Chemotherapy in acute myelogenous leukemia: high dose, higher expectations?
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Age Factors↗
Biomedical subjects
E Berman
Publications and source records attributed to E Berman.
Evaluation of the nephrotoxicity of complex mixtures containing organics and metals: advantages and disadvantages of the use of real-world complex mixtures.
As part of a multidisciplinary health effects study, the nephrotoxicity of complex industrial waste mixtures was assessed. Adult, male Fischer 344 rats were gavaged with samples of complex industrial waste and nephrotoxicity evaluated 24 hr later. Of the 10 tested samples, 4 produced increased absolute or relative kidney weight, or both, coupled with a statistically significant alteration in at least one of the measured serum parameters (urea nitrogen (BUN), creatinine (CREAT), and BUN/CREAT ratio). Although the waste samples had been analyzed for a number of organic chemicals and 7 of the 10 samples were analyzed also for 12 elemental metals and metalloids, their nephrotoxicity was not readily predicted from the partial chemical characterization data. Because the chemical form or speciation of the metals was unknown, it was not possible to estimate their contribution to the observed biological response. Various experimental approaches, including use of real-world complex mixtures, chemically defined synthetic mixtures, and simple mixtures, will be necessary to adequately determine the potential human health risk from exposure to complex chemical mixtures.
Animals↗
A phase II study of continuous infusion of trimetrexate in patients with refractory acute leukemia.
Trimetrexate, a second-generation folate antagonist, is a potent inhibitor of dihydrofolate reductase with a broader spectrum of activity and different mechanism of entry and intracellular accumulation than methotrexate. Six patients with refractory or relapsed acute leukemia were treated with a 5-day continuous infusion of trimetrexate of 8 mg/m2/day after an initial loading dose of 4 mg/m2 to achieve a target plasma concentration of 0.2-0.5 microM. In 4 patients with peripheral blasts at study entry, transient decrease or disappearance of blasts was observed, although no decrease of bone marrow blasts occurred. Mucositis was dose-limiting and severe in 4 patients. Neutrophil and platelet nadirs occurred on day 5-12 postinfusion. Because of dose-limiting mucositis, this dose schedule of trimetrexate is not recommended for further studies in refractory acute leukemia. However, other dose schedules (24- to 72-hr infusions) and its use as a modulating agent with thiopurines or leucovorin in patients that are resistant to methotrexate should be explored.
Adult↗
Myocardial protection by warm blood cardioplegia. A 31P nuclear magnetic resonance spectroscopy study of an isolated perfused rat heart.
OBJECTIVE: A study of the protective efficiency imparted by intermittent warm blood cardioplegia (WBCP) using perfused rat heart model. METHODS: Hemodynamic parameters were monitored simultaneously with metabolic changes in high-energy phosphates using 31P-NMR spectroscopy. Following 30 min perfusion with Krebs-Henseleit (KH) buffer, all hearts were arrested for one hour (G1 and G2) and than reperfused with KH for 30 minutes. A warm oxygenated crystalloid cardioplegia (WCCP, modified St Thomas' hospital solution) was used for the control group (G1). The second group of hearts (G2) were arrested with oxygenated WBCP (K+ = 15 mM; Hct = 15-20%) and the third group (G3), was subjected to a protocol consisting of 4 periods (10 min each) of WBCP interspersed by 10 min of global ischaemia. RESULTS: The post-arrest percentage recoveries of LVDP, +dP/dt and HR were respectively: 88, 93 and 90 for G1 (n = 8); 97, 100 and 98 for G2 (n = 10); 76, 79 and 91 for G3 (n = 12). The corresponding metabolic recoveries of ATP and PCr were respectively, 85 and 90 for G1; 91 and 98 for G2 and 73 and 85 for G3. The PCr level declined during the arrest period in G1 contrasting with elevated PCr level (> 140%) during the WBCP arrest in G2. After an initial rise to approximately 140%, PCr level gradually decreased during the intermittent WBCP interval (G3). CONCLUSIONS: At normothermia, with equal CF rates, continuous WBCP provides better myocardial protection, through an effective oxygen supply, compared with WCCP. During the intermittent periods of ischaemia, certain metabolic and hemodynamic dysfunction occurs.
Animals↗
Phase I trial of high-dose tamoxifen as a modulator of drug resistance in combination with daunorubicin in patients with relapsed or refractory acute leukemia.
Tamoxifen and its main metabolite N-desmethyltamoxifen (NDMTmx) have been shown to increase intracellular daunorubicin (DNR) levels in human leukemia cell lines that display the multidrug resistant (MDR) phenotype. We designed a phase I dose escalation study of Tmx (200-700 mg/day p.o. for 7 days) in combination with a fixed dose of DNR (50 mg/m2 intravenously on days 5, 6 and 7) in patients with advanced leukemia to determine whether this combination could be given safely and whether plasma levels of 10 microM, the effective in vitro MDR modulator concentration, could be achieved. Pharmacologic studies of Tmx, NDMTmx and DNR, and its main metabolite daunorubicin-ol (DNR-ol) were performed as was determination of P-glycoprotein (Pgp) using a monoclonal antibody that recognizes an external epitope of the molecule. A total of 14 patients (median age 50, range 22-67) were treated at the following dose levels: 200 mg/day: three patients; 400 mg/day: four patients; 550 mg/day: three patients; and 700 mg/day: four patients. Two patients with relapsed AML achieved remission. Toxicity of the combination was similar to that seen with DNR alone and no severe hepatic, cardiac or retinal toxicity was noted. Plasma Tmx levels approached 7 microM at the two highest dose levels studied; plasma levels of NDMTmx were slightly less. The area under the curve for DNR and its main metabolite daunorubicin-ol (DNR-ol) did not show significant changes with escalation of Tmx dose. This phase I study suggests that concentrations of Tmx high enough to reverse the MDR phenotype can be approached and that the combination of high-dose Tmx with a standard dose of DNR has an acceptable toxicity profile. More evaluation in phase II studies is necessary to define further its role as an MDR modulator.
Adult↗
Familial acute myeloid leukemia and DiGuglielmo syndrome.
A family is described in which two sisters developed acute myeloblastic leukemia (AML FAB M2) and erythroleukemia (FAB M6) at ages 60 and 53, 15 years apart. Their father was diagnosed as having chronic erythremic myelosis (DiGuglielmo syndrome) 24 years earlier at age 56. Cytogenetic analysis of bone marrow blasts in the patient with AML M2 revealed a complex hyperdiploid karyotype with clonal abnormalities -3, -5, del(5)(q13q23), -8, +i(8)(q10), -11, add(11) (q23), add(12)(p13), -13, +3mar. No environmental risk factors could be identified. Hematologic and cytogenetic analysis of all living first degree relatives of the affected persons revealed hematological abnormalities, but normal constitutional karyotypes of peripheral blood lymphocytes and no induction of cytogenetic abnormalities in folate deficient medium.
Aged↗
Confusion of tongues.
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Attitude to Death↗
Optical spectroscopy and scintillation mechanisms of CexLa1-xF3.
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Journal Article↗
All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study.
OBJECTIVE: To evaluate the safety and efficacy of all-trans retinoic acid to induce complete remission and to examine its effects on duration of remission and survival in patients with acute promyelocytic leukemia. DESIGN: Phase II evaluation and comparison with historical control patients. SETTING: Tertiary care cancer referral center. PATIENTS: Consecutive patients with morphologic diagnoses of acute promyelocytic leukemia were treated during a 2-year period with all-trans retinoic acid (daily oral dose, 45 mg/m2). Newly diagnosed patients discontinued the drug approximately 30 days after they achieved complete remission, at which time they received three courses of combination chemotherapy. Patients treated with previous cytotoxic chemotherapy who then relapsed were continued on all-trans retinoic acid as "maintenance" therapy until they relapsed again. RESULTS: 56 patients entered the study: 34 were newly diagnosed and 22 had relapsed from previous treatment. Fifty-one patients subsequently were found to have the PML/RAR-alpha gene rearrangement indicative of acute promyelocytic leukemia, and 44 of these patients achieved complete remission (86%; 95% Cl, 76% to 96%). A distinctive respiratory distress syndrome developed in 13 patients (23%) during treatment, and 5 patients (9%; Cl, 3% to 20%) died of this complication. The 5 patients who lacked PML/RAR-alpha rearrangements were withdrawn and given chemotherapy. The 13 patients given all-trans retinoic acid alone as maintenance therapy (10 of whom had relapsed from a chemotherapy-induced remission) had a median duration of remission of only 3.5 months (range, 1 to 23 months). Only 3 of 19 patients who relapsed from a remission induced by all-trans retinoic acid could be brought into remission again using this drug. The median survival time of all newly diagnosed patients has not been reached, but it now exceeds 31 months (range, 0.4 to 36+ months). No decrease in the early mortality rate was observed compared with a historical control group composed of 80 consecutive, newly diagnosed patients treated only with chemotherapy at this center; however, overall survival was superior. CONCLUSIONS: All-trans retinoic acid is an effective agent to induce remission in patients with a molecular diagnosis of acute promyelocytic leukemia, but remissions are short and resistance develops rapidly. Although the incidence of early death was not reduced, the use of all-trans retinoic acid to induce remission, followed by cytotoxic chemotherapy for "consolidation," was associated with longer survival times when compared with historical controls treated only with chemotherapy. Additional studies to prevent or mitigate consequences of the "retinoic acid syndrome" and to identify specific patients who might benefit from earlier intervention with chemotherapy are needed to maximize the advantages of this approach.
Adolescent↗
Comparative activity of tamoxifen and N-desmethyltamoxifen in human multidrug resistant leukemia cell lines.
Tamoxifen (Tmx) is one of a number of agents that can reverse the multidrug resistant (MDR) phenotype in vitro; it is unique, however, in that both the parent compound and the main metabolite, N-desmethyltamoxifen (NDMTmx), have long plasma half-lives, 7 and 14 days, respectively. To determine whether NDMTmx was as active as the parent compound in restoring sensitivity to daunorubicin (DNR) in vitro, we performed uptake and retention studies in the MDR-positive human leukemia cell lines CEM-VLB and HL-60/RV+ using laser flow cytometry to quantitate intracellular DNR concentration. Cells incubated with DNR and NDMTmx 10 microM demonstrated increased intracellular DNR levels that were very similar to those obtained with DNR and Tmx 10 microM. Cellular retention of DNR was also measured after incubation with Tmx 10 microM or NDMTmx 10 microM and resuspension in fresh medium containing Tmx or NDMTmx in order to stimulate in vivo conditions. Washout curves in both cell lines were similar with both Tmx and NDMTmx. Finally, clonogenic experiments were performed to determine whether Tmx and NDMTmx demonstrated the same degree of cytotoxicity. The combination of Tmx 10 microM plus DNR and that of NDMTmx 10 microM plus DNR each resulted in > 80% growth inhibition. These results suggest that NDMTmx is as active as Tmx in restoring sensitivity to DNR in vitro, a finding which may have important implications in clinical trials that assess the ability of Tmx to reverse the MDR phenotype.
Daunorubicin↗
Concomitant administration of chlorambucil limits dose intensity of fludarabine in previously treated patients with chronic lymphocytic leukemia.
Fifteen patients with chronic lymphocytic leukemia (CLL) were treated in a phase I-II study of chlorambucil with an escalating dose of fludarabine. The study was designed to identify a maximum tolerated dose (MTD) of fludarabine given in conjunction with a constant dose of chlorambucil. Patients were eligible for study if they had Rai intermediate or high-risk disease which had relapsed from or was refractory to conventional treatment. The initial cohort of patients received fludarabine 10 mg/m2/d days 1-5 and chlorambucil 20 mg/m2 days 1 and 15. Cycles were repeated every 28 days. Unacceptable toxicity was encountered in this cohort. The protocol was then modified to give chlorambucil 20 mg/m2 on day 1 (only). At this chlorambucil dose, cohorts of three patients were treated with fludarabine 10, 15, and 20 mg/m2/d x 5 days. The predominant toxicity was thrombocytopenia with 73% experiencing grade > or = 3 toxicity. The dose-limiting non-hematologic toxicity was infection. We identified an MTD of fludarabine of 15 mg/m2/d x 5 days when given with chlorambucil 20 mg/m2 for this group of patients. One patient achieved a CR and three patients achieved a PR for a total response rate of 27%. We conclude that concomitant administration of chlorambucil limits the dose intensity of fludarabine which can be administered to previously treated patients with CLL.
Aged↗
Steroidogenic assessment using ovary culture in cycling rats: effects of bis(2-diethylhexyl)phthalate on ovarian steroid production.
In vitro ovary culture in rats was used to characterize ovarian steroidogenesis and to evaluate changes produced by in vivo exposure to bis(2-diethylhexyl)phthalate (DEHP). Steroid profiles [progesterone (P4), estradiol (E2), and testosterone (T)] from cultures of minced ovary were obtained in untreated immature and mature rats, and from mature rats treated with DEHP. A 1-h incubation without human chorionic gonadotropin (hCG) was used to produce an initial steroidogenic profile. Three 1-h incubations with hCG were used to produce a stimulated steroid profile. A combination of initial and stimulated ovarian steroid profiles was shown to correctly identify the stage of the cycle in all untreated rats, using multivariate statistical analysis. Separately, initial or stimulated ovarian steroid profiles correctly identified the stage of the cycle in more than 90% of the rats. The statistical analysis using a combination of variables (multivariate) indicated that DEHP-treated rats were significantly different (P < 0.001) from sham-treated rats. In fact, the alteration caused by DEHP in the in vitro ovarian steroidogenic profile was most apparent in rats during diestrus and estrus. In DEHP-treated rats in diestrus, ovarian steroidogenesis appeared to shift to the production of more T and more E2 than in untreated rats in diestrus. The change seen in steroid profiles in DEHP-treated rats in estrus is to decreased E2 production. The steroid profile from ovary culture in conjunction with vaginal cytology was very useful in correctly identifying in vivo DEHP-treated rats, and will be a useful in vitro technique in the evaluation of ovarian toxicants in cycling females.
Analysis of Variance↗
Parental and relationship representations and experiences of depression in college students.
Young adults' descriptions of their parents and their relationships with their parents were used to reexamine the relations between object representation and depressive experience. One hundred eight students completed (a) four open-ended descriptions, including two written descriptions of the parents (mother and father, separately), and two written descriptions of the relationships with the parents; and (b) the Depressive Experience Questionnaire. Each of the four open-ended descriptions was rated on seven scales. Factor analysis yielded four distinct factors from the 28 dimensions of the descriptions. These factors were related to: (a) the degree of elaboration and investment, (b) the structural level of the descriptions, (c) the affective tone of the description of the father, and (d) the affective tone of the description of the mother. Significant differences and interactions were found regarding the interplay between the specific significant other represented (father or mother) and the specific framework of representation (parent description or relationship description). Measures derived from parents' and relationship descriptions significantly predicted depressive experiences of self-criticism and dependency. The results indicate the advantages of a joint exploration of the representation of distinct significant others (mother and father) and the use of two modes of relatedness (describe parent and describe relationship with parent) in the process of personality assessment.
Adolescent↗
A review of idarubicin in acute leukemia.
Since the introduction of the anthracycline idarubicin for the treatment of acute myelogenous leukemia, clinicians have questioned whether it offers significant benefit over the standard anthracycline, daunorubicin. While the three prospectively randomized US trials that compared these two agents in adults with newly diagnosed disease differed somewhat, all reported an improved remission incidence in patients on the idarubicin arm, and two reported improved survival. Overall survival curves, however--albeit better on the idarubicin arm--are still depressingly low. Nonetheless, even if the compound represents only an incremental improvement, it gives more patients the opportunity for more intensive postinduction therapy, such as bone marrow transplantation, or innovative approaches to eradicating minimal residual disease, such as the use of recombinant interleukin-2. This article describes the mechanism of action and pharmacology of idarubicin and reviews the results of clinical studies to date in both acute myelogenous leukemia and acute lymphoblastic leukemia.
Adult↗
Severe toxicity limits intensification of induction therapy for acute lymphoblastic leukemia.
Fourteen adult patients with newly-diagnosed acute lymphoblastic, leukemia (ALL), and lymphoblastic lymphoma, were treated with a dose-intense induction regimen. This regimen was designed to increase the fraction of patients achieving an early complete remission, in an attempt to increase the fraction of patients who are long-term disease-free survivors. The induction regimen included vincristine, prednisone, intermediate-dose cytarabine (Ara-C), and idarubicin, all given during the first week of therapy. This combination led to significant hepatic, gastro-intestinal, infectious, and neurologic toxicity. There was unacceptable treatment-related mortality (29%). After the first eight patients, the study was modified, omitting the Ara-C from the induction phase. Gastrointestinal morbidity was less in the cohort treated without Ara-C; however, infectious morbidity persisted at unacceptable levels and this program was terminated as too toxic to administer. There were nine complete remissions, three early deaths, and two patients with resistant disease. There have been six relapses, three of which occurred in patients who, because of protracted grade III/IV toxicity, were no longer receiving chemotherapy. With a minimum follow-up of 20 months, only three patients are still alive. We conclude that this combination of vincristine, prednisone, Ara-C, and idarubicin, is too toxic to be used as induction therapy for adult patients with ALL and lymphoblastic lymphoma.
Adult↗
Defective transport as a mechanism of acquired resistance to methotrexate in patients with acute lymphocytic leukemia.
Although the mechanisms of resistance to methotrexate (MTX) are known in experimental tumors made resistant to this drug, little information is available regarding acquired resistance to MTX in patients. A competitive displacement assay using the fluorescent lysine analogue of MTX, N-(4-amino-4-deoxy-N10-methylpteroyl)-N epsilon-(4'-fluorescein-thiocarbamyl)-L-lysine (PT430), was developed as a sensitive method of detection of transport resistance to MTX in cell lines, as well as in blast cells from patients with leukemia. Rapid uptake of PT430 at high concentrations (20 mumol/L) in leukemic blasts resulted in achievement of steady-state levels within 2 hours. Subsequent incubation with the folate antagonists, MTX and trimetrexate (TMTX), which differ in the mode of carrier transport, produced characteristic patterns of PT430 displacement. Flow cytometric analysis of the mean fluorescence intensity in the human CCRF-CEM T-cell lymphoblastic leukemia cell line and its MTX-resistant subline clearly identified the presence of transport deficiency in the resistant subline. Analysis of blasts from 17 patients with leukemia, nine with no prior chemotherapy and eight previously treated with chemotherapy, found evidence of MTX transport resistance in two of the four patients who were treated with MTX and considered to be clinically resistant to the drug. The finding that blast cells of some patients with leukemia considered clinically resistant to MTX is due to decreased MTX transport has important implications for clinical use of this drug and for new drug development.
Adolescent↗
Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemia cells.
We examined the effect of daunorubicin (DNR), the new anthracycline derivative idarubicin (IDR), and verapamil on two leukemia cell lines that displayed the multidrug resistant (MDR) phenotype and used laser flow cytometry to quantitate intracellular anthracycline content. The vinblastine-resistant human lymphoblastic leukemia cell line CEM-VBL demonstrated minimal DNR uptake; simultaneous incubation with verapamil and DNR increased intracellular DNR uptake fourfold. IDR uptake was 10 times more rapid in these cells and simultaneous incubation with IDR and verapamil resulted in only a 1.2-fold increase of intracellular IDR. Similar results were observed in the vincristine-resistant human myeloid leukemia cell line HL-60/RV+. Intracellular retention of DNR and IDR was also measured in each cell line. In CEM-BVL cells, 38% of the original DNR concentration remained after a 2-hour resuspension in fresh medium compared with 71% of the original IDR concentration. In HL-60/RV+ cells, 36% of the DNR concentration remained compared with 51% of the IDR concentration. After incubation of CEM-VBL and HL-60/RV+ cells with DNR for 1 hour followed by resuspension in fresh medium plus verapamil, intracellular DNA retention increased 5- and 5.2-fold, respectively. However, incubation of these cells for 1 hour with IDR followed by resuspension in fresh medium plus verapamil resulted in only a 1.6- and 2.4-fold increase in intracellular IDR retention. Lastly, clonogenic experiments were performed to correlate intracellular anthracycline content with cytotoxicity. DNR alone had a minimal effect on the clonogenic growth of CEM-VBL cells, whereas the combination of DNR plus verapamil resulted in approximately 80% growth inhibition. However, incubation of these cells with IDR alone resulted in greater than 95% growth inhibition. These results suggest that IDR may be more effective than DNR in leukemia cells that display the MDR phenotype.
Cell Division↗
High incidence of disseminated intravascular coagulation during remission induction of adult patients with acute lymphoblastic leukemia.
We determined the incidence and complications of disseminated intravascular coagulation (DIC) at presentation and during remission induction of previously untreated adults with acute lymphoblastic leukemia (ALL) or de novo Philadelphia chromosome-positive ALL (PCALL) seen at Memorial Hospital between January 1, 1978 and December 31, 1989. DIC was diagnosed in the presence of (1) low fibrinogen (less than or equal to 160 mg/dL), (2) prolonged prothrombin time (PT) and falling fibrinogen, or (3) prolonged PT and positive fibrin split products (FSP). L-Asparaginase was not used during remission induction. Among adequately screened patients with ALL, DIC was detected in 7 of 58 (12%) before initiation of chemotherapy and in 35 of 45 (78%) during remission induction. DIC was not simply the result of infection because clinical and laboratory signs of infection were absent in 16 patients, whereas only 2 of the 22 febrile patients with DIC had positive cultures. Among the 38 patients with DIC at presentation or during remission induction, serious complications were seen in 13 in temporal association with DIC (pulmonary embolus in one, sagittal sinus thrombosis in three, and serious hemorrhage in nine) and were major factors in the deaths of three patients. Among the 10 patients with thorough screening but no evidence of DIC there was only one hemorrhage during the same time interval. In patients with PCALL, DIC was detected in 9% at presentation and in 80% during remission induction. We conclude that DIC is rare at presentation but common during remission induction of adult ALL and PCALL and may be associated with significant thrombotic and hemorrhagic complications. We suggest daily screening for DIC during the first 14 days of remission induction. The treatment of DIC in ALL and PCALL should be a subject of future clinical studies.
Adult↗