JOURNALOF

[NDIAN

PEDIATRICS

THE P R O B L E M OF THERAPY IN ACUTE LEUKAEMIA* A.

P. MULLIGK

Calcutta in acute leukaemia the I~lood picture is characterized by an abnormal ~,~oliferation of primitive white blood cells It has been observed in 50~ more cases of acute leukaemia, that the" leueocyte count is higher tha/n g0rmal, and in the remaining cases either the leucocyte count is either ~0rmal or below normal, i.e., at the leucopenic level. According to VmcHOW ey are termed a-leukaemic forms. A c u t e leukaemia is not uncommon in children Statistics of WARD oW the greatest incidence to be in the first five years of life. Although it may develop at any time of life, only 1 9 ~ of his cases were in persons over .ifty years. From the clinical point of view, acute leukaemia may be classified ~ccording to the predominance of the type of immature white blood cells in the circulation, either lymphoid or myeloid. The acute cases in childhood ire9 according to DAMASHEK2 of the lymphocytic variety; granulocytic and monocytic variety under twelve years of age being quite exceptional. In ~ose~ cases where the white cells are of an exceedingly primitive variety, .t is very difficult to classify them and it may be called leukaemia of the stem cell" type. T h e predominant cells in the bone marrow and in the ?eripheral blood are the blast forms 3. According to HEIr.MEYER% acute .eukaemia may be termed " i m m a t u r e leucosis", because the classification if immature cells is not possible. However, under the influence of modern '.herapy more exact diagnoses can Be made as the maturation of the immature ~lood cells are noticed during the treatment 12. i[[ For some unknown reason acute leukaemia predominates in the male, jsually in the proportion of 3 : 1. In acute leukaemia the expected duration 5f life is three months or more. :7 There are different opinions regarding the occurrence of leukaemia. Some consider it to be an infective process; some to be of neoplastic origin, while others think it is due to lack of balance in regulation of the production ~n~:maturation of leucocytes by a soecific factor in the circulatin g blood 9 ~_?~ 9 . ~;: The infective theory does not hold good, because of the fact that no ~ a m s m could be ehclted xn the transmission of this disease. It has been ~,~

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~'~,~z, From ,the Universitlits-Kinderklinik. , _(Vorstand -. Prof. K. Kundratitz) in Vienna. ~,~> Subrmtted for pubhcatlon on February 6, 1956.

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Indian ,~ournal oJ Pediat~r

Jbund tl)at d u r i n g s,-vcre inli;ctions like p n e u m o n i a th,. leucocyte cou'~ can rlsc to as high as 100,000 per c.mm.; it has also I~een s~wn that durini such high lelzcocytosis a shift to the left of the polymorl)h,muehzar neutroph!~ occurs somethnes accompanied by th," presence of myeloblasts and myel0~ cytes in the peripheral blood. Experimentally, leukacmia is transmissible" " Ir~"~ fowls only by a cell free filtrate fi'om a series of leukacmia t~wls. Lymphocytk. leukaemia has be,:n transmitted in the mice, by injection of blood fron~ infected mlcc. But intravenous injection o f l c u k a e m i a blood to h u m a n being~ have failed to produce the disease, and all attempts I~, tr~nsmit the disease to lower animals by injection of blood or tissue ~.xtract pr,,ved of no value. Besides thcs% the relation o[" the m o t h e r to the i n l ~ n t d o c s n o t s u p p o r t the infective theory, as it has been found that leukaemic mothers may give birth to normal, healthy infants. Vice versa a leukaemi.c baby in the first few months of llfe, does not have leukaemic parents. R e g a r d i n g the neoplastic theory there is ample evidence that leukaemia resembles neoplasm. T h e Cancer N o m e n c l a t u r e C o m m i t t e e was of the opinion that the leukaemic neoplastic diseases arising in the h a e m o p o i e t i c tissues are closely related conditions, although it should bc clearly understood that the m a l i g n a n t nature o f these diseases has been unequivocally established. It was u n a n i m o u s l y agreed that this whole group of conditions should be classified together u n d e r the etiologic category of " n e w growth originating in specialized mesenchymatous tissue". Since they are all included in discussions of malignancy, and the therapy currently in use for the diseases is the same as is used for unquestioned m a l i g n a n t neoplasms, it was agreed that until conclusive evidence to the contrary is available, they should be classified together as m a l i g n a n t tumours. MILLER AND TURNER (1943) have noticed the presence of certain substances in the urine of leukaemic patients and normal ox liver, which have a specific control over leucocyte production and maturation. T h e extract of urine from myeloid leukaemia, when injected into animals cause myeloid proliferation; likewise lymphoid proliferation is caused by the extract of urine from l y m p h a t i c leukaemia. In acute myeloid or lymphatic leukaemia only myeloid or l y m p h o i d substances respectively are said to be present in small amounts. Therefore the normal leucocyte count is said to be m a i n t a i n e d by a balance between the effects of the normal small a m o u n t s of lymphoid and myeloid substances present in the body. Chronic myeloid leukaemia is caused by the presence of a large a m o u n t of myeloid substance with no lymphoid substance. T h e reverse is also t r u e f o r l y m p h a t i c leukaemia. .~EPOR'I." OF A C A ~

"ll~e following is the case history of a boy suffering from acute lcukacmia treated in tile Universitgts-Kinderklinik in Vienna. Case No. 702/55 M.R., male child, age 589years. The child was the fifth son of his parents. He was always hale and heart),, never became ill and was never in b~_,dfor a long time. Occasionally he used to get tonsillitis and pain in the right ear. His parents and grand-parents ncver had any disease which bore a relation to the child's history. Three weeks prior to his k

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~t~,on to the Clinic the child ~uddenly got ill. He felt very lir~:d and prefi:rred 1o lie down. ltcr on he developed fi-ver. The parent~ consulted the doctor, who prescribed some ~ir the child did not improve and l~:eame wnrse, l l;: crew very pale and tim [omen enlarged day t,y day. He lo~t his appf:tile. The parenls were very worried and conthe doctor again, when he wa~ .,ur to the countryhospital. The boy all along w,xs ~ing a temperature of 38~ ~;In the country hospital physical r revealed .~:vere anaemia, pallor and ~ttrcmc enlargement of the spleen. Gr162 enlargement of tbe lymph glands were ~1.Io noticed. Temperature: was 38.5" C., B.I'. !10[75 ram. Hg. B l ~ d examination ~li~losed file following findings: Hb. 30~,, red cell count 1,8(~),OA)0 c.mm., colour indr I, and [r count 12,fXI0 e.mm. The differential count of the pcripb,:ral blood showed pathological forms of myelobla.,d.s (98-50/o) and neutrophils (1"5~ FiR. 1. Urine: and ..ray examinations did not show any important findings. Therapy with cobalt-iron and vit Bt~ was started and a provisional diagnosis of acute t~yeloblastic leukacmia w~.s made. ~Afterwards the child wa_q brought to the Universitiits Kinderklinik in Vienna on 2.5.55, ~hen physical examination revealed that the child was severely anaemic. T h e height of the ~hild was 105 cm.,i.e. 6 cm. below the standard height fijr his age, and thr weight 17.7 kg., having been 0:2 kg. more than the normal weight. There were peticheal haemorrhage.s on the back between the scapula, on the thighs and legs and over the tibia. The haemorrhages resembled the bites of fleas. There was also bleeding from the gums and tonsils, which were enlarged and congested. The tourniquet test was positive. There was gencraliscd enlargement ~f the lymph glands, which were not tender to the touch. The feel was shotty; the glands ~r discrete and the size varied from a pin's head to a pea. Cervical, occipital, cubital, axiUary, sulcus bicipitalis medialis and inguinal glands were all enlarged. T h e lungs were normal. The heart was not enlarged, the first sound was loud and there was a systolic murmur, which could be heard with m a x i m u m intensity over the third intercostal space at the junction of the sternum on the left side. The abdomen was enlarged; the liver was enlarged two fingers below the costal margin, consistency was hard and the margin sharp. The lobe. of the liver was very m u c h enlarged. T h e spleen was enlarged four fingers from the costal margin and the consistency was hard. T h e umbilicus was in the same plane as that of the abdomen. T h e urine was normal in all respects. T h e blood group was A, R h factor positive. W.R. was negative, sedimentation rate (W) 120./172 ram., Hb. 20~o , erythrocyte 1,120,000 c.mm., colour index 0"90, leucocyte count 16,250 c.mm., pathological forms 99-5~ segmented 0.5~/o, thrombocytes 1,120 c.mm., reticulocytes 5~ bleeding time 40 minutes, coagulation time 389 minutes. Resting nitrogen 36 rag. %, total serum protein 5-6 gin. Bone marrow findings were: micromyeloblasts 99~ segmented forms 1%, occasional erythroblasts and megakaryocytes. X-ray examinations of the heart revealed a normal configuration and hilar glands were not enlarged. T h e skull from the lateral view did not show any destructive process. T h e hip-joints of both anterior and posterior views showed a soft oblique band in the region of the proximal end of femur, and on botii lower extremities, these were more marked on the left than the right. A light soft band on the end-plate near the diaphysis was also visible.

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TIIERAPY AND COURSE

Repeated blood transfilsions for a period of 9 days were given each day, the patient t'eceiving about 100 c.c. of blood. He was given 100 nag. cortisone a day along with vitamin [~a~ and Hepsol 89ee. on alternate dax~. This therapy improved the red blood cell count and haemoglobin and the leucocyte count diminished to 1,200 e.mm. by 10.5.55. (Table 1). T h e E.C.G. on 3.5.55 showed tachyeardia 143 per rain., a low T in lead II, normal augmented Goldberger leads and a normal chest lead. Phonocardiogram revealed short proto-systolie murmur~ the sounds being exact in time. i i) O n 18.5.55 electrophoresis revealed total protein 4"8 gin., albumin 64.4% a 1 and 2 globulins 10"8%, fl globulins 7-4%, and ~, globulins 17-4%. Bone marrow aspiration after

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Table t. This shows the course of the di.sca.sc and the form of therapy initiating the process of maturation of the immature white blood cells in the peripheral circulation.

Fig. 1. Blood film showing myeioblasts before treatment

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]"erspY showed improved erylhropoiesls, decrea~, in the blast forms, and increase in the ~0re mature let,coeytes: mieromyelobla~ts 19%, metamyeloeytes 390/0, unsegmented ~nular form~ 18%, ~grnented forms 8%, lyrnphocytcs G~ retk-uhlm cells 7%, plasma Ils $%, shredded nuclei 10 per 10(I white hloc~l cells, pro-erythrol,lasts 12 per 100, macro~tl 284 per 100 W.B.(;., normobl~.sts 324 per 1(~1 W.IL(.;., mittmls of red cells 16 per 100 ire blood cells. The peripheral bloegl picture rt.wealed mieromyvl~w.ytes31"5%, paraf'orms ~%, ~gmentecl granular forms 60%, eeminophils 3%, and a tolal leucocyte count of 2,000 ,am., erythrocytes 2,2211,Cq)0 c.mm., haemoglohin and reticulocyle count 51%. The jld for the first tlme felt belier since he became ill anti sat tip in bed ~m 25.5.55. E.C.G. was lone ,n 24.5.55. The standard leads were absohltely normal with a I,nl~e frequency of 94train. the phonoeardiogram was the same as heft,re. ~ Corti~,ne tablel.s wvre ~tiw,n only once a day (25 ml-.) from 6.fi.55 as the peripheral g~lood picture showed marked improvement and the thrombocyte count was 300,000 c.mm. [A, normal. On 10.6.55 bone marrow puncture reveah:d promyelf~cytcs 3%, myelocytes I%, meta~yelocytes 18%, un~:gmented granular forms 12%, segmented forms 4G%, monocytes 1%, lymphocvtes I i%, large lymphocytes G%, macroblasts 4 per 100 white: blood cells, aormoblasLs 9 per 100 white blrgx] cells. Shredded nuclei 44; per I(~) white blocgl cells. ]'he peripheral bltmg_l picture showed' Hb. 80o/0, red blr215 cells 3,800,000 c.mm., eucocytes 5,500 e.mm., micromyelocyte~ 7%: promyelocytes 1~ myelocytcm 2%, unzgmented granular forms 2%, se~4mented forms 49-5%, (Fig. 2), lymphocytes 38%, o~nophils 0"5%. ~' On I i.6.55 the child suddenly had a high temperature of 39~ but no evidence of any ~mific cause of the fever could be found out. However, cortisone therapy was withheld and he child wa.~ normal on the next day. Henceforth the child felt better, and there was marked mprovement in the general condition. The murmur in the heart disappeared. The child was lischarged from the hospital on 17.6.55, with a daily dose of cortisone 12.5 rag. as he showed ~omplete remissions in both clinical and pathological findings. Further progress of the child xmid not be. followed up as the child died on 10th September; 19.55.

DISOUSSlON I t h a s b e e n a p r o b l e m to f i n d o u t a s u i t a b l e a n d s a t i s f a c t o r y t r e a t m e n t of a c u t e l e u k a e m i a , as no t h e r a p y i n t h e p a s t p r o d u c e d a d e f i n i t e r e m i s s i o n for a l o n g p e r i o d . E v e r y o n e has b e e n in s e a r c h o f a n a g e n t w h i c h c o u l d give c l i n i c a l a n d p a t h o l o g i c a l remissions for a l o n g d u r a t i o n . T h e t h e r a p y consisted o f a n a t t e m p t to c o n t r o l t h e s y m p t o m s like a n a e m i a , m a t u r a t i o n of y o u n g w h i t e b l o o d cells a n d to p r e v e n t t h r o m b o c y t o p o e n i a . T h e j u d i c i o u s use o f s u c h s u p p o r t i v e m e a s u r e s as b l o o d t r a n s f u s i o n , c h e m o t h e r a p y , i r o n a n d v i t a m i n s h a v e g i v e n c o n s i d e r a b l e t e m p o r a r y benefit. F o w l e r ' s s o l u t i o n was a d m i n i s t e r e d in t h e t r e a t m e n t o f a c u t e l e u k a e m i a since 1860 a n d m a r k e d i m p r o v e m e n t in t h e f o r m o f c o n t r o l o f fever, r e d u c t i o n in the l e u c o c y t e c o u n t , d i m i n u t i o n in t h e size o f t h e s p l e e n a n d i m p r o v e m e n t in a n a e m i a was o b s e r v e d b y FORKN~-R~ in 1938. T o get t h e s a t i s f a c t o r y result F o w l e r ' s s o l u t i o n was p u s h e d to t h e l i m i t o f t h e p a t i e n t ' s t o l e r a n c e a n d it was f o u n d tha~; u n t o w a r d s~n-nptoms used to d e v e l o p b e f o r e t h e d o s a g e w a s r e a c h e d . :.,~~9 I r r a d i a t i o n t h e r a p y was also r e c o m m e n d e d , b u t u n f o r t u n a t e l y it was iV6und"~that in a c u t e l e u k a e m i a it m a d e the s i t u a t i o n worse. DAMASI-mKOh a s s t a t e d t h a t a c u t e l e u k a e m i a was p r o d u c e d w i t h i n a p e r i o d - o f o n e m o n t h in series o f t h r e e cases, to w h o m R 6 e n t g e n r a y t h e r a p y w a s a d m i n i s t e r e d

Indian Journal of reaza'"'~

272 'lJ.~ etucocoRncolos ,~MINOtrI'ERIt~ m.~O ~OO1) TP~$r~/OM bS, ~U.IIll21,

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T a b l e 2. T h i s shows the quick response of the leucocyte c o u n t w i t h a m i n o p t e r i n in a case o f a c u t e m i c r o m y e l o b l a s t l c i e u k a e m i a with christmas disease (by Z w e y m u l l e r a n d Deutschln).

Fig. 2. Blood fihn of s a m e p a t i e n t after t r e a t m e n t showing s e g m e n t e d fi~rms.

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i'or the treatment of byperplasla of the thymus glands. X-ray therapy if ;~zautiously administered, ILas been fo~md to be of considerable hel l) in the i~emporary control of the recurrent bone pain commonly encountered in eute leukaemla. ~! During the last world waft in 1940 a chemotherapeutic agent like 'nitrogen mustard was fimnd to be directly injurious to the cell with respect to their rate of growth. Therefore clinical trial was made in cases of acute leukaemia. CIIAnl.F.S L. Sv~:n et al ~ in their papers have mentioned that the late toxic manifi:stations of acute and chronic leukaemias may be aggravated by the use of nitrogen mustard. But they have observed that courses of two or three standard doses or reduced average daily doses of D'5 mg. per kg. body weight had established the individual sensibility to the drug. This procedure was successful in bringing down advanced cases as well as to prolong the repeated remissions. Later on it was found that this ']rug was spectacularly useful in the treatment of Hodgkin's disease and ~eneralised lymphosarcoma. Urethane in 2-4 mg. doses orally in children in the early stage of the disease was found to be very useful, especially in cases of chronic granulocytic [eukaemia. It was generally used as maintenance after X-ray irradiation in chronic leukaemias. In 1949 SKn'VER 9 demonstrated a possible synergistic tction between urethane and methyl (chloroethyl) amine nitrogen mustard against myeloid leukaemia in 1,394 mice, without at the same time increase n toxicity. It has been observed that in acute leukaemia, injection of folio acid conjugates pteroyhriglutamic acid (teropterin) and pteroyl diglutamic acid (diopterin) has an "acceleration phenomenon" in the leukaemic process in the bone marrow of the patient. FARB~IO0 in his studies of folic acid deficiency suggested that antagonists of folic acid might have a beneficial effect in the treatment of acute leukaemias. The action of this drug seems to have a selective affinity for nucleic acid antimetabolities. FARrieR in his series of 16 cases treated ~4th folie acid antagonists, observed clinical, pathological and haematological evidence of improvement in 10 cases, with a duration of remission of three months. The rest of the cases did not respond well, out of which four died. H. G. PONen~R et al xl compared 48 acute teukaemic patients (Group A) studied in the past twenty years with 38 who were treated with folio acid antagonists (Group B) in 1948-51. Aminopterin therapy was begun with 1 rag. parenteraily for two days and continued with 0-5 rag. orally each day thereafter, until a remission in the marrow was noted. Blood transfusions in both the groups were given as supportive therapy when indicated. The patients who showed bone marrow remission converted to a normal marrow a t a mean of 8"9 weeks. Actual bone marrow remissions persisted for an average of 9"4 mondas in 12 patients. The mean duration of life after initial symptoms was 5-45 months in Group A and 13.3 months in Group B. Aminopterin was markedly beneficial in cases with a high leucocyte count, specially over 20,000 per c.mm. It has been found that after the

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Indian 7ournal of Peazag '

administration of the drug there is delinite diminution in the leucoc~1 count and within a few days there is evidence ofleucopenia in the p e r i p h e ~ circulation j~ (Table 2). It has been observed that to get the best resu!~ the drug must be continued for a longer period, in which side effects l[l~ nausea, w~miting, diarrhoea, stomatltis and haemorrhage J?om the mue0~|-z~| membrane are common. Therefore the use of the drug was restricted |'~ :" cases of acute leukaemia with a-]eukaemic or sub-}(:ukacrnic forms. Amethopterin, a less toxic but less effective form of the fi~lic ac.{.~ antagonists, was used in 5 rag. doses. But side. r were also common. ~*:.~ Purinithal (6 mercaptopurine) antagonist ~f nuch:oproteln desoxyrhi~ bonuclease has also been tried for lytic effects upon the proliferation o~ leukaemic process. It has the same percentage of cure in children with acut~ leukaemia as aminopterin and is less toxic and can I~e useful in relapse. U ~ to 14 years of age the remission is 70'~, and the average life time is more~ than a year. Y,~ Cortisone or A C T H alone was found to be of immense value in th,~ treatment of acute leukaemia with either normal or subnormal leucocyte. counts. Between 30 and 50 per cent of patientg respond to treatment with either agent. I n combination with aminopterin in the treatment of acut~ teukaemia it has the following advantages. (1) It enhances the effect of ami~ nopterin. (2) Greatly enhances remissions. (3) Reduces the toxic effects of~ aminopterin (4) Decreases the bleeding tendency common in acute leuk-~ aemia specially with aminopte.,-in therapy. (5) It produces a myelostimulatory effect when bone marrow aplasia has been induced by aminopterin. The modern teatment with gluco-corticoids makes it also possible to distinguish if the stem cells are of the myelotic or lymphatic system ~. Because we often see under this therapy an increase of the more mature forms of the pathological cells this maturation makes it possible to classify them as belor_ging to the myeloid or granulopc, ietic system. As these gluco-corticoids lower the resistance of the patients, its use should be accompanied by antibiotics to prevent the possibility of intercurrent infection. The blood pressure should be recorded daily to determine the elevation of the pressure. The diet should be salt free in order to lessen the accumulation of sodium ions in the tissues and potassium ions in the form of potassium chlorate or better citrate should be administered to replace the potassium ions loss during the therapy. Sometimes there is glycosuria during the treatment due to the effect of the steroid on the renal tubules, therefore urine should be tested for appearance of sugar. Calcium should be administered during the therapy for improvement of the capillary endot h d i u m . If there is evidence of atrophy of the adrenal cortex A C T H should be replaced by cortisone alone. ~::~:ACTH combined with aminopterin in children with acute leukaemia produced an eighteen-month period of complete remission in 25 out of t h e 96 cases 13. The remission in childhood leukaemia, both leukaemia and a~l.eukaemic, appeared within one to six weeks and were maintained for ~ r i o d s of four weeks to ta~,o years. .?

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Tr~ethylene melamine (T.E,M.), a "broad spectrum" chemo-therapetllJC agenl, was found to I,c most usefid tbr therapeutic purposes, if use(1 :with appropriate caution. The drug appears t~ be of great value in chronic leukaemias, ]yrnphosarcomas and lymphogranulomas, in chJ'ozfic lcukacmia more than 5W~, of both clinical and pathological remissions after a course ~f therapy with T.E.M. have been noticed. : It would not be ~,ut oF place to give here a fi:w details of the :0utlne treatment of acute leukaemla in Germany, although every clinic has its ~wn schedule.. It is not known yet whether the e~mdfination of glucocorticoids with antirn~:tabolites, AC'I'H alone, or cortisone alone is the best. It is clear that all these difficulties do not arise when the question of the treatment oF acute ]eukaemia with the a-leukaemic form arises. But the treatment of ieukaemia with a high leucocyte count seems to be a difficult ~me. The following are three schedules of treatment fi'om German schools. In the Universit~ts-Klinik of Leipzig l~, during the acute stage A C T H 2-3 mg./kg, body weight is administered daily. Cortisone 3-4 mg./kg body weight can also; be daily' given. In case of relapse the antimetabolites like purinethol (50-0 nag.) in doses of 2"5 mg./kg, body weight is given daily. This treatment is continued for four weeks. Aminopterin (0.5 mg.) in doses of 89 tablet daily is given instead of purinethol and the duration of treatment generally does not exceed three weeks. In the latent stage, i.e. during remission, the antimetabolites in the dose of one-half of the dosage prescribed during the relapse is given as maintenance and this is continued for a few months. Supportive treatment, like blood transfusion when necessary, is given, and antibiotics are given to combat intercurrent infection. Urethan, X-ray, nitrogen mustard and T.E.M. are not used by this school. In the Medical Academy of Dusseldorf jz they differentiate the progress of the disease into two categories, by virtue of their clinical experience-The frst group, where the course seems to be very rapid and the second group, where the course of the disease is more slow. In the first group of cases, (1) aminopterin 0"25 nag. daily to younger children and (2) 0-5-1 mg. daily for older children are given for two to three weeks. Cortisone is given to smaller children in doses of 100 mg. a day for 30-40 days, (3) blood transfusions every three to four days are given till th~ erythrocyte count reaches 4.5 million per c.mm. In the second group of cases, where the course is usually slower, purinethol in doses of 2"5 mg/kg, body weight a day is given. The expected period of remission appears in 30-35 days. This therapy is supported by blood transfusion. In case the patient becomes worse, cortisone is added. During the period of remission, the Dusseldorf School observes the following line of treatment : (1) Aminopterin, 0'5 nag. daily in thefirst week. (2) Cortisone, I0 rag. daily in the second week. (3) Purinethol, 1-2 rag. daily during the third week. (4) Aminopterin is again administered in the fourth week.

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During relapses they follow the same llnr of treatment as in the stage, bt~t with higher d~mes and the dlwation of treatment is proloi Cortisone, 150-200 rag. daily is given, l~,rlnethol, 2'5 mg./kg, body w~ is also given and it is gradually increased up to 4 mg./kg, body weight a~] O n e should see that resistance at~ainst the therapy is not established dlJ the treatment. In the Vienna Universit~its-Kindcrklinik, i n cases where the .t~ leucocyte count is low, i.e. in a-leukaemic f~rms, only gluco-corticoids 11 A C T H or cortisone is given. In case:s where there are signs of msulficten of the cortex of the adrenal glands, cortisone is preferred. During the trel m e n t with A C T H or cortisone, when the Cushing's syndrome develops, dosage is lowered and if there is a high blood pressure, it becomes necess~ to stop the therapy. During this therapy sodium intake is restricted and~ there are symptoms of hypopmassem,.'a, like adynaemia or findings in't] E.C.G., potassium salts in the form of potassium citrate (I-0 gr. 2-3 tin] daily) is given. If there is high leucocyte count, aminopterin or purineth.' together with glucocorticoids are given. During this therapy, one n,ust very cautious about the leucopenia. If the total leucocyte count is ab0i 15,000 e.mm. aminopterin must be stopped, because there is possibilii of the further lowering of the leucocyte count even after the cessation of t~ therapy. If the leucocyte count rises later on, aminopterin or purinethol again added (Table 2). Naturally during this m o d e r n therapy it is necessar to give vitamins specially B and C. The old therapy of blood transfusio in similar doses is frequently administered. If there are no symptoms, th patient is allowed to go home with the advice that cortisone should b continued in smaller doses.

SUMMARY AND CONCLUSION

The problem of the therapy in acute leukaemia is stressed in this article.:~ T h e significance of the therapy with glucocorticoids is shown by one case,~ as there was a total remission by this therapy during the stay in the Clinic~ and this was maintained by the daily administration of cortisone at~ home. The comparative study of this case shows a definite clinical anct: pathological temporary remission of the acute stage, treated with cortisone. It-has been observed that with cortisone or A C T H clinical remission is obtained within a few weeks of the beginning of the treatment. " This is a case of micromyeloblastic leukaemia, because u n d e r t h e treatment with cortisone was seen a maturation of the blood picture in favour of the myeloblastic form. Therefore it can be emphasized that a temporary remission lasting fi-om several weeks to months can b e obtained by this m o d e r n therapy although there is no cure for this dreadful disease. In the case discussed remission lasted for about two months, after which the clfild died,

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mtw, G.---Brithh .7. (i'hi/d. Di~., 14~ 10, 1917. OAMAS~Vv.g,W.---Nem Eng. ,7. of Med,, 250" 13l, 1954. ~'hird, ii,urih and fifth reports of th<"comrr, it~,~- lot classilicafio,, ,,f vhc ,,,,m,~:ncl~ttur,. ,,f ~ ; ~ t cells and diseases of the blond fi~rmir,t~ ,,r~zan.~--Amer. 7. Clin. I'ath, 20 : 562, 1950 ~i]'EtLVlI~yvm, l,,.---Die Bhttk,'attkhoiten, in Itanh. inf. Mcd. 4. Attila. Spring,,r, I'leidclbcrg, I" Bd., 2, S. 628, 1951. I~,~, Mrt.r,F.R, i". R. anti "l'v.TRmt.p,,I). L.--Am~.~..']. Med. Sci., 201/: I.tG, 19t3. ,l;ogKNv.g, G. l';.--l.,~:uka<:rnia atH] Alli~:d J)i.,uwd(;v's., A,Iacmillan Co. N.Y. Ist F,(I., 1931:I. i~,,, GOOI)MA,'%i,. S. el. a[. --J.A.M A , 132 9 126, 19r ~..~. ,~I'UR, CIIARI.ES, S.MITII"1".,1{., and BI.or M.--Am..7. Met/., 8: 710, 1.950. >9. ,.~KIPI'ER, H . E.---Ca~er, 2:475, 1949. gO. FARBISK,.~., DfAMO.~IJ,L. K., MV.RCER, R. D., SYI,VESI'ISR,I/~. I". JR., and ~,~r m.-.~ .New. Eng...7. oj Med., 238 : 7 8 7 , 1 9 4 8 . , g!, POUClIER, J. H., W^,s~AN, J. A., g,cn,~oN,, J. 1,., IIORAK, O A., and LI~aAR/A, ~" L.R.--oT. Pediat., 41 : 377, 1952. 12. GAss~a, (3. and CRAMER, R.--fteh,. flaed. Acta., 8: I(), 1953. /J3. Blood Rr Laboratory: New England Ccntrc Hospital. UrJpublishcd data. ,.,]4. OeuvrE, J.--Arztt. Woch., 10: 15, 1955. !!5. HtrrH.--55 Tagung dcr Deutschen Gt~'llschaft---Fur Kindcrhcilkundc, Frciburg 1: ~ 11, 1955. ~6. Zw~imuller E. and Deutsch E.~Micromye!oblasten leukaemia with Christmas Disease, ~' "~lia Clinica international (Spain) in press.

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i:'.;-" I am grateful to Assistant DR. ZWIgYMULLERfor his kind guidance and help in obtaining the material for this article,