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TREATMENT OF CHRONIC MYELOGENOUS LEUK/EMIA WITH ARSENIC.

By D.~VID :~IITCHF~LL.

A R~SENIC, according to Forkner, who ,has done much to develop its use for this purpose, is both the oldest and the latest effective treatment for leuk~emia. Lissauer (1865)

repol~ed remarkable symptomatic improvement in a patient suffering from leukmmia, but as this was before the days of blood counts, he records no figures; and of course at this period the (trug was much used for its general tonic effect in many diseases. Some ten years later, Cutler '.and Bradford at the Boston City Hospital published the first paper on the use of Fowler's solution in leUkmmia; in their case the white cell count was reduced from over 1,000,000 to 8,700 in a few weeks; arsenic was then dis- continued and the patient given potassium iodide; in four weeks the white cell count had risen to over 600,000; Fowler's solution was then resumed, and the white cell count retL~rned to normal limits. Up to the end of the century similar results were reported by many 'authol~, but in many cases iron was given at the same time, and the beneficial effect was not always attr ibuted to a~senic.

Treatment of chronic myelo~;enous leukmmia by x-rays was introduced by Pusey in 1902, and was so successful t hut it almost completely replaced arsenic.

In 193] Forkner began to re-study the effects of the a.dministra- tion of Fowler's solution on the leukmmic process .and showed that remissions with reduction of the white cell count to normal limits and concomitant reduction in the size of the spleen were con- sistent]y produced. Other signs of improvement included decrease in ~he proportion of immaiul.e leucocytes in the blood films, arrest of anaemia with, in some cases, a retm~a of the red cell and hmmoglobin values to normal, and reduction in the basal meta- bolic rate. He further suggested that this improvement could be maintained for several months at least by the regular administra- tion of small maintenance doses of the drug.

The technique of administration is important and the following are Forkner 's directions.

(1) Begin with doses of 5 minims, t.i.d., and increase by ] minim per dose, i.e., 3 ~ninims daily, eve1T second day; when 30 minims daily are being taken, increase by 1 minim daily until the leu.cocyte count is less than 10,000, or until definite toxic symptoms are produced. Gradually decrease the dose by 1 minim a day to 5 minims t.i.d.

(2) The dosage must be continuous and the results care- tully controlled. Irregular administration is unsatisfactory.

(3) Disregard mild toxic symptoms; of these, loss of appetite, nausea or occasionally actual vomiting are the

92 IRISt t JOURNAL OF MEDICAL SCIENCE

commonest; if they occur, the medicine should be omitted for a day or two and resumed in slightly smaller dosage in a different vehicle. Mild ehemosis and occasionally d iar rhea may occur. Skin changes are rare and are confined to dry- ness and slight scaling, hyperkeratosis and the development of carcinoma were never observed; in no case did peripheral neuritis occur.

The treatment produced some improvement in chronic lymphatic leukmmia but the results were never as striking as those in the myelogenous form. Acute leuk~emia was not benefited.

Case R.eport. H. McD. , aged 35 years , a f a rmer , was a~lmit tcd to the Ade la ide H o s p i t a l on

23 /7 /42 , c o m p l a i n i n g o f loss o f e n e r g y for s o m e m o n t h s a n d a severe p a i n in t h e left side w h i c h h a d c o m e on s u d d e n l y t h r e e weeks before, b u t was m u c h be t t e r a t t h e t i m e of his admiss ion . T h e r e were no o t h e r s y m p t o m s or a n y c o n s t i t u t i o n a l d i s tu rbances . H i s we igh t was 9st . 71bs. Clinical e x a m i n a t i o n showed sp l eno . m c g a l y , t h e edge o f t h e sp leen r e a c h i n g to t h e u m b i l i cu s ; on exp lo r a t i on n e i t h e r t h e l iver n o r a n y l y m p h nodes were felt. H e h a d a c o n v e r g a n t , c o n c o m i t a n t s q u i n t ; Dr . McCrea f o u n d his f u n d i n o r m a l , a l t h o u g h t h e discs were r a t h e r pale.

H i s b lood c o u n t on a d m i s s i o n w a s R.B.C. 4.15 mil l ion, H b . 6 0 ° , W . B . C . 218 ,000 ; m y e l o c y t e s 4 7 % , n e u t r o p h i l s a d u l t p o l y m o r p h s 5 2 % , l y m p h o e y t e s 1% ; 2 n o r m o b l a s t s pe r 100 W . B . C . , V a n d e n B e r g h T e s t was nega t ive . No B . M . R . e s t i m a t i o n dose.

A d iagnos i s o f chronic m y e l o g e n o n s l e u k a s m i a was m a d e a n d t r e a t m e n t w i th F o w l e r ' s so lu t ion begun . T h e dosage w i t h t h e co r r e spond ing whi t e cell c o u n t s a re s h o w n in t h e table .

H e was d i scha rged on 3 /9 /42 w i t h 5,000 whi te cells, h i s sp leen ba re ly pa lpab le , h i s genera l cond i t ion v e r y good, a n d h is we igh t 9st: 9 lbs. H i s m a i n t e n a n c e dose was 5 m i n i m s t . i .d .

H e was r e . a d m i t t e d on 29 /10 /42 , h a v i n g b e e n free o f s y m p t o m s a n d in good g e n e r a l cond i t i on s ince d i scharge a n d h a d done ful l f a r m i n g work. H i s sp leen was a b o u t 4 ins. below t h e cos ta l m a r g i n , h i s t o t a l whi te cell c o u n t was 50,000, r ed cells 4.5 mi l l ion a n d H b . 6 0 % . Clinical e x a m i n a t i o n was aga in nega t i ve , b u t t h i s t i m e DI ~. E u p h a n Maxwel l f o u n d a h a e m o r r h a g e in t h e r igh t eye , a b o u t l .~ disc d i a m e t e r s , to t h e n a s a l s ide o f t h e lower edge o f t h e disc. T h e dosage o f a r sen ic a n d t h e whi te cell c o u n t a re s h o w n in t h e figure. B y 18/11/42 t h e wh i t e cell c o u n t was 9,500, a n d t h e sp leen 3 ins. below t h e cos ta l m a r g i n . On 23/11142 t h e p a t i e n t first c o m p l a i n e d o f d i scomfor t on t h e soles of his feet ~ e x a m i n a t i o n showed cons iderab le degree o f th icken ing , which m a y be i n t e r p r e t e d as a n a r sen ic hype rke ra tos i s .

Cases of leukmmia do not occur with sufficient frequency to allow individual physicians great experience, and it is probably true that radio-therapists see the greater number, which makes tile assessment of treatment difficult. It is not suggested by t"orkner that arsenic treatment is superior to that with x-ray, hut it would appear to have the following advantages : - - (a) it is everywhere available, (b) it is less expensive, (c) the dosage is more easily controlled.

The total amount of radiation which can be given with benefit to any case is limited and it would seem a reasonable procedure to reser~e x-ray treatment to a later stage; in other words, the treatment would begin with arsenic and only when this had lost its effect would x-ray therapy be employed.

On paper at least, such a routine should increase somewhat the expectation of ]ire and the most potent treatment would be kept

C H R O N I C M Y E L O G E N O U S L E U K ~ E M I A 93

u p o n e ' s s l e e v e , ~as i t w e r e , to d e a l w i t h t h e t e r m i n a l a n d u s u a l l y d i s t r e s s i n g s t a g e o f t h e d i sease . I n a n y c o n s i d e r a t i o n o f t h i s m a t t e r i t is w e l l to . r e m e m b e r t h a t t h e a v e r a g e d u r a t i o n o f l i fe , f r o m t h e b e g i n n i n g o f s y m p t o m s , w a s 3.5 y e a r s in p a t i e n t s t r e a t e d w i t h x - r a y , a s a g a i n s t 3.04 y e a r s i n t h o s e u n t r e a t e d . T h e s e f i g u r e s a r e f r o m a s e r i e s p u b l i s h e d b y Mino~ a n d h i s c o l l e a g u e s (1924) , a n d as t h e d i s t r i b u t i o n ~curve h a s a v e r y w i d e b~se, t h i s d i f f e r e n c e i n t h e m e a n h a s n o t m u c h s i g n i f i c a n c e . I n b o t h g r o u p s , t r e a t e d a n d u n t r e a t e d , m a n y p a t i e n t s d i e w i t h i n t w o y e a r s , a b o u t 12 p e r c en t . l i v e m o r e t h a n f ive a n d u p to t e n y e a r s s u r v i v a l f o r ;~ l o n g e r p e r i o d is e x t r e m e l y rare~ 1 h a v e n o t f o u n d a m o r e r e c e n t se r i e s , a l t h o u g h I a m s u r e s o m e h a v e b e e n p u b l i s h e d , a n d I h a v e f o u n d no c o m p a r a b l e f i g u r e s f o r :arsenic t r e a t m e n t . I t is r e c o g - n i s e d t h a t s y m p t o m a t i c . i m p r o v e m e n t a f t e r r a d i a t i o n is v e r y g r e a t , b u t I b e l i e v e i t is no less so b y t h e a r s e n i c m e t h o d .

THE MEDICAL RESEARCH COUNCIL OF IRELAND

The Medical Research Council of Ireland has made the following awards :

Dr. STEPHANIE W H E L A N : Whole time grant to carry out a goitre prophylactic scheme in the Dispensary Districts of Clonmel and Kilsheelan under the direction of the Goitre Committee of the Medical Research Council.

Dr. H. E. COUNIHAN : Part t ime grant to undertake (i) a tuberculin survey of patients attending the Rotunda Hospital, (ii) the calculation of death rates in different age groups for the counties of Ireland, (iii) the correlation of these rates with environmental factors. Professor T. W. T. Dillon will direct the research.

Dr. S. J . BOLAND : Grant-in-aid to enable him to undertake an investigation into the association of still-birth or nee-natal deaths with certain adverse pelvic characteristics, the work to be carried out at the National Maternity Hospital ~mder the general direction of the Master.

Dr. N. F A L K I N E R : Grant-in-aid in connection with his work on placenta! infarcts.

Dr. F. GEOGHEGAN and Dr. E DE VALERA : Grant-in-aid to enable them to undertake an investigation into the aetiology of pregnancy toxaemia, and a part time grant to Dr. Geoghegan. The work is to be done at t h e Nationa! Maternity Hospital under the direction of Professor J. McGrath.

Dr. P. L. B R E N N A N : Grant-ln-aid for technical assistance and materials for an investigation into tuberculosis under the direction of Professor J. McGratb.

Prof. W. J . E. JESSOP: Grant-in-aid for an investigation of rickets in children in conjunction with Dr. W Collls and Dr. H. Pringle.

The following have had their grants renewed for further periods: Dr. T. E. T. BRADSHAW. Professor J. F. DONEGAN, Dr. E. M. MASON, Dr. D. K. O'DONOVAN. Miss E. O'MALLEY, Professor R. A. Q. O'MEARA. Professor R. SACHS.

4th March, 1943.