j U NEl 9 5 4 42 9

THE TREATMENT OF LEUKEMIA*

JOSEPHH. BURCHENALProfessor of Medicine, Sloan-Kettering Division of Cornell University Medical College,

New York, N. Y.

INCEleukemia is by very definition a widespread systemicdisease at the time the diagnosis is made, the forms oftreatment such as surgery and obliterative radiation that

may be curative for localized cancers are not effective.The physician then is forced to rely on the techniques

of chemotherapy and palliative radiation. Neither of these techniquesis at present curative in any type of leukemia. Although we cannot cure

leukemia, we can prolong the lives of many patients with acute leukemia,and in the chronic forms at least the useful and perhaps even the actualsurvival time of the patient can be increased. For the purposes of thisdiscussion I propose to divide the leukemias into the acute, the chronicmyelocytic, and the chronic lymphocytic forms of the disease.

ACUTELEUKEMIA

Chemotherapy is the method of choice for the'management of theacute leukemias. Irradiation for the generalized acute leukemic pictureis contraindicated, but the use of x-ray therapy to localized lesions suchas leukemic masses pressing on the central nervous system or enlargedkidneys is occasionally of value. Chemotherapeutic agents for acute

leukemia may be divided into two groups: I) the antimetabolites, and2) the hormones.We are living now in the age of chemotherapy. The past two decades

have seen most of the infectious diseases of bacterial, rickettsial, or

protozoal etiology surrender to chemotherapy. Although considerableprogress in the treatment of leukemia has also been made in the pastten years, we still have no cure for the disease. The difficulties of the

Presented at the 26th Graduate Fortnight of The New York Academy of Medicine, October27, 1953.From the Chemotherapy Service, Memorial Center, the Division of Experimental Chemotherapy,Sloan-Kettering Institute, and the Sloan-Kettering Division of Cornell University Medical College.This investigation was supported by research grants from the National Cancer Institute of theNational Institutes of Health of the United States Public Health Service, the American CancerSociety, the Damon Runyon Memorial Fund for Cancer Research, the Lasker Foundation and theGrant Foundation.

4 3 0 THE BULLETIN

chemotherapy of leukemia in contrast to infectious disease will be evi-dent if we define an antimetabolite and consider as an example themetabolite-antimetabolite relationship of para-aminobenzoic acid andsulfanilamide.

An antimetabolite in general may be defined as a compound whosechemical structure differs only slightly from some normal metabolitesuch as a vitamin7 an amino acid, or a precursor of nucleic acid. Thechemical similarity is so close that the antimetabolite is able to enter

into the same enzyme systems as the normal metabolite, but once it hasentered into these systems the chemical difference is just sufficient so

that the reaction can go no further and the whole enzyme systemis blocked.

In the use of the sulfonamides in the treatment of infections caused byhemolytic streptococci, the chemotherapist is dealing with a particularlyadvantageous situation. The streptococcus requires para-aminobenzoicacid for its nutrition and therefore is inhibited by its antimetabolitesulfanilamide. The patient on the other hand has no requirement forpara-aminobenzoic acid and therefore is not harmed by its antimetabolite.In addition to this qualitative difference in requirements, there is alsothe factor of the patient's resistance to the infection which will serve

to eliminate the occasional organisms which are resistant to the anti-metabolite. Unfortunately, in leukemia at the present time we know ofno qualitative difference between normal and neoplastic cells to exploit,nor can we rely on the factor of host resistance to destroy the fewleukemic cells which even in the most favorable cases may be resistantto the antimetabolite. There are, however, certain quantitative differ-ences in the nutritional requirements of normal and leukemic cells whichmay be exploited to the advantage of the patient. These biochemicaldifferences vary from case to case. In the acute'leukemias blast formsindistinguishable from each other by morphologic criteria may respondquitedifferently to a given chemotherapeutic agent. In this regard, itwould seem reasonable -that in the future the acute leukemias may wellbe classified by their biochemical properties as shown by their responseto certain standard agents, rather than by their morphologic char-acteristics.

The fact that spontaneous remissions occasionally occur in acuteleukemia had led many investigators to believe that it might be possibleto find agents which would bring about such remissions. The first suc-

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The Treatvwnt of Leukemia 4 3 1

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cessful use of antimetabolites in the treatment of leukemia was theepoch-making discovery reported by Farber in 1948' of the ability ofan antagonist of folic acid to produce remissions in children with acute

2leukemia. Folic acid and citrovorum factor, its biologically more activecounterpart, are vitamins necessary for the growth and maturation ofthe normal erythroid and myeloid tissue of the marrow. Fortunatelyfrom the point of view of the chemotherapist, they are even more neces-

sary for the growth of the cells of some forms of acute leukemia. Theantagonists of folic acid such as Aminopterin and Amethopterin (Fig. 1)differ from folic, acid mainly by the substitution of an amino groupfor the hydroxyl group in the 4 position of the molecule. Treatmentwith either of these agents causes a relative deficiency of citrovorumfactor throughout the body which specifically damages certain typesof leukemic'cells.

The folic acid antagonists are generally administered in tablet formorally once daily. The dose of Aminopterin for a five year old childis 0.25 mg. to 0-5 mg. daily, and the dose of Amethopterin is from 1.25mg. tO 5.0 mg. daily. Since there is approximately a five-fold difference indosage of these two drugs, it is important to differentiate between thetwo. Both these compounds can be given by mouth and absorptionis equally rapid by the oral or intramuscular route. It has been shown.that if a 5 ing. dose of Amethopterin is administered orally to a normal

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individual on a fasting stomach, an appreciable level of the drug can bedetected in the serum fifteen to thirty minutes after ingestion, with a

rapid disappearance from the blood in from three to twelve hours. Inindividuals with impaired renal function, considerable amounts ofAmethopterin are found in the serum in from twenty-four to forty-eighthours' after administration, and particular caution should be exercisedin treating such patients'

The first signs of toxicity of Amethopterin usually are ulcerationsof the buccal mucosa. These are covered by a yellowish exudate andsurrounded by a reddish areola and are frequently very painful. Theyin themselves are not dafigerous, but they may be precursors of ulcera-tions farther down the gastrointestinal tract of which the first manifes-tations may be loss of appetite and abdominal pain. These ulcers of thegastrointestinal tract may be dangerous in a patient who has a bleedingdiathesis. Loss of hair, temporary interference with beard growth,increased susceptibility to skin infection, leukopenia and thrombocyto-penia are other signs of toxicity from these drugs.

The usual plan of therapy in children with acute leukemia is to

administer Amethopterin orally at 2.5mg. daily for three weeks or more

until such time as remission occurs as evidenced by the return of themarrow to essentially normal morphology and function, or until definitesigns of toxicity appear. If toxicity occurs, therapy is discontinued -tem-

porarily for a period of seven to ten days and then when the signssubside, started, again at a somewhat lower dosage and continued until

4 3 2 THE BULLETIN

The Treatment of Leukenfia, 4 3 3

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a remission is achieved. In the absence of a remission, if the patient isin reasonably good condition., therapy should be continued for at leasttwo months and occasionally longer at increased dosage even to thepoint of mild toxicity in hopes of obtaining a remission. Once a remis-sion is obtained maintenance therapy may be continued indefinitelyor treatment may be stopped to be resumed again at the first sign ofa bone -marrow relapse (Fig. 2). If the intermittent form of therapyis used, however, it is important to do sternal aspirations every two

weeks in order that a relapse may be detected at the earliest possiblemoment, and treatment restarted. By treatment with the folic acidantagonists, good hematological and clinical remissions in which thechild returns temporarily to normal health and in which the marrow

has a total Of 30 per cent or less of blast cells and lymphocytes, maybe obtained in 30 per cent to 50 per cent of children with acute leu-kemia. In a compilation of reportS4 on the treatment Of 425 childrenwith acute leukemia reported at the Second Conference on the FolicAcid Antagonis& 68 per cent were considered as having been improvedby therapy. In our own series," forty-four of i ig children and one ofthirty-six adults with acute leukemia experienced good clinical andhematological remissions after treatment with Amethopterin or otherrelated folic acid antagonists.

4 3 4 THE BULLETIN

At this time the relationship between citrovorum factor andAmethopterin might be mentioned. It has been shown in bacteria and inanimals that the toxic effects of the folic acid antagonists can be pre-vented by citrovorum factor. Similarly it has been shown that the anti-leukemic effects of Amethopterin in mice can be completely preventedby citrovorum factor. Figure 3 is a case in point of a three year oldchild who on eight doses Of 2-5 mg. daily of Amethopteirn developedmouth ulcerations and other signs of toxicity. She was then treated withsmall doses of citrovorum factor intramuscularly along with increasingdosage of Amethopten'n, so that finally 3 mg. daily of citrovorum factorprevented for three weeks the toxic and the anti-tumor effects ofbetween 45 and 6o mg. daily of Amethopterin. It is to be noted in thissituation that, except when the patient was in toxicity, no effect was

noted on the leukemic nodes by these tremendous doses of Amethopterin,and that at no time was any beneficial effect noted by these large doseson the composition of the- bone marrow. Our own experience with theuse of citrovorum factor has suggested that an occasional patient willhave a definite exacerbation of the disease immediately after the injectionof citrovorum factor. For this reason we feel that the administration ofcitrovorum factor to a leukemic patient is contraindicated in all situationsexcept those in which an abnormally high dosage of Amethopterin hasbeen given inadvertently to the patient or when normal dosage- hasproduced severe toxicity with manifestations endangering the life ofthe patient. At such -time, citrovorum factor alone should be given.There appears to be no evidence whatsoever of any advantage to beobtained by giving the two compounds simultaneously in the hope ofobtaining a selective effect on leukemic cells.

6-Mercaptopurine, which has recently been shown to be useful inthe treatment of acute leukemia, belongs to, another class of antimetabo-lites-the purine antagonists. The synthesis of mercaptopurine was theresult of a ten-year study of possible antagonists of precursors of nucleic

7, 8acid by Hitchings, Elion et al. In the studies on Lactobacillus, casei,6-mercaptopurine was demonstrated to be a purine antagonists althoughstudies in animals have shown that neither the toxic manifestations nor

the antileukemic effects of this compound can be reversed by simplepurines.lo," The anti-tumor effect of this compound in Sarcoma i8owas first noted by Clarke et al.", 12 who reported that mercaptopurm'enot only inhibited the growth of Sarcoma i 8o but actually caused com-

The Treatment of Leukentia 4 3 5

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plete regression Of up to 30 per cent of such tumors. Pharmacologicalstudies by Philips et al.", 13demonstrated that this compound had a

markedly depressant effect on the bone marrow, and at high doses( 2 5 to

50 mg. per kilo daily) in dogs caused definite liver damage.In patients, mercaptopurine is generally given at a dosageOf 2 .5 mg-

per kilo of bodyweight daily by mouth in a single dose. At this dosagelevel there is little or no toxicity in children but prolonged dosage at

this level in adults or higher doses in children may occasionally produceevidence of bone marrow depression and gastrointestinal toxicity.This drug will produce 'clinical and hematological remissions in acute

leukemia in children and occasionally in adults, 14, '-' but at least threeweeks of therapy and often times up to six or eight weeks are neededbefore these remissions are achieved. The patient is then maintained on

the same dose and remissions lasting from two to ten months may beexpected. In a series of sixty-eight children with acute leukemia treatedat Memorial Hospital between June, 195 2, and August, 1953, remissionswere achieved in twenty-nine patients; partial remissions in fourteen;and twenty-five were considered failures.0f these twenty-five failures,however9 eight had had less than one week of therapy. Of forty adults,five , aged fifty-two, thirty-five, twenty-one, twenty-one, and fifteenyears, respectively, had clinical and hematological remissions and anothersix showed marked clinical benefit with improvement of peripheralblood and return of the marrow to normal function but not to entirelynormal morphology. Twenty-nine were considered failures, but of thesefailures ten had had only from one to six days of therapy. Figure 4 showsa typical response to 6-mercaptopurine in a three year old girl withgradual return of pol 'morphonuclear leukocytes, platelets and boney

4 3 6 THE BULLETIN

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marrow differential to normal which lasted- for nine months. 6-Mer-captopurine will also cause remissions in patients who have developedresistance to Amethopterin or to cortisone as is shown by the fact thatout of twenty-nine of the children who had good clinical and hemato-logical remissions from 6-m'ercaptopunne, seven had developed resistanceto Amethopterin; six to cortisone; and five to both compounds before theinstitution of treatment with mercaptopurine. New patients who havebeen treated with 6-mercaptopurine for a period of time and have finallydeveloped resistance to this drug can then be treated with Amethopterin.Figure 5 demonstrates this good response to Amethopterin after develop-ment of resistance to mercaptopurine. Similarly, cortisone will alsoeffect remissions in mercaptopurine-resistant cases. In contrast to thefolic acid antagonists, 6-mercaptopurine appears to work equally wellon leukemias with either high or low total leukocyte counts and also to

have considerable effect in adults with this disease. Figure 6 shows a

very satisfactory remission in a woman fifty-two years of age with acute

monocytic leukemia which is still continuing eleven months after the-start of therapy. In children the percentage of remissions in our experi-ence has been somewhat higher with mercaptopurine than with Amethop-terin but the length of the remissions has in general been slightly less.In adults 6-mercaptopurine appears preferable to Amethopterin.

In the hormone treatment of acute leukemia, ACTH and cortisoneseem to be quite similar in their action on the disease although ACTHacts to stimulate the patient's own adrenal to put out many steroids,among them cortisone, whereas cortisone has no stimulatory effect on

the patient's adrenal but merely supplies an excess of a single adrenal

The Treatment of Leukezifia 4 3 7

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hormone. Aqueous ACTH is generally given intramuscularly either individed doses four times daily or as Acthar gel once or twice daily, or

by constant intravenous drip. ne average daily do-se for a child of fivewould be 6o mg. to i oo mg., and for an adult IOO to 200mg. by the in-tramuscular route9but if the drug is given by the constant intravenousdrip method 25mg. and 5o mg. daily in children and adults respectivelywidl suffice. Cortisone is generally given by mouth four times daily withthe usual total dose, for a child I 00 to '200mg., and for an adult I 00 to 400mg. daily. Certain undesirable side effects follow the prolonged a.dminis-tration of either of these substances but some are preventable by carefulmanagement. Excess sodium retention and consequent water retentionand edema may to a large extent be prevented by placing the patienton a low salt diet. The gain in weight which frequently occurs becauseof the abnormal appetite in children treated with these drugs can beavoided by calculating the normal diet for a child of the patient's sizeand age and limiting the intake to, this. On the other hand, the loss ofweight in adults due to the catabolic effect of the drugs can to a largeextent be counteracted by the simultaneous administration of testosterone

25 mg. daily. Metabolic alkalosis and hypokalemia should be watchedfor by frequent observation of the blood chloridesC02 and potassium.The situation can be corrected by the administration of potassiumchloride by mouth. Hypertension and psychic changes are contraindica-tions to further therapy. Cushing's facies, hirsutism, and the acne whichfrequently occur are not dangerous, and usually disappear fairly rapidlywhen the drug is discontinued. Since fulminating infections are not

uncommon in patients being treated with the hormones, massive anti-biotic therapy should be started at the first sign of such complications.

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4 3 8 THE BULLETIN

The treatment of acute leukemia with ACTH was first reported16 17by Pearson et al. and Farber et al. A summary of the investigations

conducted throughout the country was given at the Second ClinicalACTH Conference."' In eighty of 175 children, and fourteen of sixtyadults with acute leukemia, good clinical and hematological remissionswere achieved. These remissions were characterized by a fall in the totalleukocyte count to normal levels and a return of the marrow in most

cases to a relatively normal functioning state. In our experiences suchremissions were of a relatively short duration, lasting one to twelveweeks, could not be repeated in adults and could be repeated only a

second time in children. Some investigators, however, have reportedoccasional third and fourth responses. Figure 7 is a typical example ofsuch a response. As with all other agents used in the treatment of acute

leukemia, resistance develops also to the hormones and resistance to

cortisone usually is associated with resistance to ACTH and vice versa.

The Treammm of Leuke?,nia 4 3 9

On the other hand, there does not appear to be cross resistance betweenthe hormones and the folic acid antagonists or mercaptopurine.

Hormones, folic acid antagonists, and purine antagonists are allusually employed eventually in a given patient and one cannot say thatany one of these is the best agent for the treatment of acute leukemia.With the various agents available, however, one is faced with the ques-tion of which agent to use first in a given patient. Since the hormonesact more rapidly than the antimetabolites, but cause shorter remissions,we have evolved the following plan of therapy. If the patient is acutelyill and it appears unlikely that he will survive the three weeks usuallynecessary for either class of the antimetabolites to take effect, he is startedon cortisone by mouth or ACTH by constant intravenous drip, theformer being preferable because of the ease of administration, the latterhowever, having a somewhat more rapid effect. Once the patient has beenbrought into remission or tided over the acute emergency by the use

of the hormones antimetabolite therapy, using either Amethopterin or

6-mercaptopurine, may be instituted in an attempt to prolong theremission. In the patient who does not appear to be quite so acutely illand in whom it is thought that more time will be available for the effec-tive 'action of chemotherapeutic agents, the antimetabolites should betried from the very start. If the patient is a child under the age of ten

with a white count below 5oooo, Amethopterin would be expected to

produce a good remission, and is probably the therapeutic agent ofchoice because of the somewhat longer duration of remissions. On theother hand, if the patient is a child with'a total leukocyte count over

50,000 or is an adult, 6-mercaptopurine seems to offer a better chanceof inducing a remission. If either class of antimetabolites, is used as a

starting therapy, it would be best to persist with this agent as long as a

remission can be maintained, shifting to the other class when resistanceto the fits-t appears, and holding the hormones, cortisone and ACTH,in reserve for exacerbations. of the disease which do not appear to becontrolled by the antimetabolites.

It is still too early to assess the effect of this suggested sequence oftherapy on acute leukemia, but figures from the sequential use of corti-sone, ACTH, and the folic acid antagonists in children are available.In a seriesOf 2i8 children with acute leukemia selected from the litera-ture who received no treatment with either folic acid antagonists or

steroids, Tivey" found only eleven alive one year from the onset of

4 4 0 THE BULLETIN

the disease. In a series of 193 children with acute leukemia treated bythe Chemotherapy Service of Memorial Hospital usinog Amethopterinand steroid hormones, sixty-two were alive one year after the start oftheir disease. How much these figures will be increased by the additionof 6-mercaptopurine to the therapeutic armamentarium remains to

be seen.At the risk of sounding overly optimistic, I would like to make a

Plea for the treatment of all cases of acute leukemia. Too often theattitude of the doctor is that there is no cure for the disease, thereforethe child or adult should be allowed to die in peace. The answer to thatis fourfold: I) The untreated patient does not usually die in peace butfrequently suffers many of the painful complications of the disease;2 )under therapy many of these children can live happy lives, continuingin school and playing as normal children; 3) during this time the familyhave time to adjust to the situation; and 4) and most important, ifthese patients can be kept alive for another year or two, who can saythat some investigator somewhere in theworld will not come forth witha really effective agent to control the disease?

CHRONIC MYELOCYTIc LEUKEMIA

In chronic myelocytic leukemia we have many forms of treatmentwhich will yield good results in the early stages of the disease. Incontrast to the situation in acute leukemia, resistance to one therapeuticmodality usually means resistance to all as the patient is then in theacute terminal stage of the disease. In this disease radiation therapy eitherby localized x-ray, total body spray, or by the oral or intravenous use

of radioactive phosphorus remains the most thoroughly studied andmost widely employed form of therapy, but it obviously can beemployed only in cooperation with qualified radiologists. Local therapyis usually given over the, spleen at doses of 5o to i oo r. daily, alternatinganterior and posterior ports until a total of 6oo r. have been given.21This amount will usually suffice to bring the count down but in some

cases it may be necessary to go higher. It would appear advisable to

attempt to keep the white count in the 20 to 3oooo range and to startin therapy again as soon as the count begins to go above this level.Total body spray x-ray at a dose of I 5 to 2o r. given every other dayuntil the desired result is achieved is also an effective method of pro-ducing remissions in this disease.22 Osgood23 using titrated regularl'y

The Treatment of Leukewna 4 4 1

spaced total body irradiation has reported excellent results in the treat-

ment of leukemia and feels that many of the beneficial effects of suchtherapy are due to the fact that the leukemic process is kept constantlyunder control by these repeated small doses of radiation. The first use

of radioactive phosphorus in the treatment of chronic myelocytic21leukemia was reported by Lawrence et al. It was originally

thought that since there 'was selective pick up of phosphorus by themore rapidly growing cells of leukemia, P32 would give specificirradiation to these cells. This factor of specificity, however, is not

sufficient to make P32. much more than a method of 'ving total body91irradiation .25 It can be given either orally or intravenously and the usualdose is one-tenth of a millicurie per kilogram of body weight. In one

month's time, if the desired results have not been obtained, furthertherapy at a somewhat smaller dose may be given. It produces excellentremissions with little or no evidence of radiation sickness but itsuse is limited to institutions having the necessary facilities for handlingradioisotopes.

Of the chemotherapeutic agents available for the treatment ofchronic myelocytic leukemia, arsenic was the first to be employed by

211Lissauer in i865. When given by mouth in the form of Fowler'ssolution, starting off at 5 minims three times daily and gradually workingup to the maximum tolerated dose which may be as high as 20minimsthree times daily, this compound will produce definite remissions in

27the early stages of the disease. Its administration, however, is oftenaccompanied by nausea and vomiting and for this reason cannot betolerated by some patients.

The ability of urethane to cause remissions in this form of the28disease was first reported by Paterson et al. in 1946. The oral adminis

tration of two to four grams daily of urethane will induce remissions ina high percentage of these cases, but again as with arsenic a certainnumber of patients find that this drug causes nausea and vomiting whichmake its continued use uncomfortable or even impossible. Occasionalcases of liver damage presumably due to urethane have been reported.

There are several useful agents that can be considered in the groupof alkylating agents. The first of these to be used was the nitrogenmustard-methyl-bis (fl-chloroethyl)amine-known. by the code name

HN2. Its use stemmed from wartime research of the Chemical WarfareService on the toxic effects of these vesicant agents on. the bone marrow

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THE BULLETIN442

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Fig. 8

and lymphoid tissues. The usual dose is o. i mg. per kilo of body weightdaily intravenously for four doses or 0.2mg/kg daily for two doses.Such dosage is usually accompanied by nausea and vomiting but sincethe patient is only treated for two to four days and recovery occurs

within twenty-four hours, this nausea and vomiting does not seem to

be a contraindication to therapy.29-31 Remissions lasting from one to

six months may be achieved by such a course of therapy which maybe repeated.32

Triethylene melamine (TEM) 33 causes remissions in much thesame way as the nitrogen mustards but has the advantage that it causes

little or no nausea and vomiting and may be given by mouth as mainte-nance therapy. The usual dose of TEM in chronic myelocytic leukemia is5 mg. on an empty stomach one hour before breakfast on two consecu-

tive days each week until such time as the white count has reached nor-

mal levels. Maintenance, therapy -should be adjusted in an attempt to

keep the white count below 20,000.Another compound which presumably acts in much the same way

as the nitrogen mustards: is Myleran (I-4-dimethanesulfonyloxybutane),which was synthesized b' Timmis and first studied experimentally iny

31tumor-bearing rats by Haddow et al. Its use in patients has recentlybeen reported by Galton.35 who feels that it acts in therapeutic dosessimply as a depressant of myelopoiesis, in contrast to the previouslymentioned nitrogen mustard derivatives which seem to depress lymphoidtissue more than the myeloid tissue. This compound can be given orallyand the usual dose is 4 to 6 mg. daily. Galton feels that Myleran hasthe advantage of simplicity of administration, absence of side effects,and occasional effectiveness after other methods have had to be aban-

The Treatnwnt of Leukemia 4 4 3

doned. It does not, however, appear to be beneficial in the terminalacute stage of chronic myelocytic leukemia.

The only one of the antimetabolites which seems to have anypractical effect in chronic myelocytic leukemia is 6-mercaptopurine.In our studies " this compound given at a dose Of 2.5 mg. per kilo ofbody weight daily by mouth has produced remissions in all of ten

cases of ch'ronic myelocytic leukemia in the early stages. These remissionswere achieved without evidence of toxicity and have been maintainedfor periods up to one year. Usually maintenance therapy is necessaryas relapses often occur within one to two months after discontinuingtherapy. Figure 8, however, demonstrates a prolonged beneficial effectof mercaptopurine on a patient with this form of the disease. just howmuch longer these remissions will last is impossible to say at the presenttime as the drug is still under investigation. So-me temporary beneficialeffects in the acute terminal stage of chronic myelocytic leukemia' havealso been noted with this drug, but the series is entirely too small to

know whether this is a real .tffect. Much more study on this compoundwill be necessary before its practical value in the treatment of this formof the disease can be evaluated.

The method of treatment to be used in chronic myelocytic leukemiadepends largely on the facilities available. If adequate equipment andpersonnel are available it would appear at the present time that radiationtherapy is perhaps the treatment of choice with emphasis being placedon not allowing the patient to relapse too far before further treatment isgiven. 10 facilities for irradiation are not available, it would seem thata chemotherapeutic agent such as Myleran might be the treatment ofchoice inasmuch as it appears that good remissions can be achieved withthis compound without discomfort to the patients. TEM, urethane, andFowler's solution are also satisfactory forms of therapy, but have some

undesirable side effects. Where 6-mercaptopurine will eventually fitinto this picture is 'impossible to state at the present time.

CHRONic LymPHOCYTIc LEUKEMIA

Chronic lymphocytic leukemia may occasionally be an exceedinglybenign disease, particularly in the elderly patient. In such cases no

therapy may be indicated for considerable periods of time. In the averagecase the treatment of choice is probably local x-ray therapy to the in-volved nodes 21 although Osgood2,3 reported excellent results with the

444 THE BULLETIN

P32use of titrated regularly spaced total body irradiation or , andLawrence et al." have reported considerable palliative effects from F2.Of the chemotherapeutic agents that have been used in the chronicmyelocytic form of the disease, arsenic, Myleran, and mercaptopurineseem to be without any practical beneficial effect in chronic lymphocyticleukemia. Urethane is somewhat less useful he-re than in the chronicmyelocytic form. We are left then with the nitrogen mustard-typeagents, HN2 and TEM. The dosage scheme for both these agents is simi-lar to that used for chronic myelocytic leukemia but since patients withthe chronic lymphocytic form of the disease are slightly more susceptibleto the toxic effects of these drugs, the dosage should be reduced to halfand the patient treated cautiously. ACTH and cortisone have also been

37shown by Pearson et al. to be useful in the treatment of chronic lymphocytic leukemia, particularly in those cases in which there is an asso-

ciated thrombopenia or hemolytic anemia. These investigators feel thatin chronic lymphocytic leukemia, in contrast to acute leukemias, resist-ance to the hormones does not develop and that patients may be main-tained for long periods of time on hormone therapy alone.-311

SUPPORTIVETHERAPY

In leukemia, even more than in most other medical diseases, specifictherapy is only one aspect of the management of the situation. Trans-fusions should be given as often as necessary to combat anemia, andantibiotics in massive doses should be employed whenever serious infec-tion threatens the patient. The maintenance of morale is also at impor-tant factor and for this reason it is suggested that the patients be allowedto live as normal a life as possible within the limits set by their physicalcondition. Thus for instance, most patients with chronic myelocyticleukemia. can continue to work up to within a month or two of the timeof death.

The outlook for progress in the treatment of the leukemias wouldseem to be excellent. Although it appears unlikely that any marked im-provement will be achieved in the results obtained by radiotherapy alone,the many new chemotherapeutic agents which have been developed forthe treatment of this disease in the past ten years suggest that newer andfar better agents will be developed in the near future. The probableavenues of progress in chemotherapy are: i) the development of new

agents with more prolonged therapeutic effect and applicability to a

The Treatment of Leukemia 445

wider spectrum of leukemias; and2z) the prevention of the developmentof resistance to agents now in use. This latter may be accomplished bya better understanding of the fundamental mechanisms of the develop-ment of resistance to various chemotherapeutic agents or by the employ-ment of combination therapy using several chemotherapeutic agentssimultaneously, or combined irradiation and chemotherapy in an empiricattempt to prevent the development of such resistance.

SUMMARY

i.The therapeutic agents at present available for treatment of leu-kemia are irradiation and chemotherapy.

2. In acute leukemia the sequential use of the antimetabolites, Ame-thopterin, Aminopterin, and 6-mercaptopurine, and the hormones, ACTHand cortisone, may be expected to produce beneficial effects with an in-crease in survival time in a high percentage of children. Definite but lessfrequent beneficial effects have been noted in adults with mercaptopurine.

3. Irradiation either by local or total body x-ray or P32 therapyoffers perhaps a wider range of applicability and technique than any ofthe chemotherapeutic agents in the treatment of the chronic forms ofleukemia.

4. In chronic myelocytic leukemia, Myleran, TM, urethane, ar-senic, and HNz in order of preference are useful chemotherapeutic agents.6-Mercaptopurine is still under evaluation in this form of the disease butmay prove to be of considerable value.

5. In chronic lymphocytic leukemia, the only chemical agents ofvalue are the mustard derivatives, TEM, HN2, and the hormones andpossibly urethane.

6. Definite progress in the chemotherapy of leukemia has been madein the last ten years and it would appear that this discipline offers thegreatest promise for the future control of the disease.

REFERENCES

1. Farber, S., Diamond, L. K., Mercer, R.D., Sylvester, R. F., Jr., and Wolff, J.A. Temporary remissions in acute leu-kemnia in children produced by folic acidantagonist, 4-aminopteroylglutamic acid(Aminopterin), New Engl. J. Med. £38:787-93, 1948.

2. Sauberlich, H. E. and Baumann,. C. A.A factor required for the growth of

Leuconostoc citrovorum, J. biol. Chem.176:165-73, 1948.

3. Burchenal, J. H., Waring, G. B., EM-son, R. R. and Reilly, H. C. A simplemethod for determidnation of levels ofAmethopterin in blood and urine, Proc.Soc. exrp. Biol. Med. 78:603-06, 1951.

4. Farber, S. The effect of therapy on thelife history and biologic behavior of

446 THE BULLETIN

leukemia, Proc. Inst. Med. C'hicago 18:'311-25, 1951.

5. Proceedings of the Second Conferenceon Folic Acid Antagonists in the Treat-nient of Leukemia, published as Supple-ment to Blood 7, 1952.

6. Burchenal, J. H. Present status ofACTH, cortisone, and the antimetabol-ites in the treatment of leukemia, and~related (liseases, Acta haemat. 7:193-205, 1951.

7. Hitchings, G. H., Elion, G. B., Falco,E. A.,, Russell, P. B., Sherwood, M. B.an(1 VanderWerif, H. Antagonists ofnucleic aci(1 derivatives; the Lactobacil-lus casei model, J. biol. Ch'eiis 183:1-9,1950.

8. Elion, G. 1B., Burgi, E. an(1 Hitchings,G. H. Studies on condense(1 1)rimidlinesy-stenms; thle synthesis of some 6-substi-tuted purines, J. Amer. chemt. Soc. 74:411-14, 1952.

9. Elion, G. B., Hitchings, G. H. and Van-derWerif, H. Antagonists of nucleicaci1 (derivatives; purines, J. bolo. Chem.192:505-18, 1951.

10. Burchenal, .J. H., Goetchius, S. K. andKieler, E. Unpublished observations.

11. Clarke, D. A., Philips, F. S., Sternberg,S. S., Stock, C. C., Elion, G. B. andHitchings, G. H. 6-Mercaptopurine: ef-fects in mouse Sarcoma 180 and in nor-

inail animals, Cancer Res. 137:593-604,1953.

12. Clarke, 1). A., Philips, F. S., Steinberg,S. S., Stock, C. C and Elion, G. B. 6-Mercaptopurine: an inhibitor of mouse

Sarccma 180 (,abstract), Proc. Amer.Assoc. Cmacer Res. 1:9-10, 1953.

13. Philips, F. S., Steinberg, S. S., Clarke,D. A. and Hitchings, G. H. Effects of6-mercaptopurine in mammals (ab-stract), Proc. Amer. Assoc. Cancer Res.1:42-43, 1953.

14. Burchenal, J. H., Murphy, M. L., Elli-son, R. R., Karnnofsky, D. A. andRboads, C. P1. Clinical evaluation of a

new antiflietalbolite in the treatment ofleukemia (abstract), J. clin. Invest. 32:557-58, 1953.

15. Burchenal, J. H., Murphy, M. L., Elli-son, R. R., Sykes, M. P., Tan, T. C.,Leone, L. A., Karnofsky, D. A., Craver,,L. F., Dargeon, H. W. and Rhoads. C.

P1. Clinical evaluation of a new anti-inetabolite, 6-mercaptopurine, in thetreatment of leukemia and allied (is-eases, Blood 8:965-99, 1953.

16. Pearson, 0. H., Eliel, L. P. and Talbot,T. R., Jr. The use of ACTH and corti-sone in neoplastic (lisease, Bull. N. Y.A cad. Med., 26:235-39, 1950.

17. Farber, S., Schwachnman-, H.,. Toch, R.,Downing, V., Kennedy, B. H. and Hyde,J. The effect of ACTH in acute leu-kenia in childlhood, Proc. dlin. ACTHConf. 1:328-30, 1949.

18. Farlber, S., Downing, V., Schwachnian,H., Toch, It. Ap)pleton, 1R., Heald, F.,King, J. P". and Fariori, D. Action ofAi\CTH and cortisone in acute leulkeinia,Proc. clbi. ACTH Cotif. 2:251-85, 1950.

19. Kingsley-Pillers, E. M., Burchenal, J.H., Eliel, L. P. and Pearson, 0. 1H. Re-sistance to corticotropin, cortisone, andfolic acid antagonists in leukemia, J.Amer. maed. Assoc. 148:987-99, 1952.

20. Tivey, H. Prognosis for survival in theleukemias of childhood, Pediatrics 10:48-59, 1952.

21. Craver, L. F. Treatment of chronicforms of malignant Iymphonias and leu-kemias, Med. Olin. N. Amer. 33:527-40,March 1949.

2'2. Sturgis, C. C. An evaluation of the na-

ture, treatment, and prognosis of leu-kemia (Ninth Edwin R. KretschmerMemorial Lecture), Proc. Inst. Med.Chicago 18:158-69, 1950.

23. Osgood, E. E. Titrated regularly spacedradioactive phosphorus or spray roent-gen therapy of leukemias, A.M.A. Arch.intern. Med. 87:329-48, 1951.

24.. Lawrence, J. H., Dobson, R. L., Low-Beer, B. V.A. and Brown, B. R.Chronic my~eloge-nous leukemia; study of129 cases in which treatment was withradioactive phosphorus, J. Amer. med.A.ssoc. 136:672-77, 1948.

25. Diamond, H. D. Recent advances in themanagement of lymphomas and leu-kemias, Med. Clin. N. Amier. 37:843-67,May 1953.

26. Lissauer, Zwei Flille von Leucaemie,Berlin. klin. W~schr. 21:403, 1865.

27. Forkner, C. E. and Scott, T.F.M. Ar-senic as a therapeutic agent in chronicmvelogenous leukemia., J. Amer. med.

The Treatment of Leukemia 44 7

Assoc. 97:3-5, 1931.28. Paterson, E., Haddow, A., Ap Thomnas,

I. an(I Watkinson, J. M. Leukoemiatreated with urethane compared withdeep x-ray therapy, Lan~cet 1:677-82,1946.

29. Jacobson, L. 0., Spurr, C. L., Barton,E. S. G., Smith, T., Lushibauigh, C. andDick, G. F. Nitrogen mustard therapy;studlies on the effect of irnethvl-bis(hetia-chloroethyl) amnine hydrochlorideon neoplastic diseases and allied dis-ordlers of the hemopoietic system, J.Amer. med. Assoc. 1329:263-71, 1946.

30. Goodman, L. S., Wintrohe, M. M.,Damieshek, W., Goodman, M. J., Gilman,A. and McLennan, M. T. Nitrogen mius-tardl therapy; use of inethvl-bis (beta-tchioroethyl) amiine hydrochloride forHodgkin's disease, lymphosarcoma, leu-kemia andl certain allied and miscellane-ous disorders, J. Amer. med. Assoc. 1320:126-32, 1946.

31. Ka-rnofsky, D. A., Craver, L. F., Rhoads,C. P. and Abels, J. C. An evaluation ofmnethyl-his (h-chloroethyl) ainine hydro-chloride and tris (b-chloroethyl) aminehydrochloride (nitrogen mustards) inthe treatment of lymphoinas, leukemiaand allied diseases, in Approaches totulmor (chemotherapy, Washington, Amer.

Assoc. Advancement of Science, 1947,pp. 319-337.

32. Burchenal, J. H., Myers, WV. P. L.,Craver, L. F. and Karnofsky, D. A. Thenitrogen mustards in the treatment ofleukemia, Cancer 2:1-17, 1949.

33. Karnofsky, D. A., Burchenal, J. H.,Armistead, G. C., Jr., Southam, C. M.,Bernstein, J. L., Craver, L. F. andRhoads, C. P. Triethylene melamine inthe treatment of neoplastic disease,A4.M.A. Arch. initern,.1Med. 87:477-516,1951.

34. Haddow,, A. and Tinimis G. M. Myleranin chronic myeloid leukirmia; chemicalconstitution and biological action, Lan-cet. 1 :207-08, 1953.

35. Galt~m, 1). A. G. Myleran in chronicmyeloid leukoemia; results of treatment,Loncet. 1:208-13, 1953.

36. Lawrence, J. H. Low-Beer., B. V. A.and Carpenter, J. W. J. Chronic lym-phatic leukemia; a study of 100 patientstreated with radioactive phosphorus,J. Amer. mned. A4ssoc. 140:585-88, 1949.

37. Pearson., 0. H., Eliel, L. P., Rawson,1R. ".,9Dobriner, K. and Rhoads, C. P.Ac'rH-atnd cortisone-induced regressionof lv~mphoid tinnors in mian, Cancer 2:

943-45, 1949.38. Pearson, 0. H. Personal commnunication.

THE NEW YORK ACADEM\1Y OF MEDICINE

Its First Hundred Yearrs

By PHILIP \VAN INGEN

From a. huge mass of documentary inate rial -annals, records, reports, minutes -theauthor has compiled this hiistory of the first hundred years of TIhe New York Academy ofMedicine. He traces tile growth of the institution from its small and often Iprecariousbeginnings to The New York Academy of Medicine as we know it today, a strong organi-zation whose influence is nation-wide.'

Dr. Van Ingen (lescribes the growth of the Academty A-ear by year, undler successiveadministrations, recounting the lively' and important issues~that aroFe andl tile official actiontaken to mneet them. A centurv of scientific advances in niedicine is Ipresented1 in paperspresented and discussed at Academy sessions, and the history of social advances is reflectedin stands taken by the Academy throughout the century in' matters of public health andmedlical education.

$4.50. Pp. xii + 586, illus. History of Mledici-ae Serie.,:, No. 8.

COLUMBIA UNIVERSITY PRESS2960 Broadway, New York 27, N. Y.