CHLORAMBUCIL IN ERYTHRODERMIA

732

pigmentation, and persistent itching, and the axillary and inguinal lymph-nodes enlarged grossly, suggesting erythro-

CHLORAMBUCIL IN ERYTHRODERMIA JOSEF LIBÁNSKÝ

dermia. Examination revealed generalised enlargement of lymphnodes up to the size of a plum, and slight splenomegaly; the liver reached 1 in. below the costal margin.

M.D. Charles University ASSISTANT PROFESSOR AND HEAD OF THE CLINICAL

INSTITUTE OF HÆMATOLOGY AND BLOOD

JIRÍ

DEPARTMENT, TRANSFUSION, PRAGUE

TRAPL

M.D. Charles

Laboratory Studies The haemoglobin content was 17-2 g. per 100 ml. and the erythrocyte-count was 5 million per c.mm. The white-cell count was 7700 per c.mm. (neutrophils 60%, eosinophils 19%, monocytes 5%, lymphocytes 16%), and in addition there were 1’5% leucoblasts of malignant appearance, the nuclei of which resembled reticular cells containing 1-2 nucleoli. The

University

ASSISTANT PROFESSOR, SECOND DERMATOLOGICAL CHARLES UNIVERSITY, PRAGUE

CLINIC,

PRIMARY erythrodermia presents a difficult therapeutic problem. The relation of this disease to the hxmoblastoses has been known for some time but has rarely been taken into account in seeking the pathogenesis of erythrodermia, and only recently has the number of articles on

platelet-count

this subject increased considerably. Erythrodermic manifestations are often encountered within the wide framework of the hxmoblastoses of the reticuloendothelial system-particularly in the reticuloses, and less frequently in mycosis fungoides and malignant lymphogranuloma (Degos and Ossipaski 1957). The term erythrodermia is sometimes used for the benign reversible reaction of the reticular tissue (the so-called lipomelanotic reticulosis of Pautrier-Worringer) or for a true proliferation with various degrees of differentiation. Erythrodermia thus comprises many different pictures, and evaluation in a given case may present clinical, pathogenetic, and prognostic difficulties. Together with skin manifestations there may be (1) involvement of the lymph-nodes

The

smear

from bone-

per 100 ml.

Response to Therapy In March, 1958, the patient was given chlorambucil 276 mg. (4-6 mg. per kg. body-weight) in the course of 4 weeks. During the following 3 weeks the redness of the skin gradually vanished, the itching ceased, and the skin regained its normal colour. Only the inguinal lymph-nodes remained enlarged, and these had become much smaller. The spleen was no longer palpable. The leucoblasts disappeared from the blood, and the eosinophil-count rapidly became normal. The remission after this single dose of chlorambucil has persisted for 24 months. Case 2.-A man, aged 60, had had erythrodermia for 8 years. He had been treated with corticotrophin, cortisone, and anti-histamines, with only slight temporary improvement. Before he was given chlorambucil his skin was a brownishred colour, with slight desquamation. The lymph-nodes were generally enlarged to about the size of hazel nuts, but the spleen and liver were not palpable. Laboratory Studies On June 16, 1958, the hxmoglobin was 15-2 g. per 100 ml.,

and axillary) by a hyperplastic or (2) splenomegaly, (3) normal peripheral blood-smears, or (4) blood-smears showing a percentage of monocytoid cells of various differentiation or changes ranging from simple bone-marrow hyperplasia to infiltration by tumorous elements of reticuloendothelial origin. The degree of inflammation of the skin varies, and the skin may be pigmented, irregularly infiltrated, dry, oozing, itching, or burning. The symptoms may disappear after some weeks, or they may last for months or even years, causing progressive cachexia; or the course of the disease may be rapid like that of the malignant

reticuloses. Until recently treatment has been symptomatic. The steroids seemed to offer hope, but they caused only temporary improvement and alleviation of the symptoms. On the assumption that erythrodermias are associated with reticuloses, and especially when there were histo-

logical and cytological changes in the lymph-nodes, we tried chlorambucil (’ Leukeran ’), a modern cytostatic agent which had given good results in the treatment of malignant lymphomas. Because the effects were surprisingly good we decided to describe our results so far. Moreover, the response to chlorambucil throws light on the pathogenesis of hyperplastic erythrodermias by proving their close relation to hxmoblastoses of the

,

"

reticular system. The

c.mm.

Plasma-protein electrophoresis revealed: albumin 48-6%, tXi-globulin 6-34%, a2-globulin 1l’98%, (3-globulin 12-03%, y-globulin 21-7%, and total albumin and globulin 9-4 g.

process,

"

160,000 per

subcutis.

(mainly inguinal tumorous

was

aspiration showed mild eosinophilia and sporadic atypical reticuloendothelial-like cells, as in the blood itself. The lymph-node punctate showed distinct proliferation of reticular cells without pronounced malignant changes. Histologically the skin presented the picture of reticulosis, with distinct tumorous elements, mitoses, and eosinophils. Around the vessels the infiltration reached deep into the corium and

marrow

Investigation

Four patients were treated with chlorambucil. Before and during treatment they were examined in detail, including histology of the skin, full blood-counts and bone-marrow biopsy, cytology of lymph-node punctures, and histology of lymph-nodes, to assess the overall degree of involvement, and to obtain an accurate morphological classification.

the red-cell count 4,950,000 per c.mm., and the white-cell count 5800 per c.mm. (neutrophils 66%, eosinophils 8%, monocytes 6%, lymphocytes 20%). The platelet-count, erythrocyte-sedimentation rate, and bone-marrow-aspiration biopsy were within normal limits. Lymph-node biopsy revealed proliferation of reticuloendothelial elements, but the morphological picture did not show clearly whether the reticulosis was benign or malignant. Histologically, however, the focal hyperplasia of reticuloendothelial elements resembled a malignant reticulosis, but there was also melanotic pigmentation in view of which the diagnosis of dermatopathic lymphadenitis (lipomelanotic reticulosis) could not be ruled out. Plasma-protein electrophoresis showed: albumin 52.6%,

al-globulin 3°18°0, a2-globulin 7-51%, B-globulin 8-43% y-globulin 2M1°,o, and total albumin and globulin 6-8 g. per 100 ml.

’

Case I.-In June, 1957, a tailor, aged 66, started to have: violent itching, first of the legs and later of the whole body. Treatment with anti-histamines and vitamins gave no relief. His skin all became red gradually, with slight infiltration, much

Response

to

Therapy

Treatment with chlorambucil was started in July, 1958, and the patient was given a total of 360 mg. (5-6 mg. per kg. body-weight) in the course of 4 weeks. The itching decreased during treatment and finally disappeared. The skin became pale, only slight redness persisting on the inner aspect of the thighs and on the scrotum. The axillary lymph-nodes became normal, and the inguinal and neck nodes diminished considerably in size. After a remission lasting 7 months redness and desquamation

733

reappeared on the nape of the neck and the scrotum, and the inguinal lymph-nodes enlarged to the size of a plum. On July 4, 1959, the patient was again admitted to hospital for further treatment with chlorambucil. Within 2 weeks of treatthe itching ceased and most of the skin became pale. During the next month the improvement continued. There remained only slight desquamation on the inner side of the thighs, and slightly enlarged lymph-nodes. After a remission of 3 months his condition deteriorated slightly. After a third course of chlorambucil, however, all the ment

symptoms virtually disappeared. Because of these two satisfactory results chlorambucil

given to a third patient with erythrodermia. Incomplete remission followed, which we attributed to an insufficient total dose of chlorambucil-the patient having left hospital prematurely. After 6 months another course of treatment was given (total dose 360 mg.; 4-8 mg. per kg. body-weight). The skin manifestations improved strikingly. As only a short time has elapsed was

since the end of the

treatment

this

case cannot

yet be

finally evaluated. Chlorambucil was also given to a patient with mycosis fungoides, whose disease originally resembled erythrodermia and had lasted for 18 years. The improvement which resulted far surpassed any treatment (steroids, radiotherapy, &c.) he had had previously. Discussion

Chlorambucil, p-(di-2-chloroethylamino)-phenylbutyric acid, synthesised by Everett et al. (1953) and introduced by Haddow (1952, 1953) for the treatment of neoplastic disease, has proved its worth in malignant lymphogranulomas, chronic lymphatic leukaemias, and some hxmoblastoses of the reticular system (Galton et al. 1955, Altman et al. 1956, Bernard et al. 1956, Bouroncle et al. 1956, Ultmann et al. 1956). Our own experience (Libansky et al. 1957, 1959) has confirmed these findings. As far as we know, however, chlorambucil has not been tried previously in the treatment of erythrodermias when the skin manifestations overshadow the changes in lymphnodes and other organs, or when the skin alone shows evidence of a disease process. According to our concept erythrodermia always represents a proliferation of the reticuloendothelial system, even when it is not secondary to a hxmoblastic process involving the lymphopoietic tissue, as in Hodgkin’s disease. We believe, therefore, that chlorambucil should be tried even in those cases where erythrodermia is the only clinical and pathomorphulogical manifestation. Chlorambucil was more effective than any other form of therapy (anti-histamines, steroids, vitamins, &c.) in patients who had been treated previously. Although the number of cases is small and our follow-up relatively short, we thought it desirable to report our results, for any means of alleviating such a chronic and highly irritating disease should be tried. Experience with more cases will show whether chlorambucil is a suitable drug for all forms of erythrodermia. In our patients chlorambucil was well tolerated and free from side-effects, but we suggest that patients having this drug should be under observation and their blood-counts should be checked weekly.

Summary Treatment with chlorambucil (’Leukeran’) has been very effective in four patients with erythrodermia. One patient with severe itching, infiltration, and

pigmentation of the skin, gross enlargement of the lymphnodes, and atypical elements in the blood, had a remission after a single dose of chlorambucil which lasted for 24 months.

patient had a remission for 7 months, after having chlorambucil, and a second course of treatment again gave good results. In two other patients the effect of chlorambucil was very favourable, and superior to all other forms of Another

treatment.

In view of our experience so far we recommend chlorambucil for the treatment of erythrodermias. REFERENCES

Altman, S. J., Haut, A., Cartwright, G. E., Wintrobe, M. M. (1956) Cancer, N.Y. 9, 512. Bérnard, J., Mathé, G., Weil, M. (1956) Rev. franç. Étud. clin. biol. 1, 1121. Bouroncle, B. A., Doan, C. A. Wiseman, B. K., Frajola, W. J. (1956) A.M.A. Arch. intern. Med. 97, 703. Degos, R., Ossipaski, B. (1957) Ann. Derm. Syph., Paris, 84, 125. Everett, J. L., Roberts, J. R., Ross,W. C. J. {1953) J. chem. Soc. part 3, 2386. Galton, D. A. G., Israels, L. G., Nabarro, J. D. N., Till, M. (1955) Brit. med. J. ii, 1172. Haddow, A. (1952) Annu. Rep. Brit. Emp. Cancer Campgn, 30, 25. — (1953) Acta Un. int. Cancr. 9, 475. Libanskv, J., Chudomel, V., Sochman, J., Brabec, V. (1957) Čas. Lék. ces. 37, 1162. Brabec, V., Sochman, J. (1959) Neoplasma, 6, 415. Ultmann, J. E., Hyman, G. A., Gellhorn, A. (1956) J. Amer. med. Ass. 162, —

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178

Addendum

completing this article we gave chlorambucil to patient, 56 years old, who had very severe manifestations of erythrodermia with much pigmentation and On histological generalised enlarged lymph-nodes. examination a significant hyperplasia of reticuloendothelial elements was found. The leucocyte-count was raised to 16,000 per c.mm., with eosinophilia and single atypical monocytoid cells in the blood. The symptoms had persisted for a year, and prednisone had given only slight and temporary improvement. Chlorambucil (total dose 350 mg.; 5 mg. per kg. bodyweight, over 4 weeks) temporarily combined with prednisone caused marked improvement; the oozing ceased, and desquamation and itching diminished. The improvement continued for the next 2 months, leaving only slight redness and itching of the thighs. The remission has now After another

lasted for 4 months.

Preliminary

Communication

ANTIBIOTIC ACTIVITY OF HÆMOLYTIC ENTEROCOCCI STRAINS of &bgr;-hæmolytic streptococci of many Lancefield groups produce antibiotic substances under appropriate conditions. The organisms shown to be sensitive to these antibiotics are mainly other streptococci.1-3 This communication brings evidence that such inhibitory activity is a common characteristic of certain hsemolytic group-D streptococci and that it is effective against some intestinal anaerobes. The cross-streaking method was used to study the interaction of 19 strains of group-D streptococci with typical examples of the organisms listed in the table. The group-D strains consisted of 3 National Collection of Type Cultures (N.C.T.C.) strains of Streptococcus durans (8129, 8174, 8307) and 16 strains of Str. faecalis var. zy.-jzoge7zes: 2 of these were N.C.T.C. strains (5957, 8176), and the other 14 had been isolated from wound exudates and fxcal specimens. Apart from 8129 Str. durans, which was ’l.-haemolytic, all strains were B-haemolytic on horse-blood agar. The sensitivity of an organism was tested by first spreading it as shown in the figure, so that the growth density gradually diminished from one side to the other, and then cross-streaking this area with the streptococcus by a single stroke from the 1.

Sherwood, N. P., Russell, Barbara E., Jay, A. R., Bowman, K. J. inf.

2. 3.

Murray, Murray,

Dis. 1949, 84, 88. R. G. E., Pearce, R. H. Canad.J. Res. 1949, R. G. E., Loeb, L. J. ibid. 1950, 28E, 177.

27E, 254.