Central Nervous System Therapy and Combination ......272 BLOOD, VOL. 37, No. 3 (MARcH), 1971 Central Nervous System Therapy and Combination Chemotherapy of Childhood Lymphocytic Leukemia

272 BLOOD, VOL. 37, No. 3 (MARcH), 1971

Central Nervous System Therapy and Combination

Chemotherapy of Childhood Lymphocytic Leukemia

By RI1o�mEs j. A. AUR, JOSEPH SIMONE, IT. OMAR HUSTU, THOMAS \\ALTERS,

LUIS BORELLA, CHARLES PRATT AND DONALD PINKEL

In earlier combination chemotherapy

regimens for childhood acute lymphocy-

tic leukemia, nervous system leukemia

terminated complete remission in over

half the patients in a median time of 11

months. In the present study, cranial ra-

diation (2400 R, 60Co) and intrathecal

methotrexate given early in remission

were added to combination chemo-

therapy in an attempt to prevent or

delay central nervous system relapse

and termination of complete remissiOn.

Of 35 consecutive children with pre-

viously untreated acute lymphocytic leu-

kemia, 20 of 30 who attained remission

and received all initial phases of therapy

have been in continuous complete re-

mission for 23 to 30 months. Completeremission was terminated by nervous

system relapse in three patients and by

hematological relapse in five. Two pa-

tients died in complete remission of viral

infections and others experienced reversi-

ble drug toxicity. We conclude that this

combined therapy reduces the incidence

of nervous system relapse in the first 2

years and prolongs complete remission.

S INCE 1962 \\‘E hAVE EMPLOYED MULTIPLE AGENT COMBINA-TION TFIERAPY in the treatment of children with acute lyniphocytic

leukemia.15 The purpose has been to achieve prolonged continuous complete

remission and to establish a significant 5-year cure rate for this disease. Of 41

patients w’ith previously’ untreated acute lymphocytic leukemia entered into

early studies (1962_1965),12 37 experienced complete remission and seven

From time Hematology, Oncology and Radiology Services, St. Jude Children’s Research

Hospital, Memphis, Tenn.

Submitted September 10, 1970; revised October 23, 1970; accepted October 28, 1970.

Supported by Cancer Research Center Grant CA-08480, Research Project Grant

CA-07594, and Training Grant CA-0.51 76 from the National Cancer I;..st�tute, and inj

ALSAC.RIior�tE.s J. A. Aums, M.D.: Asri.slant Member in Hematology, St. Jude Children’s

Research hospital; Instructor in Pediatrics, University of Tennessee, Memphis, Ten n.

JosEPH SIMONE, �sI.D.: Associate Member in Hematology, St. Jude Children’s Res’arcIm

Hospital; Assistant Professor of Pediatrics, University of Tennessee, ?t!em p/mis, Tenn.

H. OMAn HUSTU, M.D.: ?mlember in Radiology, St. Jude Children’s Research hospital;

Associate Professor of Radiology, University of Tennessee, Memphis, Tenn. THo�mAs

WALTERS, M.D.: Associate Member in Hematology, St. Jude Children’s Research

hospital; Associate Professor of Pediatrics, University of Tennessee, Meum p/mis, Ten mm.

Luis BORELLA, M.D.: Associate Member, Laboratories of Virology and immunology,St. Jude Children’s Research Ho.rpital; Assistant Professor, Departments of Microbiology and

Pediatrics, University of Tennessee, Memphis, Tenn. ChARLEs PRATT, M.D.: Associate

Member in Chemotherapy, St. Jude Children’s Rese�ircim Hospital; Assistant Professor of

Pediatrics, University of Tennessee, Memphis, Tenn. DONALD PINKEL, M.D.: Medical

Director, St. Jude Children’s Research Hospital; Professor of Pediatrics, University of

Tennessee, Memph �s, Tenn.

For personal use only.on September 13, 2017. by guest www.bloodjournal.orgFrom

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THERAPY OF CHILDHOOD LYMPHOCYTIC LEUKEMIA 273

remain in continuous complete remission for 5 years or more and have been off

all therapy for 2 to 3% years. Thus, a 17 per cent 5-year leukemia-free remis-

sion rate has been achieved.5

In these studies complete remission has beeii most often terminated by

nervous system leukemia occurring in the presence of hematological remission.

The Iresellt therapy scheme was designed to explore the possibility that

nervous system leukemia and thus early termination of complete remission

could l)e I)reventecl l)y administermg a moderately high dose of cranial radio

therapy along with intrathecal methotrexate early during complete remission.

This study has l)een in progress for more than 2 years. It is reported at this

time because the results are currently superior to those of any previous treat-

ment program.

MATERIALS AND METHODS

Patients

Thirty-five children �vith acute lymphocytic leukemia �vere registere(l consecutively

in this study ( Protocol V ) from December 1967 to July 1968. Patients were admitted to the

study as soon as the diagnosis �s’as confirmed if they had no prior therapy excel)t for

blood transfusions or less than 7 (laYs of corticosteroids. The ages ranged in the 18 boys

( three l)lack ) from 2 years and 4 months to 15 years and 10 months, and in the 17girls from 2 years and 1 month to 10 years and 8 months. Th� median age of all 35 patients

\v_ms 4 years iIIl(l 7 months.

Diagnosis

At this hospital a diagnosis of acute lymphocytic leukemia is made when lymphoblasts

or “stem cells predominate in the bone marrow. In effect, childhood leukemia is

cons:dered lymphocytic unless cells are characterized by unequivocal Auer rods and/or

definite myelocytic or monocytic differentiation.A diagnosis of central nervous system leukemia is made when leukemic blast cells

are found in the Wright-stained centrifugate of a 2- to 5-mi. sample of spinal fluid.

\Vhenever the cellular morphology is questionable, another sample is obtained in a few

days. Because lumbar punctures are performed routinely at 10-week intervals, the

diagnosis is made most often before the appearance of papilledema, headaches, vomiting,

or other signs of increased intracranial pressure.

Definition of Terms

Complete remission duration3 is the time between the first complete remission marrow

and the first sign of relapse, whether hematological, nervous system, or visceral. Thisdefinition differs from the one currently used by many investigators who do not consider

complete remissions terminated when meningeal relapse occurs.67

Hematological remission duration3 is the time between the first complete remission

marrow and first evidence of marrow relapse. Thus, hematological remission duration

includes periods of central nervous system or other disease outside of the marrow. This

definition corresponds to that termed complete remission duration by other investigators.6’7Time to central nervous system leukemia is the period between the first complete

remission marrow and the first evidence of central nervous system leukemia. Survival is

the period between diagnosis of leukemia and death. It should be emphasized that complete

remission refers to the initial continuous remission free of all evidence of leukenmia, and

that hematological remission refers to the initial continuous remission free of hematological

evidence of leukemia. Five-year leukemia-free remission contrasts with 5-year survival

which means that the patient has lived 5 years since diagnosis regardless of leukemic

status.5




274 AURETAL.

Table 1.-Outline of Therapeutic Regimen With Dosage Guidelines0

Remission induction (4 to 6 weeks)Prednisone: 40 mg./sq. rn/day in three or four divided doses

Vincristine: 1.5 mg/sq. m./wk. intravenously

Intensive chemotherapy ( 1 week)6-mercaptopurine: 1000 mg./sq. m./day intravenously for 3 days, followed by

Methotrexate: 10 mg/sq. m./day intravenously for 3 days, followed by

Cyclophosphamide: 600 mg./sq. m. intravenously for 1 day

Central nervous system therapy (2#{189}weeks)2400 R 60Co radiotherapy to cranium and, simultaneously,Methotrexate: 12 mg/sq. m. intrathecally twice weekly for five doses

Continuation therapy6-mercaptopurine: 50 mg/sq. m. once a day by mouthMethotrexate: 20 mg/sq. m. once a week intravenously

Cyclophosphamide: 200 mg/sq. m. once a week intravenously

The following therapy was added every 10 weeks

Prednisone: 40 mg/sq. m./day by mouth for 15 daysVincristine: 1.5 mg./sq. m./week intravenously for three doses

Complete protocol available on request.

Therapeutic Regimen

An outline of therapy with dosage guidelines is shown in Table 1. Informed parental

consent was obtained before the start of therapy and before radiation. Weekly vincristineand daily prednisone were used to induce remission. If successful, patients were given

high-dose intravenous chemotherapy daily for 1 week: 6-mercaptopurine on each ofthe first 3 days, methotrexate on each of the next 3 days and cyclophosphamide on the

final day. On completion of this phase, central nervous system therapy was begun.

The skull was irradiated through opposing lateral ports using a cobalt-60 unit. A tissue

dose of 2400 R was delivered in 15 fractions over 23i weeks with concurrent administration

of methotrexate intrathecally, 12 mg. per square meter twice weekly for five doses.Following radiation, combination chemotherapy consisted of 6-mercaptopurine daily bymouth, methotrexate and cyclophosphamide weekly intravenously, and a 15-day courseof prednisone and vincristine every 10 weeks.

Modification of Chemotherapy

Patients received maximum tolerated doses of each agent. Doses were increased if

the total leukocyte count was consistently above 3000 per cubic millimeter. Doses of all

agents were reduced to one-half if the leukocyte count was between 1000 and 2000 percubic millimeter and full doses restored when the count rose above 3000 per cubicmillimeter. All agents were stopped for severe leukopenia (less than 1000/cu. mm.),

mucosal ulceration, severe vomiting or diarrhea, and in the presence of fever persisting

longer than 2 days. Chemotherapy was restored when toxicity or infection resolved.If there was evidence of hemorrhagic cystitis, cyclophosphamide was to be stopped until

the symptoms cleared, at which time it would be restored at full dosage with moreprecautions for proper hydration. A second episode of hemorrhagic cystitis was to be an

indication for permanent cessation of cyclophosphamide. Chemotherapy was reducedwhenever necessary to permit completion of cranial radiotherapy within the designatedperiod.

RESULTS

Complete remission was successfully attained in 32 of the 35 patients (91%)




00

90

80

70

60

50

PROTOCOL

#{149}-.-. Ian.-. mo-o rr

A-� V

VEAR NO PATIENTS� CNS

962-3 3 �OR C,o�.ospmot

964-5 24 200R C’on�osp.no�

965-7 2Iholf dosoge P4ooe965-7 2’ fu�I dosoge Nor’e967-8 32 24008 C,on,o14-

,t,othecot MTX

36 42 48 54 60 66 72 78 84


0U)(I)

w

0

0

z

(5zz

� 20

z 10

0

0�

MONTHS

Fig. 1.-Per cent of patients remaining in complete remission in the present study

( Protocol V) compared to earlier studies. Complete remission duration is the time

from first complete remission marrow to first sign of relapse, whether hematological

or meningeal. This differs from the definition of other investigators who do not con-sider meningeal relapse as terminating complete remission (see text). The numbersin parentheses represent the patients in continuous complete remission as of June

30, 1970. The broken lines represent the current span of complete remission dura-tions in each protocol. A total of 126 previously untreated children with acute

lymphocytic leukemia entered these studies and 114 (90%) attained remission. InProtocol IV, 42 of 45 who attained remission were randomized to receive half-dosage or full-dosage combination chemotherapy. (Central nervous system therapy

given early in remission.)

entering this study. The median time from start of therapy to remission was

27 days, with a range of 19 to 33 days. Two of the three remission induction

failures were in black children. Only one of the three black children entering

the study attained remission. This is consistent with our experience that black

children with leukemia do not respond to therapy as well as white children.8

A 13-year-old boy attained remission but expired 10 days later of fulmi-

nating pseudomonas sepsis and peritonitis related to preexisting intestinal

perforation. Autopsy failed to show histological evidence of leukemia.

During the phase of intensive intravenous chemotherapy, a 2-year-old girl

developed varicella necessitating interruption of leukemia therapy for 3 weeks.

Consequently, the phase of cranial radiation and intrathecal methotrexate was

omitted and continuation chemotherapy begun when the varicella resolved.

She has remained in continuous complete remission for 25 months.

Cranial radiotherapy and intrathecal methotrexate were tolerated without

serious difficulty by all but one patient. This 3%-year-old girl displayed per-

sistent malaise, nausea, vomiting, headache, and fever, necessitating abbrevia-tion of this phase of therapy. She received all phases of therapy in maximum

tolerated doses.

Therefore, of the 35 patients entering this study, 32 attained remission and30 received all initial phases of therapy and entered the continuation chemo-

therapy phase.




(23)

PROTOCOL

I.-.--. Ian‘-. m0-cm �X% #{149}�

A-� V

YEAR NO. PATIENTS’ CNS THERAPY4

962-3 3 SOOR Cron,ospmol

964-5 24 1200R Cron�p,noI

1965-7 2190f dosoge None

965-7 21 full dosoge None1967-8 32 2400R Ooniol +

ntrothecol MIX

(2)

6 12 8 24 30 36 42 48 54 60 66 72 78 84MONTHS

276 AUR ET AL.

U)U)

Uicm:-I

(50-I

43

UiI

z

(5zz

Ui0mEUi0�

Fig. 2.-Per cent of Patients remaining in hematological remission in the present

studs’ (Protocol \7) compared to earlier studies. Hematological remission duration is

the time from first remission marrow to first partial remission or relapse marrow.This corresponds to the definition of complete remission duration used by others(see text). The numbers in parentheses represent the patients in hematological re-

mission as of June 30, 1970. The broken lines represent the current span of hemato-logical remission durations in each protocol. A total of 126 previously untreatedchildren with acute lymphocytic leukemia entered these studies and 114 (90%) at-

tained remission. In Protocol IV, 42 of 45 who attained remission were randomized

to receive half dosage or full dosage combination chemotherapy. (Central nervoussystem therapy given early in remission.)

Remission Duration and Survieal (Figs. 1 to 3)

Twenty-one of 32 patients (64%) who attained remission and 20 of 30

(66%) receiving all phases of therapy are currently in continuous complete

remission for 23 to 30 months (median 25 months). They enjoy normal child-

hood activities and attend school regularly.

Of the remaining ten children who received all phases of therapy, two diedin remission of viral infections. A 9-year-old boy died of fulminating viral

hepatitis after 13 months of continuous complete remission. Another boy died

of disseminated cytomegalovirus infection after 14 months of continuous com-

plete remission. In neither child was the onset of infection related to leuko-

penia, granulocytopenia, or physical signs of drug toxicity. Neither child had

histological evidence of leukemia at autopsy.

Relapse of leukemia occurred in 8 of the 30 children receiving all phases

of therapy. Hematological relapse ended complete remission status in five

children after 12 to 27 months of continuous complete remission. Three ofthese developed nervous system leukemia 2, 5, and 7 months following hema-

tological relapse. A fourth child died 4 months after hematological relapse andhad no evidence of nervous system leukemia at autopsy. The fifth patient died28 months from diagnosis, one month after hematological relapse, while under

therapy for systemic histoplasmosis and encephalopathy of unknown etiology.




PROTOCOL.

..-. ion

.-. m0-cm IV

IVA.-� V

YEAR NO. PATIENTS CNS THERAPV+

1962-3 3 �OR Oo’sosposl

1964-S 24 I200R Croniospinol

965-7 2Iholf dosoge None965-7 21 full dosage None1967-8 32 2400R CranIal 4

nfrothscol MIX

6 12 8 24 30 36 42 48 54 60 66 72 78 84


U)

U)0z(543

0

0mEU-

(5

2

>

>

mE

U)

I-zUi0mELuJa-

MONTHS

Fig. 3.-Per cent of patients surviving from the date of diagnosis. The numbers in

parentheses represent the number of patients surviving as of June 30, 1970. Thebroken lines represent the current span of survival durations in each protocol. A total

of 1 26 previously untreated children with acute lymphoc�tic leukemia entered thesestudies and 114 (90%) attained remission. In Protocol IV, 42 of 45 who attained

remission were randomized to receive half dosage or full dosage combination chemo-

therapy. (Central nervous system therapy given early in remission.)

Nervous system leukemia ended complete remission status in the remaining

three children. After 6 months of complete remission, one boy developed

meningeal leukemia followed in 2 months by hematological relapse. Two chil-

dren developed meningeal leukemia without hematological relapse after 14 and

24 months of continuous complete remission. They were treated with intra-

thecal methotrexate, which cleared the spinal fluid of leukemic cells and they

remain in marrow remission for 27 and 29 months, respectively.

Twenty-three of the 32 children (72%) who attained remission (Fig. 2)

and 22 of 30 (69%) receiving all phases of therapy have been in continuous

hematological remission for 23 to 30 months. Twenty-five of the 32 children

(78 per cent) who attained remission (Fig. 3) and 25 of 35 (71%) who en-

tered the study have survived 2 years or longer from the date of diagnosis.

Infections

As noted above, one patient died of pseudomonas sepsis and peritonitis only

10 days after attaining complete remission and two died of viral infections after

13 and 14 months of continuous complete remission. Another patient developed

systemic histoplasmosis after 26 months of continuous complete remission.

Chemotherapy was discontinued and he subsequently experienced marrow re-

lapse. Pneunwcystis carinii pneumonia was diagnosed by pulmonary needle

aspiration in three children while they were in complete remission. All were

treated with pentamidine isethionate and recovered without sequelae. Also,

during complete remission three children developed herpes zoster and two

developed varicella. All recovered without direct sequelae; however, marrow




(0

9

6-

3.

0.75

#{149}Afler I year on study

o After 2 years on study#{149}#{149}

#{149} #{149} #{149}

278

>-0

HUi U)

15

2

6 9 2 15 18HEIGHT INCREASE (cm)

NORMAL MEAN EXPECTED FOR AGE

AUR ET AL.

Fig. 4.-Comparison of the increase in height of patients after 1 and 2 years of

therapy and the mean height increase for age in normal healthy children.9 The slopesare drawn to represent the ratio of the observed to the expected height increase for

age. Only 8 of 30 patients attained 75 per cent or more of the expected height in-crease after 1 year on the study. After 2 years on the study, only 12 of 25 had at-tained 75 per cent of the expected height increase.

relapse occurred in one child 5 weeks after his chemotherapy had been

interrupted because of varicella.

Less serious infections included tonsillitis, pharyngitis, otitis media, seg-

mental pneumonia, impetigo, cellulitis, blepharitis, gastroenteritis and urinary

tract infection. The frequency of these infections was greater than expected in

a general pediatric population, but most patients responded to therapy as well

as children without serious underlying disease.

Drug Toxicity

Temporary reduction of drug dosages was frequently necessary because of

toxicity. The 32 children who attained remission experienced a total of 240

leukopenic (less than 2000/cu. mm.) episodes during the 30 months of study.

Two children who developed anemia with megaloblastic erythroid changes in

the marrow recovered after reduction of methotrexate dosage. Thrombocyto-

penia prompted reduction of drug dosage in only one patient. Mucosal ulcera-

tion occurred infrequently and there was not a single episode of hemorrhagic

cystitis.

The height of each child was measured at every clinic visit. The increase inheight after 1 and 2 years on the study is compared in Fig. 4 to the meanheight increase expected for age.9 After 1 year on therapy, only 8 of 30

children had attained 75 per cent or more of their expected height increase.

Eleven of 30 had grown less than 50 per cent of the expected height increase.




ThERAPY OF CHILDHOOD LYMPHOCYTIC LEUKEMIA 279

After two years of study only 12 of 25 had attained 75 per cent of the height

increase expected for age.

Disc�rssIoN

The present study concerns itself with one of the major impediments to cure

of acute leukemia: proliferation of leukemic cells in anatomical sites not cx-

posed to therapeutic concentrations of drugs, primarily in the central nervous

system. Sequestration of leukemic cells in the nervous system serving as a

potential nidus for systemic relapse was suggested by Jolmson’#{176} from studies

��‘itit L1210 murine leukemia.

The importance of nervous system leukemia as a potential source of sys-

temic relapse as well as a clinical complication is underscored by the current

results of earlier combination chemotherapy studies. In Protocols I_11112

irradiation of the central nervous system early in remission was used for the

purpose of eradicating clinically undetectable leukemic cells, thus preventing

subsequent development of meningeal leukemia and termination o complete

remission. Of 37 patients who attained remission, 30 have relapsed and 29

have developed nervous system leukemia. In 16 of the 30 ( 53% ) , the nervous

system was the initial site of relapse in a median time of 11 months (range:

2 to 28 months).

In Protocol 1V3 nervous system therapy was not given during remission.

Thirty-nine of 42 patients who attained remission have relapsed and 35 have

had nervous system leukemia. In 25 of the 39 (64%), the nervous system was

the initial site of relapse in a median time of 10 months (range: 1 to 39

months). Therefore, nervous system leukemia terminated complete remission

at the same time and frequency whether or not patients had received 500 to

1200 R of “prophylactic” craniospinal radiotherapy early in remission.

After 23 to 30 months in the present study, only three of the 30 patients

who attained remission and received nervous system therapy have developednervous system leukemia as the initial site of relapse. As seen in Fig. 1, 66 per

cent of patients were in complete remission for 4 to 12 months in Protocols

I-IV, a striking contrast to the present study (Protocol V) in which 66 per

cent of patients currently enjoy continuous complete remission for 23 to 30

months. The greater intensity of central nervous system therapy in the current

study may be responsible for this difference.

The duration of initial complete remission in this study is superior to the

duration of initial hematological remission reported for other treatment regi-mens. The prednisone, vincristine, methotrexate, 6-mercaptopurine regimen

of Henderson (“POMP”) gave a 13.5-month median duration of hematological

remission.11 The prednisone, vincristine, intermittent methotrexate schedule ofAcute Leukemia Study Group B resulted in a 10.4-month median duration of

hematological remission.6 A cyclic regimen using prednisone, 6-mercapto-

purine, methotrexate, and cyclophosphamide led to a 14-month median dura-

tion of hematological remission.12 Another cyclic regimen using prednisone,

methotrexate, and 6-mercaptopurine yielded an 11-month median duration of

hematological remission.13Intensive combination chemotherapy programs used previously at this cen-




280 AUR ET AL.

ter have resulted in prolonged disease-free survival in 15 to 20 per cent ofpatients ( Fig. 1 ) . The complete remission duration curves have leveled off

after 2 years. In other words, the majority of children who have remained in

continuous complete remission for two years have tended to maintain this

status, at least until the present time.

Although not the primary goal of these studies, survival duration is plotted

in Fig. 3 for comparison. In the present study, 78 per cent of children who

attained remission have survived two years or longer. Recently a 75 per cent

2-year survival was reported for a chemotherapy program employing predni-

sone, vincristine, and methotrexate and a 25 per cent 5-year survival was pre-

dicted.14 However, no information was provided concerning the remission

status of the patients, and the results were criticized for retrospective selectionof chemotherapeutically responsive patients.18 If we consider survival duration

of all patients ��‘ho entered the present study, without selection, whether or

not they attained remission or received all phases of therapy, 25 of 35, or 71

per cent, have survived 2 years or longer.

Serious infection during remission resulted primarily from nonbacterial mi-

croorganisms. This is consistent with our general experience.16 Unfortunately,

granulocytopenia, leukopenia and physical drug toxicity did not precede these

infections. Better predictive indices of toxicity are needed to help avoid these

complications and are currently under study. Another index of the toxicity of

the therapeutic regimen reported here was the growth retardation seen inmost of the patients. This result differs from a study showing no change in

the growth rate of children under therapy for leukemia, but the chemotherapy

in that study was less intensive.17

The successful administration of maximally tolerated combination therapy

requires frequent observation and a readiness to adjust therapy. Although

toxicity of radiotherapy and intrathecal methotrexate necessitated dosage

reduction in only one patient, combination chemotherapy dosage was reduced

on one or more occasions in every patient.

\Ve conclude from the results of this study that continuous complete remis-

sion of childhood acute lymphocytic leukemia is significantly prolonged by

intensive nervous system therapy and combination chemotherapy. The toxicity

and infections encountered are significant, but certainly not prohibitive, inview of the results obtained.

REFERENCES

1. George, P., and Pinkel, D.: CNS radi- tion in childhood lymphocytic leukemia.

ation in children with acute lymphocytic Cancer (in press).leukemia in remission. Proc. Amer. Ass. 4. Aur, R. J. A., Ilustu, 0., Hernandez,

Cancer Res. 6:22, 1965. K., Walters, T., Simone, J., Borella, L., and2. George, P., Hernandez, K., Hustu, 0., Pinkel, D.: “Total therapy” of acute lym-

Borella, L., Holton, C., and Pinkel, D.: A phocytic leukemia; study V. Proc. Amer.study of “total therapy” of acute lympho- Ass. Cancer Res. 10:4, 1969.

cytic leukemia in children. J. Pediat. 72: 5. Pinkel, D.: Five year follow-up of

399-408, 1968. “total therapy” of childhood lymphocytic

3. Pinkel, D., Hernandez, K., Borella, L., leukemia. J.A.M.A. (in press).Holton, C., Aur, R. J. A., Samoy, G., and 6. Acute Leukemia Group B: New treat-Pratt, C.: Drug dosage and remission dura- ment schedule with improved survival in





childhood leukemia. JAMA 194:75, 1965.7. Nagao, T., Lampkin, B. C., and

Mauer, A. M.: Maintainence therapy inacute childhood leukemia. J. Pediat. 76:

134, 1970.

8. Walters, T., Bushore, M., and Pinkel,D.: Identification of black children withacute lymphocytic leukemia (ALL) as high

risk patients. Proc. Amer. Ass. Cancer Res.

11:81, 1970.9. Reed, H. B., and Stuart, II. C.: Pat-

terns of growth in height and weight frombirth to eighteen years of age. Pediatrics

24 (suppl.): 904, 1959.

10. Johnson, H. E.: An experimentaltherapeutic approach to L1210 leukemia in

mice: combined chemotherapy and centralnervous system irradiation. J. Nat. CancerInst. 32:1333, 1964.

11. Henderson, E. S.: Combinationchemotherapy of acute lymphocytic leu-kemia of childhood. Cancer Res. 27:2570,

1967.

12. Willoughby, M. L. N., and Laurie,

H. C.: Cyclic chemotherapy in childhoodacute leukemia. Arch. Dis. Child. 43:187,1968.

13. Zuelzer, W. W.: Implications oflong-term survival in acute stem cell leu-

kemia of childhood treated with composite

cyclic therapy. Blood 24:477, 1964.14. holland, J. F.: Hopes for tomorrow

versus realities of today: therapy and prog-

nosis in acute lymphocytic leukemia of

childhood (Commentary). Pediatrics 45:

191, 1970.

15. Pearson, H. A.: Prognosis of child-

hood leukemia (Letter to the editor).

Pediatrics 45:1037, 1970.

16. Holland, E., Simone, J. V., and

Johnson, W. Wy.: Remission fatalities inchildhood acute leukemia. Proc. Amer. Ass.Cancer Res. 11:38, 1970.

17. Sunderman, C. R., and Pearson, H.A.: Growth effects of long-term antileu-kemic therapy. J. Pediat. 75:1058, 1969.




1971 37: 272-281

CHARLES PRATT and DONALD PINKELRHOMES J. A. AUR, JOSEPH SIMONE, H. OMAR HUSTU, THOMAS WALTERS, LUIS BORELLA, Childhood Lymphocytic LeukemiaCentral Nervous System Therapy and Combination Chemotherapy of

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Central Nervous System Therapy and Combination ......272 BLOOD, VOL. 37, No. 3 (MARcH), 1971 Central Nervous System Therapy and Combination Chemotherapy of Childhood Lymphocytic Leukemia