59
THE TREATMENT OF ACUTE LEUKAEMIA IN ADULTS WITH 6-MERCAPTOPURINE * By M. G.
NELSON,M.D., F.R.C.P.I., and J. LOWRY,M.B., M.R.C.P.I.
URING a study of nucleic acid metabolism Hitchings, E lion e t a l . ~ investigated the biological effects of a large series of possible antimetabolites of the purine and pyrimidine bases of nucleic acid. During these investigations it was demonstrated that 6-mercaptopurine was an effective purine antagonist. Previous work had suggested some possible differences between normal and neoplastic cells in the metabolism of purine. These experimental facts aroused interest in 6-mercaptopurine as a possible effective chemotherapeutic agent for the treatment of neoplastic diseases. An extensive series of experiments showed an inhibitory effect by this compound on malignant mouse tumours and mouse leukaemia. It was not long before 6-mereaptopurine was subjected to clinical trial. Burehenal 2 investigated the effect of 6-mercaptopurine on 269 patients suffering from various kinds of malignant neoplastic diseases. The drug was found to be of no value in the treatment of carcinoma, sarcomata, ttodgkin's disease, lymphosarcoma or chronic lymphatic leukaemia. It caused remissions in the early stages of chronic myeloid leukaemia, but was most effective in acute blastic leukaemia particularly in childhood. Of the 50 adult eases of acute leukaemia in Burchenal's extensive series he produced satisfactory remissions in only 17, with failure in the remainder. In a later paper, Bethel e t al. ~ reported no good remissions in cases of acute leukaemia over 35 years of age. These general findings have been largely substantiated in numerous subsequent reports from many eentres. This present report is concerned with the treatment of 10 cases of acute leukaemi$ with 6-mercaptopurine carried out during the past two years at the Royal Victoria Hospital, Belfast. Of the 10 cases, 6 were males. The ages varied from 19 to 60 years. All were examples of acute leukaemia either because of the nature of the leukaemic cells present or in their onset and clinical course. They were classified as follows :
D
Monocytic leukaemia . . . . . . . . . . . . A c u t e blastic leukaemia . . . . . . . . . . . . Leueopenic blastic leukaemia . . . . . . . . . Acute blastic phase in chronic myeloid leukaemia ...
5 2 2 1
Of the acute blastic leukaemias no attempt has been made to impose any separation into types, because of the well-recognised difficulty of classification of primitive cells with any degree of accuracy. After diagnosis, patients were put on 6-mercaptopurine therapy in standard dosage of 2.5 rag. per kilogram of body weight. This was continued until a satisfactory remission had been produced or there was * From the Department of Clinical Pathology, Royal Victoria I~ospital, Belfast.
60
IRISH JOURNAL OF MEDICAL SCIENCE
evidence that the condition was refractory. In some instances cortisone was given with 6-mercaptopurine as adjuvant therapy. The remissions obtained could be classifed into clinical, haematological or complete. A clinical remission was one in which there was clinical improvement without significant change in the peripheral blood or bone marrow picture. The changes produced were a fall in pyrexia, increased sense of well-being, disappearance of signs of bone pain or lymphadenopathy when present, and cessation of any haemorrhagic manifestations. A haematological remission was also accompanied by clinical improvement, but here the abnormal cells disappeared from the peripheral blood. Concomitantly the haemoglobin level and platelet and differential counts returned to nol~nal. A complete remission was one in which clinical and haematological remission were associated with a bone marrow in which the primitive or abnormal cells constituted less than l0 per cent. of the total. In some cases where a satisfactory remission was produced 6-mercaptopurine therapy was temporarily discontinued, but in others a maintenance dose of 0"5-1 mgm. per kilogram of body weight was given. During treatment a careful haematological control was kept with special emphasis on the haemoglobin level, platelet count and the total and differential leucocyte count. Bone marrow aspiras wel~ performed to establish the diagnosis and also to assess the effect of treatment. General supportive measures and treatment of complications were a necessary part of management. Blood transfusions were given either to accelerate the rise in haemoglobin or to control or replace blood lo~ from haemorrhage. Cortisone was used not only as adjuvant therapy to 6-mercaptopurine, but also as treatment of haemorrhagic complications. The citric acid mouth wash recommended by Hayhoe and Whitby ~ was given for the troublesome stomatitis, gingivitis or oral ulceration. Secondary infections were treated with appropriate antibiotics. Intramuscular injections were avoided and either oral penicillin or oral oxytetracyeline used. All patients were put on a high protein diet with vitamin B supplements. Case Reports. CASE 1--Leuoopeniv Monocytic Leukaemla. Male, aged 60 years, a d m i t t e d complaining of weakness, lassitude and night sweats. He was clinically anaemic. His haematological findings were : haemoglobin 8.1 g. per 100 ml. : leucocytes 7,000 per c.mm. : differential count--neutrophi]s 8% : lymphocytes 49o/o : monocytes 4% : promonocytes 38% : plasma cells 1%. Marrow aspiration showed-infiltration- with nTlono-eytesin all stages o f development and the picture was t h a t of monocytic leukaemia. A course of 9.7 g. of 6-mereaptopurine combined with cortisone failed to produce any clinical or haematological remission. The patient died three months after the onset of the disease. CASE 2--Monocytlv Leukaemla. Male, aged 49 years, a d m i t t e d to hospital complaining of pain in the chest, duration one day. On examination he was found to have a haemorrhagic disorder with ecchymoses on both arms. The haemoglobin was 13.6 g. per 100 ml. The leucocyte count was 19,800 per c.mm. and four days later had risen to 34,800 per c.mm. Differential leucocyte count revealed that 71% of the leucocytes w e r e primitive monocytes. The diagnosis of acute monocytic leukaemia was confirmed by marrow biopsy. A few days after admission to hospital he developed gross haematuria and purpuric lesions in the mouth. A transfusion of fresh blood was administered a n d t r e a t m e n t with 6-mercaptopurino was initiated. The total duration of treatment w a s only ten days and 1.8 g. of 6-morcaptopurin~ were administered. I-Ie died suddenly 14 days after the onset of the disease from a right-sided intraeerehral haemorrhage. No clinical or haematological effect was produced by 6-mercaptopurine.
T H E T R E A T M E N T OF A C U T E L E U K A E M I A
I N ADUI~TS 61
CASE 3--Monocytlc Leukaemia. Male, aged 42 years, a d m i t t e d to hospital ecru, plaining of anorexia, nausea, malaise, sweating and myalgic pains of three days duration. Pyrexia, cervical and inguinal lymphadenopathy and bony tenderness auaoa't~ | II Jl ! II IIII were present on clinical examination. PLATs The haemoglobin was found to be 5.9 g. per 100 ml. ; the erythrocytes 2.16 x 10 a x per e.mm. and the leucocytes 13,100 per e.mm. Differential count revealed that 55% of the leucocytes were monoblasts. The diagnosis of monocytic leukaemia 6r was confirmed by marrow aspiration, Because of a pulmonary infection he LE t ~ ' W T E S was given a course of penicillin. A blood XIO31CMM transfusion was also administered in 3C order to raise the haemoglobin level. 6-mercaptopurine and cortisone were then given in full dosage, producing two) fl remissions of five weeks' and three weeks' duration, The dosage necessary to produce the first remission was 1.85 g. of 0 20 40 60 80 6-mercaptopurine given over a period DAYS of 14 days. This patient survived five FIe. I--Response of case 3 (Monocytic Leukaemia) to 6-Mcrcaptopurine Therapy. months after the onset of symptoms.
Olc~ :
CASE 4---MonocyticLeukaemia. Male, aged 46 years, a d m i t t e d to hospital complaining of angina of effort, dyspno~a, loss of energy, weight and eolour, duration three months. On haematological examination the haemoglobin was 8.2 g. per 100 ml, and total leucocytes 71,000 per c.mm. Differential count revealed 19% neutrophils, 2]~ lymphocytes, 24% monocytes, 33% promonocytes and 3% monoblasts. The diagnosis of monocytio leukaemia was confirmed by marrow aspiration. Treatment with 3-9 g. of 6-mercaptopurine given in 30 days produced a fall in the leucocyte count to 8,200 per c.mm. and a rise in the haemoglobin level to II g. per 100 ml. A partial haematologieal remission of 6 weeks' duration followed during which a maintenance dose of 25 rags. of 6-mercaptopurine was given daily. Thereafter the leucocyte count rose to 100,000 per e.mm. and the haemoglobin fell to 8-2 g. per 100 ml. ]~epeated blood transfusion, 13 pints in all, and an increase in the dosage of 6-mercaptopurine to 150 mgm. daily produced another partial haematological remission of three weeks' duration. During this course 4.3 g. of 6-mercaptopurine were given. These remissions were accompanied by only slight clinical improvement. The total survival time of this case from the onset of symptoms was seven months. CASE 5--Monocytlc Lcukaemia. Female, aged 51 years, admitted to hospital with dysphagia, loss of weight and appetite and lassitude of seven months' duration. A nasal polyp was removed for persistent nasal catarrh. Subsequently an erythematous papular rash appeared on the legs. The haemoglobin was 10.8 g. per 100 ml. ; leucocytes 48,000 per e.mm. with a differential count of neutrophils 3%, lymphocytes 12~ promonocytes 3o~o and mature monocytes 82o~o. The diagnosis of monocytic leukacmia was confirmed by bone marrow aspiration. Treatment with 6-mereaptopurine produced a partial haematological remission lasting 14 days, which was not accompanied by clinical improvement. Only 1-7 g. of 6-mercaptopurine had been administered over 17 days. The total survival time of this patient from the onset of symptoms was ton months. CASE 6 - - Acute Blastic Leukaemia. Female, aged 26 years, with a history of pleurisy seven months and acute otitis media four months prior to admission to hospital. Following the attack of otitis media the patient had four brief influenza-like illne:ses. One m o n t h before admission she developed painful ulceration of her tongue and gums. The leucocytes were 160,000 per c.mm. of which 93% were primitive blasts. Treatment with 6-mercaptopurine to a total dose of 3.05 g. over a period of 26 days produced a clinical remission, during which the leucocyte count fell to 9,700 per c.mm., but 80% continued to be primitive blast cells despite continued therapy. The platelet count, which on admission was 58,000 per c.mm. rose during treatment to 136,000 per c,mm. Although this patient was kept on a 50 mgm, maintenance dosage of 6-mercaptopurine daily, this remission lasted only 14 days. The survival period after diagnosm was 4,~months. CASE 7--Acute Blastic Leukaemia. Female, aged 26 years, first attended the Dermatological Department with a generalised erythematous rash. l~allor drew attention to clinical anaemia, and haematologieal investigations were carried out. The haemoglobin was 6-3 g. per 100 ml. : the leucocytes were 35,000 per c.mm. of which 90% were undifferentiated blast cells. Treatment with 6-mereaptopurine produced an excellent
62
IRISH JOURNAL OF MEDICAL
SCIENCE
clinical a n d partial haematological response, during which the leucocyte count fell to 3,900 per c.mm. The clinical remission lasted 11 months, during which period there were three haematological relapses which were treated with full dosage of 6! mercaptopurine and cortisone. (See Fig. 2.) Initial therapy of 1"55 g. t~ of 6-mercaptopucine was given ~r t ~ o c ~ r ( s W.tST over 16 days. Maintenance therapy x o $ / C MM of 75 mgm. daily was given during the ensuing remission for 14 days. Four further courses of therapy '11 varying from 2.25 g. to 4.3 g. were 'I ! given during periods of relapse, SO and in all she received a total dosage of 14.6 g. The total survival period of this patient was 16 O 2 months, a n d for 13 months of this 9 i - ~ ~ I I I I I a - ' period she carried out her duties as
a nurse.
MONTHS
O
S
~
IS
Fro. 2--Response of case 7 (Acute Blastic Leukaemia) to 6-Mercaptopurino Therapy.
CAs~ 8-- Leucopenic Blastic Leukaemia. Female, aged 19, was a d m i t t e d to an isolation hospital with a 12-hour history of pyrexia and vomiting and pains in the knees of two days' duration. A clinical diagnosis of food poisoning was entertained. This patient was found to have a normocytic normochromic anaemia, the haemoglobin being 9.8 g. per 100 ml. and the erythrocytes 3-5 • l0 s per c.mm. The leucocytes were 5,150 per c.mm. and the differential leucocyte count--neutrophils 27% ; lymphocytes 70% ; monocytes 3~o. The erythrocyte sedimentation rate was 35 rams. per hour (Wintrobe). Hypoplastic marrow containing a large proportion of i m m a t u r e undifferentiated white cells, t h o u g h t to be myeloblasts, p.k4, I Q -*"-"~%~ I 14 3~ IO0 104 90 plI S2 7~ was aspirated. I n view of the hypoplastic nature of the marrow wC the condition was thought to be a S toxic hypoplasia with a my_elo~id 6 maturation defect. The anacmla ~103/C at this stage was therefore treated b y blood transfusion only. /k repeat marrow examination was done six weeks later and a hypercellular marrow with complete ~b ~ *klli replacement b y primitive blast cells was found. A diagnosis of leucopenie blastic leukacmia was made. A complete clinical and partial haematelogical remission . I L . was produced, b y 1-6 g. of 6-merA Y$ 0 9 I0 ~0 30 40 SO eaptopurine given over a 10-day Fro. 3--Response of case 8 (Leucopenic period. During this remission, Blastic Leukacmia) to 6-Mercaptopurine which lasted two months, 50 rags. of 6-mereaptopurine was given Therapy. daily. A n interesting feature of this case is t h a t radiography of the left wrist and t h e lowdr end of the right femur prior to therapy showed multiple small osteolytic lesions in the metaphysis. Repeat radiographs after t r e a t m e n t for one m o n t h with 6-mercaptopurine showed appreciable regression of these changes. Later, clinical deterioration occurred a n d a course of 2-5 g. of 6-mercaptopurine combined with oral cortisone in full dosage controlled the haemorrhagie disorder associated with this relapse and produced some clinical improvement. Despite temporary remission the patient died five m o n t h s after the onset of symptoms of the disease.
;/
C A s ~ 9--Leucopenw B~sr Leukaemia, Male, aged 21 years, was a d m i t t e d to hospital complaing of headache, dyspnoea and dizziness of five weeks' duration. One week prior to admission he developed pain over the right costal margin. On examination pallor was obvious, the spleen just palpable and minor enlargement of the supra. clavicular a n d axillary lymph glands was noted. The haemoglobin was 6.3 g. per 100 ml.: erythrocytes 1.96 • 106 per c.mm. : leucocytes 420,000 per c.mm. Differential count showed t h a t the leucocytes were almost entirely undifferentiated " blast " cells and the diagnosis of leucopenic blastic leukaemia was confirmed b y marrow aspiration. Initial
T H E T R E A T M E N T OF A C U T E L E U K A E M I A IN A1)ULTS 63 t h e r a p y of 2.9 g. of 6 - m e r c a p t o p u r i n e a d m i n i s t e r e d over 31 d a y s p r o d u c e d clinical a n d h a e m a t o l o g i c a l i m p r o v e m e n t of I0 w e e k s ' d u r a t i o n . T w o f u r t h e r c o u r s e s of 6.05 g. a n d 2.1 g. o f 6 . m e r c a p t o p u r i n e were g i v e n d u r i n g s u b s e q u e n t relapses a n d t h e s e prod u c e d clinical r e m i s s i o n s e a c h of t w o w e e k s ' d u r a t i o n . T h i s case h a d a " r h e u m a t i c " t y p e of course w i t h s e v e r e g e n e r a l i s e d b o n e padn. No b o n e lesions were d e m o n s t r a t e d raAiologically e a r l y in t h e disease. R e p e a t s k i a g r a m s one m o n t h before d e a t h s h o w e d mnall osteolytie lesions in t h e m e t a p h y s i s a t t h e lower e n d of t h e r a d i u s w i t h slight periosteal r e a c t i o n s u g g e s t i n g l e u k a e m i c infiltration. H e d i e d f r o m a n u n s u s p e c t e d streptococcal s e p t i c a c m i a . T h e t o t a l s u r v i v a l f r o m period t h e o n s e t of s y m p t o m s w a s seven months. CASE 1 0 - - Acute Blastie Relapse of Chronic Myeloid Leukaemia. Male, a g e d 60 y e a r s , suffering f r o m chronic m y e l o i d l e u k a e m i a , w a s u n d e r t r e a t m e n t for 2 y e a r s a n d 7 months with tri-ethylenc-melamine when he developed a severe acute myeloblastic crisis. ]-[e w a s g i v e n 1.2 g. of 6 - m e r c a p t o p u r i n e w h i c h p r o d u c e d a s h o r t clinical a n d h a c m a t o l o g i c a l r e m i s s i o n l a s t i n g t w o w e e k s . Courses of 6 - m e r c a p t o p u r i n e v a r y i n g f r o m 1.05 g. to 6.6 g. were g i v e n alone or c o m b i n e d w i t h cortisone d u r i n g s u b s e q u e n t relapses. A l t o g e t h e r he received a t o t a l of 13.98 g. of 6 - m e r c a p t o p u r i n e . O n l y one f u r t h e r s a t i s f a c t o r y r e m i s s i o n w a s i n d u c e d d u r i n g t h i s t h e r a p y before r e s i s t a n c e to t h e d r u g d e v e l o p e d . H e s u r v i v e d e i g h t m o n t h s a f t e r t h e o n s e t of t h e blastic p h a s e .
Discussion. It is recognised that this is neither a large nor a homogeneous group of cases of acute leukaemia. It represents only our own personal experiences with 6-mercaptopurine as a chemotherapeutic agent in the management of this tragic disease in adults. Of the 10 cases treated 5 showed a clinical remission, one showed a haematological remission; in one the remission was complete and in 3 the drug failed to produce any benefit. The duration of the remissions varied from two weeks to eleven months. Subsequent relapses responded to f u r t h e r 6-mercaptopurine t h e r a p y in those cases in which f u r t h e r treatment was used until the condition became r e f r a c t o r y to therapy. It is well to remember that the action of 6-mercaptopurine is usually slow in producing its effects and in some cases may require up to three weeks' treatment before benefit is obtained. Furthermore, it is unusual for a partial remission to be obtained with a total dose of less than 2 grams and complete remissions with a total dose of less than 4 grams. F o r this reason combined cortisone and 6-mercaptopurine therapy is best instituted from the onset. During the course of our investigations two points which have already been noted were confirmed. These were that the presence of a low leucocyte or platelet count was not a contraindication to therapy with 6-mercaptopurine. Both leukaemic and leueopenic blastic leukaemia responded equally. It was also noted that an original low platelet count may rise during therapy. This latter effect is in all probability due to restoration of megakaryocytic function as the marrow infiltration is relieved. It was also found that when maximum therapeutic effect was obtained, this was often associated with a t e m p o r a r y but often marked leucopenia. The reason for this is that in acute leukaemia in relapse the majority of the cells in the peripheral blood are primitive forms. Chemotherapy, if successful, eliminates these and the few remaining normal cells give a leucopenic total count. Consequently, it is evident that a fall in the white cell count during t h e r a p y with 6-mercaptopurine is not necessarily an indication for discontinuing treatment. One case was of singular interest. It presented as a possible case of food-poisoning and was therefore admitted to a fever hospital. The
64
1RfISH JOURNAL OF MEDICAL SCIENCE
presence of pyrexia and joint pains raised the possibility of a diagnosis of rheumatic fever. Radiological examination of the wrists and knees showed leukaemic bones changes which were most marked in the lower radius and femur. These changes consisted of translucent areas of focal bony erosion occurring in the regions of the metaphysis. The lesions disappeared during treatment. Such leukaemic changes have been most commonly described in acute leukaemia of childhood, particularly in the leucopenic form. Although specific search for these changes has been made radiologieally, we have been able to demonstrate them in only two other cases. Although clinical and haematological improvement is possible with 6-mercaptopurine in some cases of acute leukaemia it would be of interest to know whether the life-history of the disease has been fundamentally altered. In a statistical study by Haut et al2 it was computed that the median survival time, i.e., the period of survival of 50 per cent. of the cases (if untreated leukaemia, was 4~ months in one series and 4 months in another. In a group of 78 patients comprising both children and adults treated with 6-mercaptopurine, folic acid antagonists and steroid hormones, the median survival time was 5~ months. Although survival times in such a limited series as ours can have no possible statistical significance, it is of interest that the median survival times in our cases were of the same order as the treated group reported by Haut et al. Although it is clear that treatment with 6-mercaptopurine does not substantially prolong life in acute leukaemia, it has undoubted value. In many cases it produces marked clinical remission with freedom from symptoms, thus enabling the patient to lead a comfortable life. Also, unlike the folic acid antagonists, 6-mereaptopurine is singularly free from toxic side-effects, so that once the distressing clinical manifestations are controlled, the treatment can be given as an out-patient. In some instances it may be possible to produce such a satisfactory remission as to allow the patient to resume, albeit temporarily, normal activities. This was possible in two of our cases, one of whom was a nurse who was able to continue light duties for thirteen months. What is of great interest is that we have now available a chemotherapeutic agent for the treatment of acute leukaemia which, in a few instances, especially in children, is capable of restoring the bone marrow to an apparently normal state. This suggests that the day may not be far distant when this effect may be not temporary as at present, but sustained. Unfortunately, at the moment, it is not possible to talk in terms of cure of acute leukaemia, but only in terms of remission. Summary. Ten cases of acute leukaemia in adults treated with 6-mercaptopurine are presented. Remissions of varying type and duration were obtained in seven cases, three failed to respond. Remissions lasted from 14 days to 13 months. The median survival time was better than that reported for untreated cases and one patient lived for sixteen months after diagnosis.
T H E T R E A T M E N T OF A C U T E L E U K A E M I A I N A I ) U I , TS
65
SUMMARY OF TREATMENT OF TEN ADULT CASES OF ACUTE LEUKAEMIA WITH 6-MERCAPTOPURINE.
Result of Initial Therapy
Diagnosis
Initial 6-Mercaptopurine Therapy
6C
Monocytic Leukaemia.
0"7 g. in 35 days
2
4~
Monocytic Leukaemia
3
42
4
46
5
Total Dosage 6-Mercaptopurine given during illness
Survival time froan onset of symptoms to death
No effect
0'7 g.
3 months
1.8 g. in 10 days
No effect
1'8 g.
Monocytic Leukaemia
1.85 g. in 14 days
Complete remission.
2'95 g.
5 months
M
Monocytic Leukaemia
3.9 g. in 30 days
Clinical improvement.
8"32 g.
7 months
51
F
Monocytic Leukaemia
1.7 g. in 17 days
No effect
1"7 g.
10 months
6
26
F
Acute Blastic Leukaemia.
3.05 g. in 26 days
Clinical remission.
4"0 g.
7
26
F
Acute Blastie Leukaemia.
1.55 g. in 16 days
Clinical and haematological remission.
8
19
F ! Leueopenic Blastic Leukaemia.
1"6 g. in 10 days
Clinical and haematological remission.
6"08 g.
5 months
9
20
M
Leucopenic Blastic Leukaemia.
2"0 g. in 31 days
Clinical remi.~don.
8"98 g.
8 months
10
60
M
Acute Blastie Relapse Chronic Myeloid Leukaemia.
1"2 g. in 12 days
Clinical and partial haematological remission.
Cas( No. A~ Sex
1
14'6 g.
13'98 g.
14 days
489 mouths
16 months
8 months after onse~ of blastic phase.
Acknowledgement ' ' W e w i s h t o t h a n k o u r c l i n i c a l c o l l o a g u o s f o r r e f e r r i n g c a s e s t o u s a n d also M r . A. L a m o n t , F . I . M . L . T . f o r t h e p r e p a r a t i o n o f t h e f i g u r e s . "
Refer~8. 1. 2. 3. 4. 5.
H i t c h i n g s , G. H . , Burehonal, J. H., Bethel, F. D., and Hayhoe, F. G. J., H a u t , A., A l t m a n , 10, 875.
a n d E l i o n , G . B . (1954). et al. (1954). Ann. New T h o m p s o n , D . S. (1954). a n d W h i t b y , L . (1955). S. J . , C a r t w r i g h t , G . E . ,
Ann. York Ann. Brit.
New York Ae.ad. S~i., 60, 195. Acad., Sci., 60, 359. New York Acad. Sci., 60, 4 3 6 . J. Haematology, 1, 1. a n d W i n t r o b e , M. M. (1955). Blood,