Evolution of clinical studies with high-dose cytosine arabinoside at the M.D. Anderson Hospital.
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Arabinofuranosylcytosine Triphosphate↗
Biomedical subjects
M J Keating
Publications and source records attributed to M J Keating.
Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival.
The prognostic importance of patient pretreatment clinical and laboratory features was investigated in a group of 303 patients with Philadelphia chromosome-positive benign-phase chronic myelogenous leukemia. Intensive chemotherapy was given to 97 patients, and 78 underwent an early elective splenectomy. The overall median survival time, dated from hospital admission, was 39 months. Patient characteristics associated with shortened survival were age 60 years or older, black race, the presence of hepatomegaly, splenomegaly, symptoms, weight loss, and poor performance status. Adverse blood and bone marrow parameters were anemia, thrombocytosis or thrombocytopenia, a high proportion of peripheral blasts plus promyelocytes or of basophils, a high proportion of marrow blasts or basophils, decreased marrow megakaryocytes, and cytogenetic abnormalities in addition to the Philadelphia chromosome. Several of these factors were interrelated. A multivariate regression analysis demonstrated that the combination blood basophilia, race, additional cytogenetic abnormalities, age and marrow basophilia had the strongest predictive relationship to survival time. This resulted in a model segregating patients into low-, intermediate-, and high-risk groups, with median survivals of 53, 39, and 25 months, respectively. Another model was derived that did not include the marrow features and identified splenomegaly and platelet counts as adding to the prognosis prediction by blood basophilia, race, and age. Evaluation of the effect of therapy, after adjusting for differences in prognostic characteristics, showed that intensive chemotherapy was associated with survival prolongation among patients at intermediate and high risk of death. We conclude that a combination of pretreatment factors identifies different risk subcategories in patients with chronic myelogenous leukemia and is helpful in assessing overall prognosis and treatment effect.
Adult↗
Preferential expression of double-stranded ribonucleic acid in tumor versus normal cells: biological and clinical implications.
In an effort to develop a new tumor marker suitable for flow cytometric analysis, we examined the value of double-stranded ribonucleic acid (ds-RNA) measurements using propidium iodide after DN'ase treatment. Cellular ds-RNA content was evaluated both in experimental cell lines and in clinical specimens. Higher levels of ds-RNA were present in tumor cells as compared with normal cells. In tumor cells, fluorescence was intensely localized in the nucleolus and was more diffuse in the cytoplasm. Change of less than 10% in the ds-RNA levels was observed in cell lines as a function of cytokinetic determinants such as cycle phase, culture age, and cycle traverse rate. Tumor differentiation by dimethylsulfoxide resulted in a significant decrease in cellular ds-RNA content. For quantitative comparison of clinical material, a ds-RNA excess was defined in relationship to normal peripheral blood lymphocytes. ds-RNA excess greater than 30% was observed in only one of 34 normal tissues (3%) as compared with 124 of 201 neoplastic tissue samples (62%). This incidence was higher in patients with acute leukemia (76%), high-grade and intermediate-grade lymphoma (75%), and high tumor stage myeloma (83%), as compared with chronic leukemia (20%), low-grade lymphoma (25%), and intermediate or low tumor mass myeloma (43%). Prognostically, a high pretreatment ds-RNA excess in myeloma was associated with a lower remission rate. The persistence of ds-RNA excess in the bone marrow of patients with acute myelogenous leukemia in remission predicted for a shorter remission duration (seven v 22 months; P = .05). We conclude that ds-RNA excess, as readily measured objectively and quantitatively by flow cytometry, may have important diagnostic and prognostic implications for the management of patients with malignant disease.
Animals↗
Pharmacologically directed ara-C therapy for refractory leukemia.
During a two-year experience treating patients with refractory acute leukemia with a fixed 12-hour schedule of high-dose ara-C, cellular ara-CTP pharmacodynamics were ascertained in circulating blasts of these patients. A strong correlation was found between achievement of complete remission and cellular ara-CTP levels. We therefore, attempted to improve the complete remission rate in patients with low ara-CTP levels by decreasing the intermittent ara-C dosing interval, thereby raising the minimum ara-CTP level in leukemic cells between doses. This initial attempt at pharmacologic direction of chemotherapy was successful in elevating minimum ara-CTP levels but did not produce an increase in response rate, probably because the total duration of ara-CTP exposure was decreased when the dose intervals were shortened. Currently we are engaged in a new approach based on the knowledge accumulated over the past three years. Patients receive a test ara-C dose from which data on ara-CTP cellular metabolism is derived, followed by a CI of ara-C at a dose calculated individually for each patient. Preliminary results of this approach thus far indicate an increased response rate and a different spectrum of toxicity than that observed with intermittent dose ara-C. Further clinical trials will determine the true effectiveness of this approach.
Arabinofuranosylcytosine Triphosphate↗
Prognostic factors in hairy cell leukemia (leukemic reticuloendotheliosis).
Prognostic factors were examined in 31 patients with hairy cell leukemia seen at M. D. Anderson Hospital. Long survival from presentation was significantly associated with ease of aspiration of iliac crest bone marrow, absence of major infection, hemoglobin greater than 10 g/dl, and absence of a prior history of pneumonia. Long survival from splenectomy was associated most closely with absence of a prediagnosis history of pneumonia, suggesting that a long-standing host defense abnormality may exist that is not corrected by splenectomy. Generally, patients with sustained improvement in hematologic parameters postsplenectomy lived longest from splenectomy, although the results were not statistically significant.
Age Factors↗
Human tissue distribution of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (NSC 141549, AMSA).
Concentrations of AMSA were determined by HPLC in autopsy tissue samples from five patients who had received the drug antemortem. Relative organ concentrations of AMSA varied from patient to patient; however, concentrations were generally highest in gallbladder, liver, and kidney, while low levels were generally but not invariably found in lung, testicle, muscle, fat, spleen, bladder, pancreas, colon, prostate, and brain. One patient with ventricular fibrillation and seizures had high tissue AMSA concentrations in myocardium, but low concentrations in brain. Another patient with seizures during treatment had high brain concentrations of AMSA. Relative organ concentrations were similar to those found in mice, except that mice have high AMSA concentration in their spleens whereas our patients did not, even when the spleen was infiltrated with leukemic cells. High tissue concentrations of AMSA were still present 2 weeks after treatment. AMSA concentration was lower in a renal oncocytoma (1.1 micrograms/g) than in surrounding kidney (2.4 micrograms/g).
Adult↗
Chemotherapy-associated oral hemorrhages in adults with acute leukemia.
The frequency, nature, and management of chemotherapy-associated oral hemorrhages were studied in 1,093 adult inpatients undergoing treatment for acute leukemia or the blastic phase of chronic leukemia. Of this number, 163 (14.9%) manifested gross bleeding from the mouth during the course of treatment. The most common oral bleeding sites were the lips, tongue, and gingiva. Thrombocytopenia was the underlying cause in 88% of the cases, disseminated intravascular coagulation in 6%, and combinations of thrombocytopenia and hypofibrinogenemia and of thrombocytopenia and vitamin K deficiency in 5.5% and 0.6%, respectively. The vast majority of the patients with mouth bleeding had platelet counts below 40,000/mm3. Approximately 50% had indirect evidence of a coagulation factor deficiency in the blood. The oral hemorrhages were best managed by transfusions of HLA-compatible fresh platelets and fresh frozen plasma, together with topically applied clot-promoting agents, until hemostatic control was restored.
Acute Disease↗
In vitro suppression of DNA synthesis by a remission induction agent and its correlation with response in adult acute leukemia.
Fifty-three adult patients who presented with previously untreated acute leukemia had leukemic cells incubated in vitro with five doses of cytosine arabinoside (0.001-0.1 microgram/ml) and adriamycin (0.1-10 microgram/ml). Thymidine incorporation was measured in treated and untreated cells. Greater than 80% suppression of pretreatment thymidine incorporation after treatment with 0.004 micrograms/ml of cytosine arabinoside correlated with complete remission (CR) of the patient. A Mahalanobis' D2 score, which provides an index of the deviation of patient's in vitro drug response from the mean profile of responders, was calculated for each drug. Patients who had D2 values greater than 10 for Ara-C were less likely to respond to therapy. Patients with low D2s had rates of CR higher than predicted by the prognostic model employed at U.T.M. D. Anderson Hospital. However, unlike in our previous report, responders and non-responders were not clearly separable on the basis of the D2 value.
Adolescent↗
Prediction of complete remission in patients with refractory acute leukemia treated with AMSA.
The relation between characteristics known at start of therapy and response in 102 adults with refractory acute leukemia who received 4'-(9 acridinylamino)-methane-sulfon-m-anisidide (AMSA) was examined. Twenty-three (23%) of these patients attained complete remission (CR). Univariate analysis showed that the following characteristics were associated with CR: a fewer number of prior induction and maintenance regimens, a shorter time between latest relapse and AMSA therapy, the presence of Auer rods, a circulating blast cell count of less than 25,000/mm3, a marrow cellularity less than 90%, a ratio of marrow blasts and promyelocytes to more mature myeloid cells (differentiation ratio) less than 15, and a first-course AMSA dose of greater than or equal to 375 mg/m2. Some of these factors were interrelated. Multivariate analysis using logistic regression techniques was carried out to determine which of the above factors added independent prognostic information. This analysis produced a statistical model that related probability of response to the following in order of selection: Auer rod status, first-course dose, differentiation ratio, and absolute circulating blast cell count. Such a model could be useful in identifying patients with high, intermediate, or low probability of response to AMSA. AMSA could then be prescribed only for patients likely to respond while affording other patients alternate salvage programs at an earlier time.
Acute Disease↗
Human malignancy-associated nucleolar antigen as a marker for tumor cells in patients with acute leukemia.
Tumor burden in adult patients with acute leukemia is assessed using the percentage of blast cells in the bone marrow or blood. It is clear, however, that not all blast cells are leukemic cells, especially during rapid marrow regeneration. Similarly, some leukemia cell lines have been shown to differentiate in vitro, and the same process also occurs in vivo. Therefore, the leukemic burden may be due to more differentiated cells as well as to blast cells. The purpose of this study was to investigate whether the human malignancy-associated nucleolar antigen (HMNA) could be used as a marker for leukemic cells and to examine its potential as a diagnostic tool. The proportion of HMNA-positive cells in the bone marrow of patients with acute leukemia was determined by indirect immunofluorescence with antibodies to HMNA and was compared with the differential counts routinely made in the clinic laboratory. The percentages of HMNA-positive cells among the nucleated cells in the marrow of 72 patients with clinical evidence of leukemia were significantly higher (range 9%-98%, median 83%) than those observed for nonleukemic individuals (range less than 0.05%-2.5%, median 1%) or for fractions of marrow cells from normal volunteers enriched for normal early progenitor cells (less than or equal to 2%). Patients with leukemia in remission had a lower percentage of HMNA-positive cells (range 0%-83%, median 3%). The percentage of HMNA-positive cells increased as patients approached relapse. Although the percentage of HMNA-positive cells was related to the percentage of blast cells in the bone marrow of the patients with leukemia, some partially differentiated cells were also HMNA-positive in some specimens, and some blastic cells were HMNA-negative in other specimens. These studies indicate the potential usefulness of HMNA as a marker for leukemic cells.
Acute Disease↗
Moxalactam plus ticarcillin or tobramycin for treatment of febrile episodes in neutropenic cancer patients.
Moxalactam disodium in combination with ticarcillin disodium or tobramycin sulfate was used to treat 445 episodes of suspected or confirmed infection in patients with cancer. The majority had leukemia and neutropenia. The rate of cures during the 231 confirmed infections was 65% for moxalactam and ticarcillin and 64% for moxalactam and tobramycin. Both regimens were comparable against aerobic gram-negative and polymicrobial infections. In gram-positive infections, the response rate for moxalactam and ticarcillin was 73% and for moxalactam and tobramycin, 53%. Only three of nine enterococcal infections responded to treatment. Thirteen percent of all organisms recovered were resistant to moxalactam. Side effects occurred infrequently; the most important was coagulopathy due to moxalactam. Nephrotoxic effects occurred in six patients receiving moxalactam and tobramycin and in none of those receiving moxalactam and ticarcillin. In 39 patients, a superinfection was confirmed. Fourteen were fungal, three were due to enterococcus, and one due to Klebsiella species. Eleven of the 14 fungal episodes occurred in the moxalactam-ticarcillin group. Moxalactam with ticarcillin and moxalactam with tobramycin are equally active for the initial treatment of presumed infection in patients with neutropenia.
Adolescent↗
Premature chromosome condensation studies in human leukemia: 5. Prediction of early relapse.
Previous reports have suggested that the technique of premature chromosome condensation (PCC) is useful for predicting relapse in patients with acute leukemia. However, these studies involved patients had been in complete remission (CR) for various periods of time and had heterogeneous expectations for relapse. The purpose of this study was to further determine the value of PCC in predicting relapse by examining the PCC characteristics of bone marrow specimens from patients with acute leukemia on a common therapeutic regimen after similar periods in CR. The remission durations after the PCC determinations were compared between patients with high or low proliferative potential indices (PPI, or the fraction of G1 cells in late G1 phase). Of 60 patients studied between two and eight weeks after achieving CR, 14 of the 16 patients exhibiting high PPI values (greater than or equal to 35) have relapsed. The mean time from PCC measurement to relapse was 23 weeks. In contrast, only 19 of the 44 patients exhibiting low PPI values have relapsed, with an estimated mean time to relapse of 68+ weeks. Likewise, of 38 patients studied between nine and 15 weeks of CR, nine of the ten patients exhibiting high PPI values have relapsed (mean time to relapse, 23 weeks), while only 16 of 28 patients with low PPI values have relapsed (estimated mean time to relapse, 54+ weeks). The predictive value of the PCC technique was found to be independent of other prognostic factors for the duration of CR, and it identified those patients within the poor prognostic category with a high likelihood of imminent relapse. While similar trends were observed at later time intervals in CR, the differences in relapse rate between patients with high or low PPI values is not significant. These results confirm the usefulness of the PCC technique in predicting relapse in acute leukemia and could aid in the identification of patients who might benefit by an alteration of therapeutic strategy.
Aminoacridines↗
Bone involvement in hairy cell leukemia.
Four patients with a diagnosis of hairy cell leukemia complicated by bone involvement are described. This is an uncommon complication of the disease. Manifestations included osteolytic lesions, severe osteoporosis, and aseptic necrosis of the femoral head. The osseous complications do not seem to bear on the prognoses for these patients. Radiotherapy or chemotherapy provides symptomatic relief and may prevent further morbidity from the bone lesions.
Adult↗
Malignant gingival and skin "infiltrates" in adult leukemia.
The clinicopathologic and histopathologic features of leukemic gingival and cutaneous "infiltrates" were studied in 1,076 adults hospitalized for cancer chemotherapy. Leukemic gingival hyperplasia was present in 3.6 percent and leukemia cutis in 3.1 percent of the patients. Only 7.6 percent of those with leukemic "infiltrates" had simultaneous gingival and skin involvement. Histologically, the lesions consisted of extravasated and proliferating monocytoid or myeloid cells. The infiltrative-proliferative tendency was most pronounced in patients with, in a sharply descending order, acute monocytic leukemia, acute myelomonocytic leukemia, and acute myelocytic leukemia. Formation of lesions in the skin and gingiva was unrelated to sex, age, and white blood cell count. Gingival lesions were particularly prone to infectious complications in patients with poor oral hygiene. Aside from the morphologic predisposition, the propensity for adults with leukemia to develop chemotherapeutically reversible malignant mucocutaneous lesions was highly individualistic and unpredictable.
Adolescent↗
Philadelphia chromosome-positive adult acute leukemia with monosomy of chromosome number seven: a subgroup with poor response to therapy.
Thirty-four adult patients were seen at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Texas between 1969 and 1980 with acute leukemia (AL) and a deleted G-group chromosome that was shown by Giemsa banding to be a Philadelphia (Ph1) chromosome t(9;22) in 21 patients. Fourteen had the Ph1 chromosome as the sole abnormality, 12 had the Ph1 chromosome and loss of one chromosome of the C-group (identified by Giemsa banding analysis as number 7 in eight patients), while eight had the Ph1 chromosome and other changes. These three groups were similar in sex, age distribution and hematologic parameters. The median age of 40 was lower than usually seen in AL. The distribution of the morphologic subtypes was similar to that seen at this institution, with 50% being acute myeloblastic, 12% acute myelomonocytic, 20% lymphoblastic and 18% acute undifferentiated. The complete remission rate with chemotherapy was low: 25% in the Ph1 +/- 7, 50% in the Ph1 +/other group and 43% in the Ph1 +/other group. Median survival time was 8 months for the Ph1 +/- 7 group, 5.5 months for the Ph1 +/other group and 9.0 months for the Ph1 +/alone group. These patients with Ph1 + AL had higher white blood cell counts, increased extramedullary disease and poorer responses to therapy than usual for patients with AL. The deletion of chromosome 7 and the acquisition of the Ph1 chromosome identifies a group of patients with characteristics similar to all the patients with Ph1 + AL but a poor response to therapy and short remission duration.
Adolescent↗
Development of the orientation of the visuo-tectal map in Xenopus.
Eye rudiments from Xenopus embryos of stage 28 or younger were explanted on to the flank of similar embryos with normal or nasotemporally reversed orientation. After some hours the eyes were retransplanted to an orbit of a stage 32/34 embryo, with either normal or reversed nasotemporal orientation. Later the visuotectal projections through the operated eyes were mapped electrophysiologically. The maps obtained were oriented as if the mapping orientation of the eye had already been determined in the donor orbit before the first transplantation; i.e. if normally oriented in the final host orbit the eye gave a normal map, and if the eye was reversed in the final host orbit it gave a reversed map. In only one out of 25 cases did it seem that the orientation of the map could have been influenced by the orientation of the eye on the flank of the intermediate host, and here the evidence was weak. Two eyes gave reduplicated maps and 4 maps were uninterpretable. It was concluded that the orientation of the map is determined before stage 26 and is not altered by information derived from the flank during stages 26-34.
Animals↗
Coagulation abnormalities induced by beta-lactam antibiotics in cancer patients.
The records of 714 neutropenic cancer patients who were treated with high doses of a combination of beta-lactam antibiotics were analyzed. In 268 patients, coagulation parameters were measured at least once before, during, and after therapy. Alterations on the prothrombin time, activated partial thromboplastin time, and thrombin time were found in those regimens containing a semisynthetic penicillin, cefamandole, and moxalactam. Mild and severe hemorrhage was observed in some patients receiving these regimens. After prophylactic administration of vitamin K to all patients treated with moxalactam, no further hemorrhage was noted. Alteration of the prothrombin time, with preservation of other parameters, was found in patients receiving antibiotic regimens containing semisynthetic penicillin and cefoxitin. No evidence of hemorrhage was found in this group of patients. In neutropenic cancer patients, the occurrence of another impairment in the clotting process, in addition to thrombocytopenia, greatly increases the risk of serious hemorrhage. Coagulation parameters must be routinely monitored when these patients receive antibiotics known to cause coagulation abnormalities.
Anti-Bacterial Agents↗
A randomized study of ceftazidime compared to ceftazidime and tobramycin for the treatment of infections in cancer patients.
Three hundred and twenty-one febrile episodes in cancer patients were treated with ceftazidime alone or in combination with tobramycin. Patients were grouped according to their neutrophil count into neutropenic and non-neutropenic (less than 1000 and greater than 1000/mm3) respectively. Two hundred and seventy-five episodes were evaluated. The overall response rate in 83 episodes of infection treated with ceftazidime alone was 60 and 73% in those who received the combination. In those bacteriologically proven the response rate was 72% in both groups of the study. The overall response rate in septicaemia was 75% with ceftazidime alone and 85% with the combination. High response rates were obtained in Gram-negative bacillary septicaemias in both groups even in neutropenic patients treated with ceftazidime alone. Pneumonias in neutropenic patients responded equally well. However, patients with adequate neutrophil counts responded better to the combination than to single-agent therapy. The response rate for Gram-positive infections was 41% for ceftazidime alone and 57% for the combination, which was inferior to the results obtained for Gram-negative infections (P = 0.001). The rates of superinfection and toxicity were very low. Ceftazidime is a useful antibiotic against Gram-negative infections in cancer patients. It should be combined with an agent active against Gram-positive pathogens in neutropenic patients.
Adolescent↗