Rose Ruth Ellison

PH1-positive megakaryoblastic leukemia

A case of megakaryoblastic leukemia is presented. Megakaryoblastosis and erythrocytic hyperplasia of the bone marrow, thrombocythemia, and hepatosplenomegaly were the essential features; 100% of the marrow‐derived metaphases were found to be Ph1‐positive. Cytologic and chromosomal findings are compatible with the assumption that all three marrow systems were involved in the leukemic process.

CLINICAL STUDIES ON 6‐MERCAPTOPURINE

Profiting by the studies of Elion and Hitchings,’~2~3~4 of the Wellcome Research Laboratories, and of Stock, Clarke, Philips, Brown, and others of the Sloan-Kettering Institute,3. 6 , 6 * the Chemotherapy Service of Memorial Center has had the opportunity to evaluate 6-mercaptopurine in 269 patients having various forms of neoplastic disease. 6-Mercaptopurine has been administered almost entirely by the oral route, the usual dosage being 2.5 mgm./kg. of body weight once daily.8 At this level, in children, we have seen almost no evidence of toxicity. A t higher doses in children or, occasionally, a t this dose in adults, evidence of marrow depression and gastrointestinal disturbances have been noted. On the other hand, in many patients, we have administered 5 mgm./kg. and even higher doses without toxic manifestations, and one patient had increasing dosage until finally a level of 12.5 mgm./kg. was given daily for a period of a week with no apparent ill effects. Since most of the patients who were given these very large doses had previously been treated with the ordinary therapeutic level for varying periods of time, it is conceivable, however, that they may have developed some tolerance to the drug. On the question of dosage schedule we have always given a single daily dose, and we have no information a t the present time as to whether there might be an advantage in giving the drug by a fractionated technique either three times daily or as often as every two hours. It is also possible that a high loading dose of 5 to 10 mgm./kg. for one to two days might decrease the usual 3to 8-week latent period before the beneficial action of this drug becomes apparent. Despite the fact that Philips et uL6 and Clarke et al? have demonstrated that mercaptopurine has a hepatotoxic effect in dogs, we have seen no definite clinical evidence of liver damage which could be ascribed to this drug, although an occasional case of what appeared to have been serum hepatitis has occurred in patients under therapy who have previously had transfusions. In some patients having acute leukemias with high total leukocyte counts, we have seen a rapid fall in white count after a relatively short period, 8 to 10 days, of mercaptopurine therapy. Whether this change represents a toxic or purely a therapeutic effect of the drug cannot be stated definitely a t this time. Metastatic carcinomas, sarcomas, Hodgkin’s disease, lymphosarcoma, and chronic lymphocytic leukemia have not responded to 6-mercaptopurine in our experience. There has been some decrease in size of metastatic nodules of

Some aspects of the metabolism of 5-bromouracil☆☆☆

Abstract 5-Bromouracil-2-C14 was synthesized and administered to a human with leukemia. Evidence has been obtained that, in the human as in other species, there is some conversion of 5-bromouracil to urinary uracil, and that extensive reduction and cleavage of the pyrimidine ring occurs. A useful method for determining the presence and nature of pyrimidine reduction products is outlined.

Symposium on the experimental pharmacology and clinical use of anti metabolites

Two classes of antimetabolites, the purine antagonists and the pyrimidine antagonists, have assumed an important role in the clinical chemotherapy of cancer in the past 8 years. Since 6-mercaptopurine30, 33 was first reported to inhibit sarcoma 180 in mice20 and to produce remissions in patients with acute leukemia resistant to the folic acid antagonists,16 there have been a succession of derivatives such as 6-methylmercaptopurine,41 6-chloropurine,1,35 thioguanine,64 thioguanosine,40, 58 and 6(1-methyl-4-nitro-5-imidazolyl)thioguanine,32,49 all of which have been active against acute leukemia and chronic granulocytic leukemia. None of these, however, have been a significant improvement over 6-mercaptopurine. In the pyrimidine field, 2,4-diamino-5-(3, 4-dichlorophenyl )-6-methy lpyrimidine 5 3 was the first to show activity against leukemia.63 Reversal studies in bacteria51 and

Concurrent monoclonal igm and iga proteins in lymphocytic lymphoma

A case of lymphocytic lymphoma with monoclonal elevations of both IgA and IgM is described. The cytogenetic and immunoglobulin findings in this case suggest that the cells producing the abnormal elevated proteins were different cells that appeared to be derived from a common precursor cell.

Selection of patients for evaluation of chemotherapeutic procedures in advanced cancer

Abstract It is estimated that there are more than 500,000 new cases of cancer in the United States each year [1]. Of this number about 350,000 will have nonresectable, recurrent or advanced disease. If all patients with nonresectable neoplastic disease could be assigned to planned chemotherapeutic studies, and if adequate funds, medical and hospital facilities were available, therapeutic trials could be designed and completed with optimal efficiency.

Therapy of acute leukemia in adults.

A CUTE leukemia is seen in all age groups with about half of the cases occurring in persons who are over the age of 1.5.’ When the figures are expressed in terms of the incidence per million population in a given age group, the incidence is as high or higher above the age of 50 as under the age of 20.2 The incidence of all types of leukemia is increasing, and there are now an estimated 11,000 new cases of leukemia in the United States each year3 with 9,841 deaths certified from this cause in the United States in 1952, 9,918 in 1953, and 10,443 in 1954.4 The diagnosis of acute or subacute leukemia is a morphologic one and is dependent upon the invasion and at least partial replacement of the marrow by a predominant type of immature leukocyte (myeloblast, promyelocyte, monoblast, lymphoblast, or undifferentiated blast). In most cases, this finding is associated with sudden onset and rapid progression of symptoms. A review of the literature6 indicated that 50 per cent of a group of 577 patients (both adults and children) who were treated only with supportive therapy (transfusion and antibiotics) or supportive treatment and therapy which is now generally thought not to affect acute leukemia (x-ray, P32, urethane, or Fowler’s solution) survived 4 months. A group of 56 adults with acute leukemia treated at Memorial Center from January, 1948, to January, 1952 (when the treatment used consisted of the folic acid antagonists and/or the adrenal steroids and ACTH) showed a median survival time of 6 months. A recent survey of a group of patients over the age of 50 with acute leukemia6 suggested that symptoms initially might be insidious and slowly progressive in these individuals. Once the symptoms were sufficient to require medical attention, and the diagnosis was established, the course Was brief. The management of patients with acute leukemia involves both “specific” and supportive measures. The, use of “specific” antileukemic therapy with resultant temporary hematologic remissions (and consequent clinical well-being) is the most the physician has to offer at present. In adults the remission rate is relatively low. Supportive treatment, therefore, aimed at handling the various

The reproducibility of acute lymphoblastic leukemia phenotype determinations: evaluation of monoclonal antibody and conventional hematopoietic markers

Peripheral blood and/or bone marrow lymphoblasts from 25 patients with acute lymphoblastic leukemia (ALL) were tested with a panel of monoclonal antibodies (MoAbs) and conventional hematopoietic markers by three different laboratories. The results were analysed to evaluate the reproducibility of ALL phenotype determinations. Specimens were transported between laboratories by 24-h courier service and were classified on the basis of indirect immunofluorescence MoAb reactivities as follows: B-lineage ALL (BA-1+T-MCS-2-); T-lineage ALL (T+BA-1-MCS-2-); myeloid antigen ALL (MCS-2+BA-1-CALLA-T-) and unclassified ALL (BA-1-MCS-2-CALLA-T-). Conventional marker studies for surface immunoglobulin (sIg), cytoplasmic immunoglobulin (cIg), sheep erythrocyte rosette formation (E) and nuclear terminal deoxynucleotidyl transferase (TdT) were also performed. In the cases with sufficient marker data to permit classification, 90% (18/20) were identically classified by different laboratories and this concordance was statistically significant (p less than 0.05). The agreement between laboratories for individual MoAb and conventional marker analyses was statistically significant (p less than 0.05) for all markers with the exception of BA-2, cIg and TdT determinations. Six of 7 discordant BA-2 cases represented BA-2+ evaluations which had subsequent BA-2- results following specimen transportation. These findings suggest instability of the BA-2 antigen to transport conditions. A similar pattern of positive to negative evaluations following transportation was observed in 5/5 discordant results involving other MoAbs. Disagreement between laboratories for cIg and TdT determinations implies that the detection of cytoplasmic or nuclear antigens may be more prone to subjective interpretation than cell surface antigen marker analyses. Our findings suggest that immunofluorescence marker studies employing MoAbs to cell surface antigens are in general highly reproducible. Our results also indicate that specimen storage conditions and the cellular location of target antigens are important variables which may affect the reproducibility of ALL phenotype determinations.

PANEL DISCUSSION ON CHEMOTHERAPY IN THE PALLIATIVE TREATMENT OF CANCER

Moderator: JOSEPH H. BURCHENAL, M.D., Professor of Medicine**, and Attending Physciant. Panelists: HENRY D. DIAMOND, M.D., Associate Professor of Clinical Medicine**, and Associate Attending Physician]. ROSE RUTH ELLISON, M.D., Assistant Professor of Medicine**, and Assistant Attending Physician]. GEORGE C. ESCHER, M.D., Instructor in Medicine**, and Assistant Attending Physiciant. DAVID A. KARNOFSKY, M.D., Associate Professor of Medicine**, and Associate Attending Physician]. W. P. LAIRD MYERS, M.D., Assistant Professor of Medicine**, and Assistant Attending Physician].

Chemotherapy of leukemia

The chemotherapy of leukemia has made great progress since Lissauer in 1865 described benefit from the use of arsenic in the treatment of two cases of chronic leukemia. Although radiation re mains the most used therapy for the chronic leukemias, most recent progress has been made in chemotherapy. Some of the real advances in this discipline, how ever, lie in the theoretical realm rather than in practical therapy. Neither radiation nor presently avail able chemotherapy is curative of any type of leukemia. The clinician can, however, prolong the lives of many patients with acute leukemia, and in the chronic forms at least the useful and perhaps even the actual survival time of the patient can be increased. Agents available for the chemo therapy of the ]eukemias are as follows: