G. Hamilton Fairley

Combination chemotherapy using L-asparaginase, daunorubicin, and cytosine arabinoside in adults with acute myelogenous leukaemia.

Cytosine arabinoside and daunorubicin used in an intensive intermittent regimen have been shown to be an effective combination for the induction of complete remissions in 14 out of 23 adult patients with acute myelogenous leukaemia. This gives an overall complete remission rate of 60%. A further patient had a good partial remission. The addition of L-asparaginase to the regimen has not increased the incidence of remission and there were more side effects in the L-asparaginasetreated group. Of the 10 patients treated with L-asparaginase in addition to cytosine arabinoside and daunorubicin, five achieved a complete remission. Of the 13 patients treated with cytosine arabinoside and daunorubicin without L-asparaginase, nine achieved a complete remission and one a good partial remission.

Production of Antibodies against Viruses in Leukaemia and Related Diseases

PATIENTS with primary malignant diseases of lympho-reticular tissue (reticuloses) frequently suffer from infections, and previous work using bacterial and blood group antigens has shown that antibody formation to new antigens may be defective in all these diseases (Greenwood, Smellie, Barr and Cunliffe, 1958; Barr and Fairley, 1961). However, with antigens encountered in the past, the formation of antibodies is impaired in malignant diseases of lymphocytes and plasma cells, such as chronic lymphatic leukaemia and multiple myeloma, but is frequently normal in other reticuloses, and in acute leukaemia the secondary antibody response may even be increased (Larson and Tonhnson, 1953 ; Silver, Utz, Fahey and Frei, 1960; Fairley and Akers, 1962). These investigations have been extended by studying antibodies against influenza and mumps viruses in patients with reticuloses, with the ultimate aim of correlating them with susceptibility to common respiratory infections.

Significance of the changes in the circulating lymphoid cells in Hodgkin's disease.

The lymphoid cell population in the peripheral blood in Hodgkins disease differs from normal blood in three ways. Firstly, the number of large lymphoid cells actively synthesizing deoxyribonucleic acid is increased; secondly, the number of medium-sized lymphoid cells with intensely basophilic cytoplasm is increased; and, thirdly, occasional plasma cells are seen. These changes are related to the activity but not to the stage of the disease. Similar changes are found under conditions of known antigenic challenge—that is, in infections, and after immunization, and in rheumatoid arthritis and systemic lupus erythematosus.

Hypogammaglobulinaemia in Chronic Lymphatic Leukaemia

and Norwich Hospital; Northampton General Hospital; Northern General Hospital, Edinburgh; Orpington Hospital; Princess Louise Hospital; Queen Elizabeth Hospital, Birmingham; Queen Marys Hospital, Sidcup; Radcliffe Infirmary, Oxford; Redhill County Hospital, Surrey; Royal Alexandra Hospital, Rhyl; Royal Infirmary, Cardiff; Royal Infirmary, Manchester; Royal National Hospital for Rheumatic Diseases, Bath; Royal Sussex County Hospital, Brighton; St. Alfeges Hospital, Lewisham; St. Asaph Hospital, Flints; St. Davids Hospital, Cardiff; St. Martins Hospital, Bath; St. Mlarys Hospital, Paddington; St. Thomass Hospital, London; University College Hospital, London; Western General Hospital, Edinburgh; Westminster Hospital, London; Willesden General Hospital, London.

Method of Removing Abnormal Protein Rapidly from Patients with Malignant Paraproteinaemias

On 48 occasions large quantities of abnormal protein were removed from the blood of 11 patients with malignant paraproteinaemias (plasmacytomas) by exchanging their plasma with reconstituted blood bank plasma. The IBM continuous flow blood cell separator was used to exchange the plasma, a procedure that is safe, very rapid, and with clinical benefits which are much better than can be obtained by conventional plasmapheresis. In addition, the constituents of reconstituted plasma correct deficiencies in normal immunoglobulins found in these patients. Clearly for the management of some patients with paraproteinaemia a cell separator is essential.

Hypoplastic Acute Myelogenous Leukaemia

The clinical course, diagnosis and management of nine cases of hypoplastic acute myelogenous leukaemia are described. Such cases may follow a slowly progressive course and should not receive anti‐leukaemic chemotherapy unless the disease is advancing rapidly or unless some specific complication develops. If chemotherapy has to be given, usually because of severe and recurrent infections, then prompt and prolonged remission of disease may occur.

Autoantibodies in Malignant Disease

The occurrence of autoantibodies in a variety of diseases is now well established, but on many occasions their significance remains obscure. Autoimmune haemolytic anaemia, however, is an example of a situation where whatever the cause of the production of the antibody may be, there is a direct and measurable effect of the antibody on a normal body constituent. Professor Dacie’s contribution to this subject has been considerable, and in his series of 175 patients with autoimmune haemolytic anaemia he found that 25 (14%) were suffering from malignant disease. Of these 25 patients, 24 had some form of leukaemia or lymphoma (Dacie, 1962). This was one of the earliest observations suggesting the occurrence of antibodies against normal body components in malignancy. Its significance then became obscured by the finding of antibodies and lymphoid cells directed against the malignant cells in patients with a variety of malignant diseases. For example, antibodies in malignant melanoma may be directed against antigen(s) on the cell surface or within the cytoplasm; some of these antibodies have been found to react with cells from many different tumours, while others may be individually specific reacting only with the autologous malignant diseases. Similarly, lymphocytes reacting with tumour cells have been described in many malignant diseases, and in malignant melanoma Currie et a1 (1971) have shown that even if circulating cytotoxic lymphocytes are absent they can be produced by immunization of patients with their o m irradiated tumour cells. In acute leukaemia it has been shown that tumour-associated antigens exist on the surface of the leukaemic cells (Friedman & Kourilsky, 1969; Viza et al, 1969) and again immunization of patients in remission increases the ability of their circulating lymphocytes to recognize their own leukaemic cells as ‘foreign’ (Powles et al, 1971). The significance of these findings is far from clear. In one series of patients with acute leukaemia reported by Math6 (1972)~ immunization with irradiated leukaemic cells and non-specific stimulation of the reticulo-endothelial system with BCG was able to maintain remissions previously obtained by chemotherapy for long periods of time. With this exception there is no evidence that immunization to augment any immunological reaction which may be present against the tumour cells is of any avail in the treatment of patients with disseminated malignant disease. It is, of course, very difficult to assess the importance of antibodies or cytotoxic lymphocytes directed against tumour-specific antigens unless one knows whether there are also reactions with normal body constituents. Autoimmune haemolytic anaemia is rare, but there is some new evidence that in the sera of many patients with malignant disease smooth muscle antibody (SMA) exists. This is an interesting antibody which can be demonstrated by immunofluorescence to react with the smooth muscle fibres between the gastric glands, in the muscularis mucosae, and in the walls of arteries. Sera giving positive staining at these sites also give

Immunotherapy in the Management of Leukaemia

Now that it has been clearly established that tumour associated antigens exist in acute leukaemia in man, as in animals, the possibility of stimulating the patients immune system to react against them arises. In animal experiments the most effective method of influencing the progress of leukaemias and lymphomas after the implantation of living malignant cells has been a combination of nonspecific stimulation of the reticulo‐endothelial system, with agents such as BCG or Corynebacterium parvum, either with chemotherapy or with specific immunization with irradiated leukaemic cells. However, such treatment is only effective if the number of living malignant cells is small as it takes a powerful immune response to overcome even a small number of malignant cells. It is for these reasons that most of the studies in man have been on patients with acute leukaemia in remission. Mathé, in 1969, produced evidence that BCG and irradiated allogeneic leukaemia cells could lengthen the duration of remission in ALL in children, but the subsequent results of intensive combination chemotherapy together with prophylactic treatment of the central nervous system by Pinkel and his colleagues are so encouraging that immunotherapy is not being extensively used in this form of leukaemia at the moment. The situation in AML, particularly in adults, is completely different. The maintenance of remission with chemotherapy in this type of leukaemia is difficult and relapses occur quite rapidly. Various centres have now shown that both remission lengths and overall survival are significantly prolonged by using BCG with or without irradiated allogeneic leukaemia cells. The significance of these are reviewed and the problems for the future are discussed.

Chemotherapy of Hodgkin's Disease with Cyclophosphamide, Vinblastine, and Procarbazine

Hort, E. C., and Penfold, W. J. (1912). 7. Hyg. (Lond.), 12, 361. Horvath, S. M., Radcliffe, C. E., Hutt, B. K., and Spurr, G. B. (1955). 7. appl. Physiol., 8, 145. Hull, D., and Segall, M. M. (1965). 7. Physiol. (Lond.), 181, 449. Iampietro, P. F., Buskirk, E. R., Bass, D. E., and Welch, B. E. (1957). 7. appl. Physiol., 11, 349. Johnson, R. H., Smith, A. C., and Spalding, J. M. K. (1963). 7. Physiol. (Lond.), 169, 584. ____ and Woollner, L. (1965). Lancet, 1, 731. Kaiser, H. K., and Wood, W. B. (1962). 7. exp. Med., 115, 27. Kappas, A., Soybel, W., Fukushima, D. K., and Gallagher, T. F. (1959). Trans. Ass. Amer. Physns, 72, 54. Kerslake, D. M., and Cooper, K. E. (1950). Clin. Sci., 9, 31. King, M. K., and Wood, W. B. (1958a). 7. exp. Med., 107, 291. (1958b). Ibid., 107, 291. Knigge, K. M., and Bierman, S. M. (1958). Amer. 7. Physiol., 192, 625. Ladell, W. S. S., Waterlow, J. C., and Hudson, M. F. (1944). Lancet, 2, 491. Liebermeister, C. von (1875). Handbuch der Pathologie und Therapie des Fiebers. Vogel, Leipzig. Loveless, A. H., and Maxwell, D. R. (1965). Brit. 7. Pharmacol., 25, 158. Macpherson, R. K. (1959). Clin. Sci., 18, 281. Magoun, H. W., Harrison, F., Brobeck, J. R., and Ranson, S. W. (1938). 7. Neurophysiol., 1, 101. Menkin, V. (1945). Arch. Path., 39 28 Nakayama, T., Hammel H. T., Hardy, J. D., and Eisenman, J. S. (1963). Amer. 7. PRysiol., 204, 1122. Nielsen, B., and Nielsen, M. (1965a). Acta physiol. scand., 64, 314. (1965b). Ibid., 64, 323. Nielsen, M. (1938). Skand. Arch. Physiol., 79, 193. Perera, G. A. (1941). Arch. intern. Med., 68, 241. Pickering, G. W. (1932). Heart, 16, 115. Renbourn, E. T. (1960). 7. psychosom. Res., 4, 149. Siebert, F. B. (1925). Amer. 7. Physiol., 71, 621. Snell, E. S. (1954). 7. Physiol. (Lond.), 125, 361. (1961). Clin. Sci., 21, 115. (1962). Ibid., 23, 141. Goodale, F., Wendt, F., and Cranston, W. I. (1957). Ibid., 16, 615. Stern, R. (1892). Z. klin. Med., 20, 63. Taylor, G. F. (1964). Brit. med. 7., 1, 428. Villablanca, J., and Myers, R. D. (1965). Amer. 7. Physiol., 208, 703. Wendt, F., Snell, E. S., Goodale, F. and Cranston W. I. (1956). Chn. Sci. 15, 485.

Antibodies to Blood Group A and B Substances in Reticuloses

THE formation of circulating antibodies on primary immunization has been shown to be impaired in a variety of disorders of lymphoreticular tissue including sarcoidosis and the primary malignant diseases reticuloses (Greenwood, Smellie, Barr and Cunliffe, 195 8). This was confirmed in patients with reticuloses by Barr and Fairley (1961), who also showed that antibody formation on re-immunization was grossly defective in primary malignant diseases of lymphocytes (chronic lymphatic leukaemia and lymphosarcoma) in contrast with Hodgkin’s disease and the myelo-proliferative syndromes, in which antibody production was normal or only slightly reduced. The purpose of this work was to extend the study of the response to re-immunization by measuring the anti-A and anti-B agglutinin and haemolysin titres before and after immunization with blood-group substances A and B. This time patients with primary malignant disease of plasma cells (multiple myeloma), who were not included in the previous study (Barr and Fairley, 1961), have been investigated. The results in malignant diseases of lymphocytes and plasma cells (the cells believed to be responsible for the formation of circulating antibodies) have been grouped together and contrasted with the results in patients with other forms of reticulosis. In addition the anti-A and anti-B iso-agglutinin levels have been estimated in a larger number ofpatientswho were not immunized, and an attempt madeto correlate them with the type of reticulosis, the extent, duration and severity of the diseases, and the treatment used.