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Biomedical subjects

M J Keating

Publications and source records attributed to M J Keating.

At least 217 records · Page 12Linked to original sources
PubMed1990

Stimulation of myelopoiesis in chronic lymphocytic leukemia and in other lymphoproliferative disorders by recombinant human granulocyte-macrophage colony-stimulating factor.

In an attempt to stimulate granulopoiesis, we administered recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to 11 patients with lymphoproliferative disorders. Ten patients had neutropenia, six of whom had severe neutropenia (less than 500 neutrophils), including two with agranulocytosis. GM-CSF (60-250 micrograms/m2/day) was administered by continuous intravenous infusion daily for 14 days at 2-week intervals. Significant increases in white blood cell counts (1.3-to 11.7-fold) and neutrophils (1.7- to more than 29-fold) were seen in 10 of 11 patients, including one patient with agranulocytosis. Eosinophils (3.9- to greater than 65-fold) and monocytes (1.3- to 5-fold) increased as well. In contrast, no significant increases were seen in total lymphocytes or in different phenotypic subsets of lymphocytes during treatment. The overall proportion of myeloid and lymphoid elements in bone marrow remained stable. These results indicate that GM-CSF is effective in stimulating myelopoiesis in neutropenic states associated with lymphoproliferative disorders. Further studies will be necessary to determine whether the correction of neutropenia ultimately translates into clinical benefit.

Bone Marrow↗
PubMed1990

Treatment of poor-prognosis, newly diagnosed acute myelogenous leukemia with high-dose cytosine arabinoside (Ara-C) and rHUGM-CSF.

We gave 4 days of high-dose Ara-C followed 2 days later by rHUGM-CSF (which continued until the neutrophil count was greater than 1000/microliters) to 12 patients with newly diagnosed AML and a relatively poor prognosis. Six CRs occurred, there were four deaths during induction, and in only one case was there an rHUGM-CSF-associated growth of leukemia. The pattern of hematologic recovery was variable but in some patients rHUGM-CSF seemed to accelerate normal myelopoiesis following chemotherapy. Continued investigation of rHUGM-CSF and chemotherapy in AML is warranted.

Aged↗
PubMed1990

Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia.

PURPOSE: Several prognostic models or staging systems have been published that identify different risk groups in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). The aims of this study were (1) to test, in an independent population, the prognostic reproducibility of these staging systems; and (2) to develop a synthesis staging system that could be easily applied in clinical practice. PATIENTS AND METHODS: A total of 406 patients with newly diagnosed Ph-positive CML were evaluated by the four published staging systems of Tura, Cervantes, Sokal, and our group. The proposed synthesis staging system was developed based on the most consistent prognostic characteristics, and the presence or absence of accelerated disease features at diagnosis. The staging systems were compared according to survival outcome, as well as by looking for differences of survival outcomes within a specific stage of a defined system, when patients in this stage were subclassified by a second staging system. RESULTS: Whereas the staging system of Cervantes et al identified only two prognostic groups (median survivals of 49 versus 40 months; p = 0.01), the remaining three staging systems were able to segregate patients into stage 1, 2, and 3 risk groups with respective median survivals of 56 to 57, 41 to 42, and 28 to 36 months, respectively (p less than 0.001 to p less than 0.002). The new proposed staging system, based on the existence of zero to one (stage 1), two (stage 2), or three or more unfavorable (stage 3) characteristics, or the presence of accelerated disease features (stage 4), categorized patients into four prognostic groups with median survivals of 56, 45, 30, and 30 months, respectively (p less than 0.001), the latter stage (stage 4) being associated with a higher one-year mortality rate (29%). The synthesis staging system was also able to subclassify patients within most of Tura's and Sokal's stages into significantly different prognostic groups by survival outcome. CONCLUSION: The predictive prognostic capacity of three of the four published staging systems was confirmed in this independent or test population. The new proposed staging system was superior to the staging systems of Tura and Sokal in identifying different prognostic subgroups.

Humans↗
PubMed1990

The importance of cytogenetic studies in adult acute lymphocytic leukemia.

PURPOSE: The prognostic importance of pretreatment bone marrow cytogenetic studies in adults with acute lymphocytic leukemia treated at a single institution, with an identical treatment program, is described. PATIENTS AND METHODS: A total of 105 patients with a documented morphologic diagnosis of acute lymphocytic leukemia were reviewed for the purpose of this analysis. All patients had an extensive workup at presentation, and cytogenetic analysis was performed in 103 patients, using the Giemsa banding technique with trypsin pretreatment on 24-hour cultured cells. RESULTS: The specific cytogenetic classification in the 103 patients who had the karyotypic analysis was as follows: diploid 27%; Philadelphia chromosome-positive 13%; hyperdiploid 12%; B-cell karyotype 6%; 6q- and 14q+ abnormalities 4%; pseudodiploid 8%; hypodiploid 2%; and insufficient metaphases 28%. B-cell, 6q- or 14q+, and Philadelphia chromosome-positive karyotypes tended to correlate with other known negative prognostic factors. Patients with diploid, hyperdiploid, pseudodiploid, and hypodiploid karyotypes or with insufficient metaphases could be combined into one group with a favorable prognosis. In this group, the remission rate with induction chemotherapy was 89%, the median complete remission duration was 26 months, and the median survival was 25 months, with a 3-year survival rate of 45%. Patients with Philadelphia chromosome-positive, B-cell, and 6q- or 14q+ abnormalities collectively had an unfavorable prognosis. Their response rate to induction chemotherapy was 65%, the median response duration was 7 months, and the median survival was 8 months, with a 3-year survival rate of less than 10%. CONCLUSION: We conclude that the pretreatment bone marrow karyotype is an important part of the evaluation of adults with acute lymphocytic leukemia and provides significant prognostic information.

Adolescent↗
PubMed1990

Nutritional deficiencies in patients receiving cancer chemotherapy.

Cancer often causes malnutrition and specific vitamin and protein deficiencies. Chemotherapy also causes deficiencies by promoting anorexia, stomatitis, and alimentary tract disturbances. Antimetabolite drugs in particular inhibit synthesis of essential vitamins, purines, and pyrimidines. Because vitamin levels in the blood are often nondiagnostic, nutritional deficiency is identified almost exclusively on the basis of clinical signs and symptoms and the patient's response to therapy. Signs and symptoms of cachexia and hypoalbuminemia are common in patients with advanced cancer. Deficiencies of vitamins B1, B2, and K and of niacin, folic acid, and thymine also may result from chemotherapy. Nutritional deficiencies are chemically correctable; however, the tumor must be eradicated to relieve cachexia.

Antineoplastic Agents↗
PubMed1990

Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.

The National Cancer Institute (NCI) sponsored a workshop to develop a set of standardized diagnostic and response criteria for acute myeloid leukemia (AML) clinical trials. The French-American-British (FAB) classification was retained for diagnosing AML, with the addition of patients with bone marrow morphologic features of a myelodysplastic syndrome and less than 30% bone marrow blasts, but with greater than or equal to 30% blasts in the peripheral blood. In this report, there are four important subgroups of AML not defined in the FAB classification that are discussed: undifferentiated acute leukemia, MO (AML lacking definitive myeloid differentiation by morphology or conventional cytochemistry but with ultrastructural or immunophenotypic evidence for AML), mixed lineage leukemia, and hypocellular AML. Definitions of response for clinical trials are presented to facilitate comparisons among different studies. Complete remission is considered the only response worth reporting in phase III trials, since lesser responses do not improve survival. Partial remissions may be of interest to identify active new agents in phase I and II studies. Monoclonal antibodies and cytogenetic studies are not part of the routine assessment of remission or reassessment at relapse, and their role in the evaluation of patients with AML is currently being evaluated in clinical trials. Although we recognize that some of the definitions in this report are arbitrary, generalized use of these guidelines will make results of clinical trials more comparable and interpretable.

Antibodies, Monoclonal↗
PubMed1990

Results of the vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and high-risk acute lymphocytic leukemia.

One hundred five untreated adult patients with acute lymphocytic leukemia (ALL) were entered on the vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and Decadron (dexamethasone; Merck Sharp and Dohme, West Point, PA) (VAD) regimen. Induction therapy with VAD and VAD plus cyclophosphamide (CVAD) was followed by a 2-year rotating maintenance program with multiple antileukemic combinations, and included early intensifications with Adriamycin and high-dose cytarabine (ara-C) and a late intensification with cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) followed by autologous bone marrow transplantation (BMT). Duration of therapy was 24 to 30 months. Eight-eight patients (84%) achieved complete remission (CR) with VAD-CVAD, and 94 (90%) ultimately had CR with continuation of the maintenance as planned. Induction mortality was 3%; only half of the patients required prolonged hospitalization of 1 week or longer, or intravenous antibiotics. Maintenance therapy was given to 79 patients, while nine with histocompatibility locus antigen (HLA)-matched related donors underwent allogeneic BMT. The median remission duration was 22 months, and the median survival was 19 months. Factors associated with significantly worse CR rates were older age, the presence of hypoalbuminemia or hyperbilirubinemia, L2 or L3 morphology, and myeloid markers on leukemic cells. Those associated with significantly worse remission durations were the presence of elevated leukocyte or absolute peripheral blast counts, Philadelphia chromosome (Ph)-positive or B-cell ALL, L2 morphology, and more than one course to achieve CR. Patients could be divided into standard-risk ALL (28% of patients) and high-risk ALL (72% of patients) with long-term remission rates of 70% versus less than 30%. The 26 patients who underwent CBV autologous BMT had similar long-term outcome compared with 21 patients who did not (older age, medical contraindications, or socioeconomic problems). The presence or absence of myeloid markers on leukemic cells did not affect long-term prognosis. We conclude that VAD therapy is a well-tolerated effective induction regimen. High-risk ALL patients require alternative maintenance investigational approaches.

Adolescent↗
PubMed1990

Formulary decision making in a specialty hospital: effective management of potent and costly drug therapies.

Substantial progress has been made in the treatment of cancer in the past few decades. Complex drug therapy regimens, supportive-care therapies, and therapeutic complications--namely, infection--have made clinical management challenging, however. In this exclusive Hospital Formulary interview, Michael Keating, MD, and William Dana, PharmD, Chairman and Secretary, respectively, of the University of Texas M.D. Anderson Cancer Center's P & T Committee, discuss successful methods of maintaining an effective formulary in a cancer center. Although efficacy and toxicity of therapy remain the primary considerations when evaluating drugs, with a formulary weighted with cancer chemotherapeutic agents, antibiotics, and other supportive intravenous formulations, cost is also critical. These health professionals describe how they balance the issues associated with rational, yet cost-effective drug therapy.

Antineoplastic Agents↗
PubMed1990

Fludarabine phosphate in the treatment of chronic lymphocytic leukemia.

Fludara I.V. (fludarabine phosphate) is a purine analogue that has been synthesized and found to have activity in lymphoid neoplasms in phase I and II studies. Fludara I.V. has been used extensively in the management of chronic lymphocytic leukemia in the last 5 years. In studies of Fludara I.V. as a single agent, the response rate was 59% in 78 patients. The true complete remission (CR) rate (no evidence of disease) was 13% with 16% having a CR with persistent lymphoid nodules. These patients are considered to be in CR using the National Cancer Institute Working Group Guidelines. The other patients (31%) achieved a partial remission (PR). Fludara I.V. has also been used as a single agent in previously untreated patients. Thirty (83%) of the 36 patients obtained a complete or partial response. Thirty-six percent of the patients achieved a true CR and 39% a CR with persistent lymphoid nodules in the bone marrow. Thus, the complete remission rate was 75%. Fludara I.V. has now been combined with prednisone in the management of 101 previously treated patients with chronic lymphocytic leukemia. Fourteen percent of patients have achieved a true CR, 24% a nodular CR, and 19% a PR. The results were very similar to those obtained with Fludara I.V. as a single agent. Other investigators have explored Fludara I.V. by continuous infusion. Twenty-two of 42 evaluable patients, in that study, achieved a PR. Fludara I.V. had minimal evidence of toxicity except for episodes of fever. The episodes of fever were more common in patients who had received previous treatment and had stage III or IV disease according to the Rai staging system. Some of these episodes of fever were associated with pneumonia. It appears that the spectrum of organisms causing the febrile episodes is that usually associated with immune deficiency (monocyte or T-cell deficiency). Future studies with Fludara I.V. will explore different schedules and combination approaches.

Antimetabolites, Antineoplastic↗
PubMed1990

Fludarabine phosphate therapy in other lymphoid malignancies.

The promising results obtained with Fludara I.V. (fludarabine phosphate) treatment in the common indolent B-cell neoplasms have led to their further evaluation in other unusual B-cell malignancies, in Hodgkin's disease, and in T-cell diseases. A significant response rate has been found among patients with macroglobulinemic lymphoma, those with prolymphocytic leukemia or prolymphocytoid variant of chronic lymphocytic leukemia, and those with mycosis fungoides. The limited therapeutic data in hairy-cell leukemia and in Hodgkin's disease are also interesting.

Antimetabolites, Antineoplastic↗
PubMed1990

Cellular ara-CTP pharmacokinetics, response, and karyotype in newly diagnosed acute myelogenous leukemia.

We evaluated relationships between ara-CTP pharmacokinetics in myeloblasts, response, and karyotype in 147 patients with newly diagnosed AML treated on three protocols each initiated by a 3 g/m2 ara-C dose given over 2 h. Area under the curve of ara-CTP concentration times time (AUC) or peak ara-CTP concentration after this dose did not predict response or response duration, suggesting that inability to form ara-CTP is an unlikely mechanism of ara-C resistance. Following high-dose bolus ara-C therapy patients with INV [16] or del [16q] had long remissions despite low AUC and peak values while patients with -5, del [5q], -7, or del [7q] were frequently resistant despite average AUC and peak values. In 55 patients treated with high-dose continuous infusion ara-C as a single agent, steady-state ara-CTP concentrations were significantly lower in resistant patients (who again were disproportionately those with -5, del [5q], -7, or del [7q]) although there was no correlation with CR duration.

Amsacrine↗
PubMed1989

Modulation of arabinosylcytosine metabolism by arabinosyl-2-fluoroadenine in lymphocytes from patients with chronic lymphocytic leukemia: implications for combination therapy.

Our previous studies indicated that K562 cells loaded with arabinosyl-2-fluoroadenine 5'-triphosphate (F-ara-ATP) accumulated arabinosylcytosine 5'-triphosphate (ara-CTP) at a threefold higher rate compared to the control cells. In the present study lymphocytes were obtained from patients with chronic lymphocytic leukemia before and after F-ara-A monophosphate therapy. The rate of ara-CTP accumulation after in vitro ara-C incubation was compared in lymphocytes obtained prior to therapy without any other manipulation, after ex vivo F-ara-ATP (100 mumol/L) treatment, and after in vivo F-ara-A monophosphate therapy. Lymphocytes showed a 2.2-fold (n = 23) and 1.7-fold (n = 23) median increase in the cellular concentration of ara-CTP after an ex vivo incubation with 100 mumol/L F-ara-A and 20 to 24 hours after the first dose (25 or 30 mg/m2) of F-ara-A monophosphate in vivo treatment, respectively. Although the rates of F-ara-ATP and ara-CTP accumulation varied among patients, a relationship was observed in individuals between the cellular concentration of F-ara-ATP at the beginning of the ara-C incubation and ara-CTP accumulation. These studies strongly suggest that a protocol designed to administer F-ara-A monophosphate prior to ara-C infusion will augment ara-CTP accumulation by leukemia cells.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Environmental exposures in cytogenetically defined subsets of acute nonlymphocytic leukemia.

Three previous investigations have reported a relationship between clonal chromosome abnormalities in marrow of patients with acute nonlymphocytic leukemia and employment in occupations involving mutagenic chemicals, but the effects of other exposures were not described. Environmental exposure profiles, gathered by questionnaire, were therefore compared using a case-control study design in 235 newly diagnosed patients with acute nonlymphocytic leukemia: 126 with abnormal and 109 with normal karyotypes. The univariate odds ratio for occupation at diagnosis was 4.6, which, when adjusted for demographic and other exposures by logistic regression, was reduced to 2.5 (95% confidence interval, 0.5 to 12.8). Adjusted point estimates for other exposures were 4.3 (1.4 to 13.3) for prior cytotoxic therapy, 1.7 (0.9 to 3.1) for cigarette smoking, and 1.9 (1.0 to 3.4) for alcohol use. Dose-response relationships were present for both tobacco and alcohol consumption. Associations between specific abnormalities (+8, -7I-7q, [corrected] inv16, t[8;21]) and certain exposures were also present. These results suggest that life-style exposures may be associated with cytogenetic lesions in persons with acute nonlymphocytic leukemia.

Alcohol Drinking↗
PubMed1989

Experience with vincristine, doxorubicin, and dexamethasone (VAD) chemotherapy in adults with refractory acute lymphocytic leukemia.

Sixty-four adult patients with refractory acute lymphocytic leukemia (ALL) received salvage therapy with the vincristine, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), and dexamethasone (VAD) regimen consisting of induction chemotherapy with the three agents followed by multiple-agent maintenance therapy for 2 years. Overall, 25 patients (39%) achieved complete remission. The median remission duration was 28 weeks with 20% of these patients remaining disease-free at 2 years. The median overall survival was 23 weeks. Prognostic factors associated with differences in remission rates included patient performance status, hemoglobin and platelet levels, and degree of peripheral and marrow blastosis. Factors related to differences in survival were patient age and performance status, hemoglobin and platelet levels, percentage of peripheral blasts, and albumin and bilirubin levels. The toxicity of the regimen was minimal, with 33% of patients requiring hospitalization because of febrile episodes of unknown origin (17%) or documented infections (16%). Therapy-related mortality occurred in four patients (6%). We conclude that the VAD program has significant antileukemic efficacy and acceptable toxicity in adult salvage ALL.

Adolescent↗
PubMed1989

Phase II study of low-dose continuous infusion homoharringtonine in refractory acute myelogenous leukemia.

Thirty-one patients with a diagnosis of refractory acute myelogenous leukemia received homoharringtonine as their first (15 patients) or second (16 patients) salvage therapy. Homoharringtonine was given as a continuous infusion of 2.5 mg/m2 daily for 15 to 21 days to 13 patients (schedule 1), and of 3.0 mg/m2 daily for 15 days in 18 patients (schedule 2). Overall, one patient achieved complete remission (3%), and three (10%) had a hematologic improvement with normalization of the marrow and peripheral blood picture except for persistent thrombocytopenia. Six patients (19%) demonstrated prolonged myelosuppression, three (23%) on schedule 1 and three (17%) on schedule 2. Cardiovascular complications were minimal consisting of hypotension in one patient (3%) and supraventricular arrhythmias in two patients (6%). Hyperglycemia was observed in 42% of patients and was significant in 10%. The authors conclude that homoharringtonine, at the dose schedule investigated, has definite but low antileukemic efficacy. The low-dose continuous infusion schedule was associated with prolonged myelosuppression but no serious cardiovascular complications. The role of such therapy in myeloproliferative disorders, especially chronic myelogenous leukemia, deserves consideration.

Adult↗