such as anorexia and nausea were observed in some cases, they were all controllable by conventional treatments. The serum concentration of ara-C was measured in 4 cases. The peak level of serum ara-C concentration, 3.62-18.9 ng/ml (mean: 11.74 ng/ml), was observed at the time of cessation of infusion of BHAC, and an ara-C level of 2.75-4.89 ng/ml (mean: 3.54 ng/ml) was still present in the blood 6 hours after the cessation of infusion. It was concluded that LD-BHAC was useful in the clinical management of atypical leukemia and acute myelocytic leukemia in the aged.
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PMID:[Low-dose 4N-behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC) in the treatment of atypical leukemia]. 346 49

Ten patients with acute myeloid leukemia were treated with a high-dose ara-c regimen (3 g twice daily for 6 days). 5 patients (50%) achieved a complete remission lasting for a median duration of 5 months. These patients had all achieved a complete remission following standard treatment with ara-c. High-dose ara-c was ineffective in 2 patients resistant to standard ara-c protocols. The most important side effects of high-dose ara-c were conjunctivitis and cerebellar symptomatology. In one case a severe diffuse encephalopathy with cerebellar predominance set in at a remarkably late stage (45 days after starting treatment). Our results and those of other authors suggest that treatment with high-dose ara-c should be used with caution.
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PMID:[Effectiveness and toxicity of high-dosage Ara-C. Clinical observations in 10 cases and review of the literature]. 346 40

To define the relationship between leukemic cell growth, intracellular metabolism of 1-B-D-arabinofuranosylcytosine (ara-C), and the clinical response to timed sequential induction therapy with ara-C in adult acute myelogenous leukemia (AML), growth kinetic and biochemical pharmacologic determinants were examined in AML bone marrow populations. Leukemic blasts from 45 previously untreated patients obtained prior to therapy were cultured in vitro in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). Cell populations cultured in HSA demonstrated both increased proliferation, as measured by both [3H]dThd incorporation into DNA and [3H]dThd leukemic blast labeling index, and greater [3H] ara-C leukemic blast labeling index relative to cells maintained in APS. HSA-cultured marrow cells from the 31 patients who achieved complete remission with ara-C-containing therapy demonstrated enhanced intracellular formation of ara-C 5'-triphosphate over three hours and retention of this active form during one subsequent hour in drug-free medium relative to cells maintained in APS. In contrast, cells from the 14 nonresponsive patients demonstrated no such HSA-induced increases in intracellular ara-C metabolism. These studies of human AML marrow cells identify behavior patterns of ara-C activation and net metabolism in the kinetically perturbed, proliferative state that may discriminate clinical sensitivity from clinical resistance to ara-C-based timed sequential therapy. Sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA-perturbed growth and pharmacologic parameters, while refractory cells demonstrate uncoupling of these determinants in the growth-stimulated state. These in vitro measurements may further serve as a template for prediction of clinical outcome to timed sequential therapy with ara-C, where both pharmacologic and cytokinetic determinants of response are intrinsic to the success of the designed drug scheduling.
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PMID:Correlation of drug-perturbed marrow cell growth kinetics and intracellular 1-B-D-arabinofuranosylcytosine metabolism with clinical response in adult acute myelogenous leukemia. 347 54

The cytotoxic effect of cytosine arabinoside (ara-C) depends on the capacity of cells to form and retain intracellularly the phosphorylated metabolite cytosine arabinoside triphosphate (ara-CTP). In this study accumulation and cellular retention of ara-CTP have been measured in vitro in the bone marrow cells of 69 patients with acute leukemia. Cells were incubated with 3H-ara-C and the amount of ara-CTP formed was determined after separation of the nucleotides by thin-layer chromatography. Phosphorylation of ara-C to ara-CTP appeared to be a saturable process. The Km-equivalents varied between 1.1 and 16.2 microM ara-C. Maximal ara-CTP formation ranged from 12 to 125 pmol ara-CTP/10(6) cells in 30 min. The phosphorylation activity did not correlate with the percentage of S-phase cells. The intracellular half-life time of ara-CTP measured in vitro ranged from 53 to 210 min. Phosphorylation of ara-C was comparable in patients with acute myeloid leukemia (n = 51) and in patients with acute lymphoblastic leukemia (n = 18). Ara-CTP elimination appeared slower in lymphoblasts than in myeloblasts. The average intracellular ara-CTP level in relapsed patients (n = 34) appeared higher than in previously untreated patients (n = 52). The less favourable outcome of second remission induction therapy with conventional doses of ara-C compared to the first remission induction treatment is not explained by an alteration in the intracellular metabolism of ara-C.
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PMID:In-vitro studies on phosphorylation and dephosphorylation of cytosine arabinoside in human leukemic cells. 347 May 78

The relationship between in vitro leukemic cell growth kinetics, intracellular biochemical pharmacology of 1-beta-D-arabinofuranosylcytosine (ara-C), and clinical response to ara-C-containing timed sequential therapy was examined in leukemic marrow populations from 62 adults with acute myelogenous leukemia (AML). Leukemic blasts from 45 previously untreated and 17 relapse patients were obtained before therapy, and cultured in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). While all cell populations cultured in HSA demonstrated increased proliferation, only growth-stimulated cohorts from those patients achieving complete remission with ara-C-based therapy demonstrated enhanced intracellular drug activation and active drug retention relative to cells maintained in APS, whereas cells from nonresponsive patients demonstrated no such HSA-induced increases in intracellular ara-C metabolism. In this in vitro model system, sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA-perturbed growth and net pharmacologic parameters, while refractory cohorts evince uncoupling of these determinants in the growth-stimulated state. This model identifies behavior patterns that may discriminate clinical sensitivity from clinical resistance and may serve to predict clinical outcome to timed sequential therapy with ara-C.
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PMID:An in vitro model to predict clinical response in adult acute myelogenous leukemia. 347 76


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