The New England
`Journal of Medicine
`
`Copyright, 1948, by the Massachusetts Medical Society
`
`Volume 238
`
`JUNE 3, 1948
`
`Number 23
`
`TEMPORARY REMISSIONS IN ACUTE LEUKEMIA IN CHILDREN PRODUCED BY
`
`FOLIC ACID ANTAGONIST, 4-AMINOPTEROYL-GLUTAMIC ACID (AMINOPTERIN)*
`
`SIDNEY FARriER, M.D.,~ Louis K. DIAMOND, M.D.,~: ROBERT D. MERCER, M.D.,§
`
`ROBERT F. SYLVESTER, JR., M.D.,¶ AND JAMES A. WOLFF, M.D.[[
`
`BOSTON
`
`I T IS the purpose of this paper to record the re-
`
`suits of clinical and hematologic studies on 5
`children with acute leukemia treated by the intra-
`muscular injection of a synthetic compound, 4-
`aminopteroylglutamic acid (aminopterln). This
`substance is an antagonist to folic acid regarding
`the growth of Streptococcus faecalis R.
`The occurrence of what he interpreted as an
`"acceleration phenomenon" in the leukemic process
`as seen in the marrow and viscera of children with
`acute leukemia treated by the injection of folic
`acid conjugatesl--pteroyltrlglutamic acid (terop-
`terin) and pteroyldiglutamic acid (diopterin) -- and
`an experience gained from studies on folic acid
`deficiency suggested to Farber that folic acid an-
`tagonists might be of value in the treatment of pa-
`tients with acute leukemia.2 Post-mortem studies
`of leukemic infiltrates of the bone marrow and
`viscera in patients treated with folic acid conju-
`gates were regarded by Farber as evidences of an
`acceleration of the leukemic processes to a degree
`not encountered in his experience with some 200
`post-mortem examinations on children with acute
`leukemia not so treated. It appeared worth while,
`therefore, to ascertain if this acceleration phenom-
`enon could be employed to advantage either by
`radiation or nitrogen mustard therapy after pre-
`treatment with folic acid conjugates or by the ad-
`ministration of antagonists to folic acid3 A series
`of folic acid .antagonists was made available by
`Dr. Y. Subbarow and his colleagues)-~
`The objective data sufficient to justify research in
`the direction of antagonists to folic acid in the treat-
`*Presented at a meeting of the Division of Laboratories and Research,
`The ChiMren’s Medical Center, Boston, April 8, 1948.
`This stud?" was supported in part under Grant No. 250 of the National
`Cancer Insutute United States Public Health Service, and in part under a
`grant from the Charles H. Hood Da ry Foundation.
`~’Asslstant professor of pathology, Harvard Medical School; pathologlst-
`in-chief and chairman, Division of Laboratories and Research, The Chil-
`dren’s Medical Center, Boston.
`.~Asslstant professor of pediatrics, Harvard Medical School; hematologist
`and physician to The Children’s Medical Center, Boston.
`§Research fellow in pathology and tumor research, The Children’s
`Medical Center, Boston.
`¶Research fellow in pathology and tumor research, The Children’s
`Medical Center, Boston.
`[[Research fellow ~n ped[atrlcs, The Children’s Medical Center, Boston.
`
`ment of leukemia were obtained from studies On a
`four-year-old girl with a rapidly progressing acute
`myelogenous leukemla3 Treatment from Febru-
`ary 17 to March 24, 1947, with pteroyldiglutamic
`acid (diopterin), in a dosage of 100 to 300 mg. intra-
`muscularly daily, had no effect upon the hematologic
`picture. The patient appeared to be moribund. A
`second bone-marrow biopsy on March 25 verified
`the diagnosis of myelogenous leukemia. Pteroyla-
`spartic acid, the first antagonist to folic acid to be
`employed in our studies, was given intramuscularly
`from March 28 to April 4 in amounts of 40 mg.
`daily without altering the clinical course. Post-
`mortem examination on April 4 revealed a markedly
`hypoplastic bone marrow, with a few immature
`ceils. A change of this magnitude in such a short
`time has not been encountered in the marrow of
`leukemic children in our experience.
`This observation was followed by clinical, labora-
`tory, and post-mortem studies** on a group of 14
`children with acute leukemia treated with pteroyl-
`aspartic acid and on 7 treated with methylpteroic
`acid. The details of these observations will be re-
`ported separately.
`Sufficient encouragement was obtained from these
`observations to justify further studies on the effect
`of more powerful antagonists to folic acid on the
`course of acute leukemia in children. Since Novem-
`ber, 1947, when a sufficiently pure substance be-
`came available, to the time of this writing (April 15,
`1948) we have made studies on 16 children with
`acute leukemia to whom the most powerful folic
`antagonist we have yet encountered, 4-aminopteroyl-
`glutamic acid (aminopterin~) was administered by
`intramuscular injection. Many of these children
`were moribund at the onset of therapy. Of 16 in-
`fants and children with acute leukemia treated with
`aminopterin 10 showed clinical, hematologic and
`pathological evidences of improvement of important
`
`**These studies were carried out by a group consisting of Sidney Farber,
`Gilbert G. Lenz, James W. Hawkins, Ernst Eichwald, Robert D. Mercer
`and E. Converse Peirce, II.
`~f’fThis compound was first synthesized by the Calco Chemical Division
`of the American Cyanamid Company.
`
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`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`June 3, 1948
`
`nature of three months’ duration at the time of
`this report. Six patients did not respond well; 4
`of these are now dead, and 2 were unimproved.
`This paper presents detailed clinical, hematologic
`and bone-marrow studies in 5 children selected from
`these 10 who showed evidences of important im-
`provement-the course in the other cases was
`essentially similar. The patients are selected for
`the purpose of illustrating some of the problems
`concerned with the use of aminopterin and because
`they demonstrate the best results that we have
`
`FXCURE 1. Course of Leukemia in Case 1.
`
`observed. The toxic effects are stressed in these
`histories, and the temporary nature of the remissions
`is emphasized.
`
`CASE REeOKTS
`C^sE 1. W.G., a 7 2/12-year-old boy, entered the hos-
`pital for the first time on April 9, 1947, with complaints of
`joint pain and fever. He had been generally well until 7
`weeks before admission, when pain developed in the right
`knee. There were no associated physical abnormalities,
`and the pain promptly subsided. Five days later pain re-
`curred in the right elbow, and a low-grade fever was noted.
`Migratory arthralgia and fever continued until admission.
`Physical examination revealed only moderate pallor and
`slight enlargement of the liver and spleen. The boy ap-
`peared well developed and nourished and not particularly ill.
`Examination of the blood disclosed a red-cell count of
`3,670,000, with a hemoglobin of 10.6 gin., and a white-cell
`count of 56,000, with 73 per cent blast forms. The plate-
`let count was normal. A bone-marrow biopsy revealed
`leukemia.
`The patient was treated with pteroylaspartic acid begin-
`ning on April 16 in doses of 20 to 60 mg. daily while in the
`hospital, in a convalescent home, where he remained until
`May" 20, and at home, where the injections were given by
`the family physician. During that time he was active and
`fairly well, although the white-eel1 count remained high and
`the red-cell count and hemogl6bin fell slowly.
`On July 1 diopterin, in a dosage of 200 mg. by mouth daily,
`was begun. This therapy was continued for about 1 month,
`during which the patient steadily became more ill. The
`liver and spleen enlarged, and he became very anemic. The
`blast forms in the peripheral blood rose to 94 per cent. ]oint
`pain and fever recurred, and by August 13 he was critically
`ill, with a temperature reaching 106*F. He was readmitted to
`
`the hospital and received several transfusions. Pteroylaspar-
`tic acid and methylpteroic acid, in doses of 40 mg. each,
`were given intramuscularly daily. The patient was dis-
`charged after about 2 weeks, and pteroylaspartic acid and
`methylpteroie acid, in doses of 20 rag. each, were continued
`in the Tumor Therapy Office. A period of remission en-
`sued, during which the red-cell count and platelets returned
`to normal levels, the liver and spleen receded in size and
`the nutrition improved remarkably. He returned to school
`part time in October and was in quite good condition. The
`white-cell count had risen to high levels, however, and in
`November general deterioration began. The liver and
`spleen enlarged, and he became so anemic that transfusion
`was necessary by November 24. Only temporary benefit
`resulted and transfusions were required at about 3-week in-
`tervals.
`Aminopterin was started on December 16 and given daily,
`in doses of 0.5 mg. intramuscularly, for six doses. By Decem-
`ber 30 the white-cell count had fallen from 60,000 to 19,000.
`There was moderate improvement in activity and appetite.
`Thereafter unfavorable weather made daily visits to the
`clinic impossible, and 1 mg. of aminopterin was given ap-
`proximately three times weekly for about a month. During
`that time there was no striking clinical or hematologle im-
`provement, although the patient was not seriously ill.
`On February 3 daily injections of 1 mg. of aminopterin
`were begun. A bone-marrow biopsy and aspiration revealed
`85 per. cent blast forms, no megakaryocytes and no eryth-
`ropmes~s. After 10 days of regular therapy the white-cell
`count had fallen from 78,000 to 5000, but severe stomatitis
`made cessation of therapy imperative. Within a week
`without therapy, the stomatitis had healed completely,
`and the patient had developed a ravenous appetite. The
`nutrition gradually improved. By February 21 the liver was
`no longer palpable, and only the tip of the spleen could be
`felt. Bone-marrow aspiration and biopsy revealed a slight
`decrease in blast forms and slight erythropoietie activity.
`The platelets reached normal levels about 1 month after
`this course of daily therapy. On March 1 the white-cell
`count began to rise in spite of daily administration of 0.25
`mg. of aminopterin, and by March 6 was 75,000. The spleen
`again enlarged. The dosage of aminopterin was raised to
`1 rag. on March 8, and after about 10 days the white-cell
`count had fallen to 12,000. Slight stomatitis again appeared,
`and the dosage of aminopterln was reduced to 0.5 rag;
`daily, with 1 unit of crude liver extract weekly. The white-
`cell count has remained at a high-normal level, and the spleen
`is again slowly receding. The stomatitis is still present but
`is not progressing and does not interfere with ability to eat.
`
`The leukemia in this case progressed slowly dur-
`ing treatment with pteroylaspartie acid and methyl-
`ptefoic acid, but during a course of diopterin be-
`came rapidly worse (Fig. 1). The liver and spleen
`enlarged, severe anemia developed, and the blast
`forms in the peripheral blood rose above 90 per
`cent. The patient appeared critically ill, with a
`maximum temperature of 106°F. Transfusions
`and therapy with these two folie acid antagonists
`were followed by a marked but temporary remis-
`sion. Irregular therapy with amlnopterin has been
`of no benefit, but on two occasions daily injections
`have produced good clinical and hematologic re-
`missions. On both occasions, stomatitis has in-
`terfered with optimal use of the drug. At the time
`of writing the patient is in excellent physical con-
`dition.
`
`CAS~ 2. R.P., a 6 4/12-year-old boy, was admitted to
`the hospital on March 4, 1948, with the chief complaint of
`increasing pallor. His growth, development and general
`health had been excellent until about 3 weeks before ad-
`mission, when tonsillitis had developed. This had sub-
`sided promptly, but the patient had become lethargic, and
`increasing pallor was noted. About 10 days before admission
`his parents began to notice that he bruised easily.
`
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`VoI. 238 No. 23
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`ACUTE LEUKEMIA--FARBER ET AL.
`
`789
`
`returned to normal and he is in school part time.
`The red-cell count and hemoglobin are still high,
`and the white-cell count is within normal limits.
`Immature cells or blast forms have disappeared
`from the peripheral blood, and the bone marrow
`shows a moderate shift toward maturity of leuko-
`cytes, with an increase of erythrocyte precursors
`and megakaryocytes. The course is demonstrated
`in Figure 2.
`
`CAs~ 3. G.J.,a 3 8/12-year-oldboy, was admitted to the
`hospital on November 2, 1947- 5 days after the onset of
`an acute illness with sore throat and fever.
`The past history, birth anddevelopmentaI history were
`not remarkable.
`Physical examination disclosed a critically ill patient
`w[th an acute follicular tonsii[itis and enlarge~t tender cer-
`
`XXX X
`
`Physical examination disclosed a well developed and
`fairly well nourished boy who was very pale and lethargic.
`Many small ecchymoses were noted over the extremities.
`The liver edge extended 4 cm. below the costal margin, and
`the tip of the spleen could be felt at the costal margin. There
`was slight generalized lymphadenopathy.
`Examination of the blood revealed a red-ceil count of
`1,880,000, with a hemoglobin of 5.65 gm. and platelets of
`46,000, and a white-cell count of 4200, with 20 per cent im-
`mature or blast forms. A sternal-marrow aspiration revealed
`75 per cent blast forms. No megakaryocytes were seen.
`Shortly after admission the patient developed a spiking
`temperature up to 104 or 105°F. daily, and rapidly became
`more lethargic. Blood cultures revealed no growth. Fre-
`quent transfusions raised the red-cell count and hemoglobin
`to normal levels, but there was no favorable clinical response.
`The white-cell count fell to 1500. He appeared critically ill.
`On the 7th hospital day penicillin was started, and the tem-
`perature decreased although it continued to reach 101 to
`102°F. daily.
`On the 8th hospital day, aminopterin (1 my.) and crude
`liver extract (1 unit) were given intramuscularly. The white-
`cell count was 1500. This medication was continued daily,
`and the patient rapidly became more alert and active. The
`white-cell count remained near 2000. He was discharged
`moderately improved on March 15. After discharge he
`was seen 6 times weekly in the Tumor Therapy Clinic and
`1 my. of aminopterin and 1 unit of crude liver extract were
`given at each visit. Rapid improvement in appetite and ac-
`tivity continued. A second sternal-marrow biopsy and
`aspiration after one week of therapy revealed a 2.5 per cent
`decrease in blast forms and an increase in more mature
`leukocytes and megakaryocytes. By March 25 the white-
`cell count had reached 5000, with 34 per cent neutrophils,
`63 per cent lymphocytes and 2 per cent blast forms. His
`activity and appetite were normal and easy bruising was no
`longer a complaint. At about that time he developed minor
`
`CRUDE LIVER , l unU ............
`
`a~o’,,,,
`so[ 5?:
`
`EARLY MYELOIOS
`MATURE MYELOIDS
`LYMPHOGYT~S
`NUCLEATED RBG
`
`~’IGURE 2. Course of Leukemia in Case 2.
`
`lesions of the oral mucosa. The dosage of aminopterin
`was reduced to 0.5 my., and the liver extract was given once
`weekly. Steady improvement has continued. The liver and
`spleen are no longer palpable. The patient is active in out-
`door games~ and his endurance is good. On March 31 he
`returned to school, where his teacher noted marked improve-
`ment in l~is appearance and interest. Sternal-marrow aspira-
`tion on April 1 revealed a slight further reduction in blast
`forms, a moderate increase in megakarocytes and a marked
`increase in erythropoiesis. He continues on daily injections
`of 0.5 my. of aminopterin with liver extract once weekly.
`
`This patient had rapid progression of leukemia
`until one month after the onset, when he appeared
`critically ill. After three weeks of daily aminop-
`terin therapy his activity and appearance have
`
`Floug~ 3. Course of Leukemia in Case 3.
`
`vical lymph nodes. There was no generalized adenopathy
`and no hepatomegaly or splenomegaly. A blood culture
`was positive for beta-hemolytic streptococcus.
`Examination of the peripheral blood showed a red-cell
`count of 1,900,000, a white-cell count of 480 and a platelet
`count of 123,000. Bone-marrow aspiration showed 16.4 per
`cent blast forms, 3.2 per cent. mature polymorphonuclear
`leukocytes, 76.2 per cent lymphocytes and 1.6 per cent eryth-
`roid elements. On the basis of the bone-marrow asplra-
`tion a diagnosis of leukemia was made. The bacteremia was
`treated with penicillin and streptomycin.
`After recovery from the infection the patient went into a
`complete clinical and hematologic remission for about 2
`months. The course is demonstrated in Figure 3. At that
`time bilateral acute otitis media developed. Two week~
`later the total nucleated count of the sternal bone marrow
`was 910,000 (normal 200,000 to 250,000), with 96 per cent
`blast forms (Fig. 4A). By February 26, 1948, the white-
`cell count was 17,2~0, with 80 per cent blast forms, the spleen
`extended to the umbilicus, petechiae began to appear, and it
`was obvious that the child was entering a rapidly progressive
`phase of the leukemia.
`tie was readmitted to the hospitalon March 6. He appeared
`chronically ill, with pallor, petechiae, moderate generalized
`lymphadenopathy and marked hepatomegaly and spleno-
`megaly. The white-cell count, which was 30,400, with 86
`per cent blast forms, on admission, fell rapidly to 900 by
`March 12, and the patient appeared moribund. Blood
`cultures were negative.
`Aminopterin was started on March 13 in doses of 0.5 my.
`and given for 5 consecutive days. Crude liver extract, in a
`dosage of 1 unit daily, was given in the same syringe. At
`
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`June 3, 1948
`
`the end of that time there was no noticeable clinical improve-
`ment, but the white-cell count, which was still 900, contained
`only 5 per cent blast forms. A sternal-marrow smear made
`at the end of this short period of therapy and compared to
`one just before therapy was started showed a shift to the
`right, with some reduction in blast forms and an increase in
`more mature forms of granulocytes, as well as a slight increase
`in erythroid elements. Aminopterin was discontinued until
`it became apparent that the leukopenia was not increasing.
`After 4 days without treatment 0.5 mg. of aminopterin
`daily, with 1 unit of crude liver extract, was given once more.
`The white-ceil count increased gradually, and blast forms
`
`CASE 4. C.C., a 2 1/12-year-old girl, was admitted to the
`hospital on August 22, 1947. Six weeks previously her
`father had noticed lumps about the head and neck. Two
`weeks previously her family physician had made a diag-
`nosis of leukemia on the basis of a peripheral blood smear.
`Physical examination revealed a pale girl, with ecchymotic
`areas over the lower extremities. There was marked general-
`ized adenopathy, particularly about the parotid region,
`and the liver edge and tip of the spleen extended down to
`the iliac crests.
`Examination of the blood disclosed a white-cell count
`of 75,000, with 80 per cent blast forms. The platelet count
`
`A
`
`B
`
`F,cvRr 4. Photomicrographs of the Sternal Bone Marrow in Case 3, Showing Giemsa-Stained Section on January 29,
`(A) and April 3 (B), 1948 (xlO00).
`.Vote that the microscopical field is composed mainly of blast forms characteristic of leukemia (cell type undetermined)
`in the early section (A) and that a marked shift to mature cell forms, particularly of the polymorphonuclear series,
`with no leukemic cells, had occurred on the later examination (B).
`
`disappeared from the peripheral blood. The child began
`to show c!inical improvement, his appetite became better,
`and the liver and spleen became scarcely palpable. The
`petechiae and generalized adenopathy disappeared.
`At the present writing there is a partial contracture of
`the left leg, probably resulting from leukemic infiltrations
`about the knee joint and in the gastrocnemius muscle. The
`tip of the spleen is still palpable. Otherwise the child is
`normal on physical examination. The white-cell count is
`6700, with a normal differential. The platelet count is
`152,000. Aspiration of the sternal marrow on March 29 re-
`vealed 8 per cent blast forms, with an increase in more
`mature granulocytes, erythrocyte precursors and mega-
`karyoeytes (Fig. 4B).
`
`This child with acute leukemia had a remission
`of about two months’ duration after a bacteremia.
`At the time aminopterin was started he was in a
`rapidly progressive phase of the leukemia and ap-
`peared moribund. After five days of therapy there
`was marked improvement in the peripheral-blood
`and sternal-marrow picture. He has continued
`to demonstrate rapid and remarkable clinical im-
`provement. Eighteen days after therapy was
`started the sternal-marrow aspiration showed only
`a slight shift toward immaturity of the myeloid
`elements and a moderate reduction of lympho-
`cytes and erythroid elements. The peripheral
`blood at present shows slight thrombocytopenia,
`with a white-cell count of 8000 and a differential
`count that is essentially normal except for a large
`number of band forms.
`
`was 54,000. The patient was discharged and given x-ray
`therapy to the parotid region in the outpatient department.
`A total of 600 r was given from September 4 to September 8.
`The white-cell count, which was 94,000 on September 4,
`had dropped to 5000 by September 11.
`The patient was readmitted on September 27. She was
`much worse, with a poor appetite, marked pallor and mas-
`sive adenopathy. The white-cell count was 1000, with 30
`per cent blast forms. Several transfusions before discharge
`produced only slight improvement.
`The third admission, on November 6, followed a general-
`ized convulsion. The patient was comatose, with a tem-
`perature of 103.6°F.
`Physical examination was essentially unchanged except
`that the kidneys were definitely enlarged and easily pal-
`pable. There was no positive evidence of infection. A
`transfusion and penicillin were given, and the patient was
`discharged in fair condition.
`The fourth and last admission was on December 2, when
`there was a temperature of 105°F. There was a severe
`stomatltis and pharyngitis, with extensive exudation. The
`left ear was inflamed but not suppurating. Bronchopneu-
`monia was present on the left. A lumbar puncture showed
`evidence of subarachnoid hemorrhage. A blood culture
`was positive for Staphylococcus aureus, coagulase positive.
`For the first 6 hospital days thepatient ran a septic tem-
`perature ranging between 105 and 103°F. She was given
`penicillin and sulfadiazine, as well as repeated blood trans-
`fusions, throughout the hospital stay. At this admission
`she was seen for the first time by the Tumor Clinic and re-
`ceived 20 me. of teropterin per day for eighteen doses, from
`December 3 through December 20.
`On several occasions the patient appeared moribund but
`on about the 7th hospital day she began to improve and
`continued to improve until the time of her discharge. The
`white-cell count, which had dropped to 650 on the 4th hos-
`pital day, rose to 6400 on the day before discharge. The
`differential count included 68 per cent neutrophils, 24 per
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`ACUTE LEUKEMIA- FARBER ET AL.
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`791
`
`cent lymphocytes and 8 per cent monocytes. There were
`no blast forms,
`After this severe infection there was a remission in the
`clinical and hematologic condition. During that time the pa-
`tient was given an occasional dose of teropterin to a total of
`140 my. By January 13 small lymph nodes over the scalp,
`parotid and cervical regions had begun to develop. These
`rapidly increased, and by January 19 there was massive
`generalized adenopathy. The peripheral blood and bone
`marrow continued at values approaching normal. There
`were only occasional to 5 per cent blast forms in the periph-
`eral blood, with a normal total white-cell count, and
`8.4 per cent blast forms in the bone marrow, with a slight
`depression of mature forms and a moderate depression of
`erythroid forms. On January 20 aminopterin was started
`in doses of 1 rag. daily with 20 my. of teropterin daily. This
`was given on twenty-six clinic visits from January 20 to
`February 21. Four days after treatment had been started
`there was a marked decrease in the size of all the lymph
`nodes. In 2 weeks the patient was normal on physical ex-
`amination. Her appetite became very good, her disposi-
`tion happy, and she began to play and run about like a nor-
`mal child. Her parents stated that she was better than
`she had been before she became sick for the first time. Since
`treatment was stopped she has continued to do well She
`has been without treatment since February 21 and at present
`is completely normal on physical examination. The total
`white-cell count is 9000, with an occasional blast form. The
`platelet count is 256,000, the red-cell count 4,600,000 and
`the hemoglobin 14.8 gin.
`
`This child is known to have had acute leukemia
`since early in August, 1947. Her course was rapidly
`and progressively downhill until December, when
`she had a fulminating generalized infection with
`bacteremia. After this she had clinical and hema-
`tologic evidence of remission. In the middle of
`January a relapse was taking place, as evidenced
`by massive generalized adenopathy although the
`blood and bone-marrow picture remained the same.
`After aminopterin therapy the adenopathy dis-
`appeared. The patient has remained clinically
`well for forty-three days Without treatment and
`shows an essentially normal hematologic picture.
`at the time of writing. The course is shown in
`Figure 5. At the end of forty-seven days without
`treatment a few nodules appeared beneath the
`scalp and in the subcutaneous tissue over the
`face. It is probable that these represented leukemic
`deposits, although at the time of their appearance
`the peripheral blood was still essentially normal.
`Because of this finding the treatment has been
`reinstituted.
`
`C^sz 5. R.S., a 2 2/12-year-old boy, was admitted to the
`hospital on August 26, 1947, with the chief complaint of
`increasing pallor. He was one of identical twins, and his
`birth, growth and development, and general health had been
`unremarkable. About 10 days before admission he had
`developed a low-grade fever, soon followed by increasing
`pallor, lethargy, anorexia and intermittent vomiting.
`Physical examination showed a fairly well developed and
`well nourished and only moderately ill boy. He was very
`pale. There was generalized enlargement ~f the lymph nodes
`and moderate hepatomegaly and splenomegaly. X-ray study
`showed marked infiltration of the long bones. The hemo-
`globin was 5.5 gin., and the white-cell count 12,400, with
`41 per cent immature or blast forms.
`During 2 weeks in the hospital the patient received trans-
`fusions, which restored the hemoglobin to normal levels.
`After discharge he was seen in the Tumor Therapy Clinic
`daily except Sunday and on each visit received 20 my. of
`pteroylaspartic acid intramuscularly. He continued on
`this regime for about 2 months, during which the disease
`
`progressed slowly but steadily. He became less alert and less
`active. He developed a limp. There was gradual weight loss,
`and the liver and spleen continued to enlarge. The leuko-
`cytes remained at normal levels but the percentage of blast
`forms increased. The red-cell count and hemoglobin slowly
`fell, until on November 6 it was necessary to admit him to
`the hospital for transfusion. At that time a small patho-
`logic fracture was noted in the left tibia. After discharge
`he was seen in the Tumor Therapy Office three times weekly
`and on each visit received 40 mg. of pteroylaspartic acid
`intramuscularly. Late in November there was a definite
`acceleration in the progress of the disease. The white-cell
`count began to rise, and the platelets fel!. The patient be-
`gan to bruise easily and had occasional slight oozing from
`the gums. I-Ie developed moderate exophthalmos. He re-
`fused to walk. Hospitalization was necessary twice in the
`
`early weeks of December for treatment of arthritis and
`upper respiratory infection. Sternal-marrow aspiration at
`that time revealed 40 per cent blast forms and little erythro-
`poiesis. By the end of December the patient appeared mori-
`bund. He had marked generalized adenopathy, marked
`he~patomegaly and a spleen whose tip extended into the
`pelvis. There was moderate dyspnea and stridor, pallor,
`marked wasting and exophthalmos. There were many ecchy-
`moses, and oozing occurred at the gingival margins.
`Aminopterin therapy was .begun on December 28. On each
`of 3 successive days the patzent received 1.0 my. of the drug
`intramuscularly. During that time the white-cell count
`began to fall rapidly from the pretreatment level of 60,000.
`By.December 31 the count was 9000, and respiratory diffi-
`culty was even more marked. He was admitted to the hos-
`pital, aminopterin was discontinued, and a transfusion was
`given. He was discharged on January 3, 1948, slightly im-
`proved, but with the white-cell count only 2700. After dis-
`charge he was again followed in the Tumor Therapy Clinic.
`By January 13 marked clinical improvement had become
`apparent. The patient was walking for the first time in 2
`months, and respiratory difficulty had disappeared. His
`appetite was ravenous. There was no more bleeding. "His
`clothes became loose about the abdomen." On January 27
`the white-cell count reached 5000, and 0.5 my. of aminop-
`terin was started and given three times weekly. Gradual
`improvement continued, but a white-cell count of about
`3000 persisted. In the middle of February, tero.pterin in 10-
`my. amounts was given with each dose of am~nopterin for
`five doses. Early in March a rise in the hemoglobin and red-
`cell count began. Since then fslic acid for a time and lately
`crude liver extract have been used in conjunction with aminop-
`terin. There had been steady clinical and hematologic im-
`provement so that at the time of writing, activity, alertness
`and nutrition are equal to or better than those of the well
`twin. The liver and spleen have decreased in size, so that
`they are barely palpable beneath the costal margins. Ex-
`ophthalmos has disappeared. The red-cell and white-cell
`
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`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`June 3, 1948
`
`count, differential counts and platelets are within normal
`limits. Tim sternal marrow, examined by biopsy, is normally
`cellular, and the differential count is normal. Erythropoiesis
`is active, and megakaryocytes are present in normal number.
`
`This boy exhibited slow but regular progression
`of leukemia from the time of diagnosis in August,
`1947, until December, when he became rapidly
`worse. By January, 1948, he appeared moribund.
`After three daily doses of 1 mg. each of aminopterin
`there was a rapid fall in the white-cell count, fol-
`lowed in about ten days by remarkable clinical
`improvement. On maintenance therapy there has
`been continued improvement until at present the
`
`X
`
`Fmu~ 6. Course of Leukemia in Case
`
`patient is clinically well and all the laboratory data
`are within normal limits. The course is demonstrated
`in Figure 6.
`
`DISCUSSION
`
`Clinical, hematologic and histologic details are
`given concerning 5 children with acute undifferen-
`tiated leukemia treated with aminopterin. These
`pat