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NINE YEARS' EXPERIENCE WITH "TOTAL THERAPY" OF CHILDHOOD ACUTE LYMPHOCYTIC LEUKEMIA

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(

Received July 26; revision accepted for publication October 30, 1971.)

Presented at the Annual Meeting of the Society for Pediatric Research and the American Pediatric So-ciety, Atlantic City, New Jersey, April 30, 1971.

Supported by cancer research center grant CA 08480; research training grant CA 05176; research

proj-ect grant CA 07594; and clinical training grant CA 08151 from the National Cancer Institute; by general

research support grant RR 5584 from the Division of Research Facilities and Resources, National

Insti-tutes of Health; and by ALSAC.

ADDRESS FOR REPRINTS: (D.P.

)

St. Jude Children’s Research Hospital, 332 N. Lauderdale, P.O. Box 318, Memphis, Tennessee 38101.

PEDIATRICS, Vol. 50, No. 2, August 1972

248

NINE

YEARS’

EXPERIENCE

WITH

“TOTAL

THERAPY”

OF

CHILDHOOD

ACUTE

LYMPHOCYTIC

LEUKEMIA

Donald Pinkel, M.D., Joseph Simone, M.D., H. Omar Hustu, M.D.,

and Rhomes J. A. Aur, M.D.

From St. Jude Children’s Research Hospital and the Uniuersity of Tennessee

Medical Units, Memphis, Tennessee

ABSTRACT. Experience with combined

chemo-therapy and radiotherapy of acute lymphocytic leu-kemia (ALL) in children is reviewed. Multiple anti-metabolite chemotherapy is effective in prolonging

duration of continuous hematological remission.

Cra-niospinal irradiation or cranial irradiation corn-bined with intrathecal methotrexate in adequate

doses inhibits relapse in the central nervous system.

The high frequency of lengthy continuous corn-plete remission achieved with “total therapy” mdi-cates that ALL in children cannot be considered

an incurable disease. Palliation is no longer an

ac-ceptable approach to its initial treatment.

Pediat-rics, 49:246, 1972, LEUKEMIA, RADIOTHERAPY,

CHEMOTHERAPY, 6060 TELETHERAPY, PREDNISONE,

METHOTREXATE, VINCRISTINE, MERCAPTOPURINE.

I

N 1962 it was generally assumed that

acute lymphocytic leukemia

(

ALL) was a uniformly fatal disease and that antileu-kemic agents were only useful for paula-tion, the prolonging of life in comfort. At that time we initiated a series of

investiga-tions to determine whether significant 5-year

leukemia-free survival was attainable with

available antileukemic agents and if so, how

best this might be accomplished.

The purpose of this communication is to

review these studies and to summarize their results. Detailed descriptions and discus-sions of the studies are contained in the references.5 Detailed protocols are avail-able from the authors.

The general procedure consisted of: (1) induction of complete remission, usually

with prednisone and vincnistine;

(

2

)

a 1-week course of intensive intravenous

chem-otherapy with mercaptopurine

methotrex-ate and cvclophosphamide to reduce fur-then the leukemic cell population; (3) “pro-phylactic” central nervous system therapy with irradiation or irradiation and

intrathe-cal methotrexate early during complete remission to eliminate residual leukemic cells in the central nervous system ; (4)

continuation chemotherapy, consisting of

simultaneously administered multiple drugs for 2 to 3 years, to eradicate all remaining leukemic cells.

Duration of complete remission was de-fined as the time between first complete

remission bone marrow and first evidence of relapse at any site-meningeal, visceral, or hematological.2 This differs from the

definition used by many, who do not

con-sider meningeal relapse as terminating com-plete remission. Duration of hematological remission was the time bet’een first com-plete remission marrow and first evidence of partial or complete relapse in the mar-row. This corresponds to the definition of

complete remission duration used by others.

EXPLORATORY STUDIES1-2 (I 962-65)

In the first pilot study remission induc-tion with vincristine and prednisone was

(2)

mercap-S CNS = central nervous systeiti.

C),llinuation (‘/iemnotherapy

Full Dosage 7’S. JIa/fI)osage

50 45

21 ‘- 42 -‘ 21

15 1110 6 mo

33 1110 16 mmio

10 15

8(59-74 mmio) 1(64 mmio)

4(59-73 moo) 1(64 mmio)

1(67 mmio) None

3*(5() 74 mmio) None

3-30mno

-topurme daily and intravenous

adminis-tration of vincristine and cyclophosphamide

weekly. The second pilot study also used

prednisone and vincristine for remission

in-duction hut for continuation the patients re-ceived either mercaptopurine daily or methotrexate weekly. Vincristine and cyclo-phosphamide were administered every 2

weeks. In both studies the patients received

500 rads of craniospinal irradiation early during complete remission.

Of 15 consecutive previously untreated

patients with ALL entered into studies I and II, 13 developed complete remission

(

Table I

)

. The median duration of com-plete remission was 8 months and of hema-tological remission 14 months. Two patients

are in complete remission 8 years after di-agnosis and have been off all therapy 2% and

4 years. Despite the 500 nads of

craniospi-nat irradiation, three of the 13 patients had initial relapse in the central nervous

system.

In study III remission induction with prednisone and vincnistine was followed by

1 week of intensive intravenous

chemother-ap consisting of mercaptopunine,

metho-trexate and cyclophosphamide, and 1,200

rads of craniospinal irradiation.

Continua-tion chemotherapy consisted of oral

men-captopunine daily and intravenous

metho-trexate, vincristine, and cyclophosphamide weekly.

Of 26 consecutive, previously untreated patients \Vitil ALL entered into study III, 24

developed complete remission

(

Table I).

Median duration of complete remission was

15 months and of hematological remission

22 11lOflthS. Five patients are in complete

re-mission for 61 to 73 years and have been off

thera1)v 4:c years. Despite 1,200 rads of

era-niospinal irradiation 12 patients had initial

relapse

in

the central nervous system. From these studies we concluded that:

(

1

)

multiple agent continuation

chemo-thera1)V results ill superior duration of

com-plete remission and hematological remis-sion, and in a significant frequency, 7 of 37,

of prolonged leukemia-free survival; (2) 500 rads and 1,200 rads central nervous sys-tem irradiation are not effective in

prevent-TABLE I

‘I’oTAL ‘I’IIEIIAPY OF ACUTE LYMPIIO(’YTIC

LEUKEMIA STUDIES 1-Ill, 1962-65

Studies 1-11 Study Ill

Number patients 15 26

Nurnl)ercornplete remission 13 24

Median coiiiplete remission 8 1110 15 iiio

Median hematologic

rernis-SiOll 14 mo 22 nio

Number patients initial

re-lapse CNS 3 12

Patients 110W fl complete re.

IllissiOll (tinie) 2(96, 98 iiio) 5(81-91 iiio)

Titiie off therapy 33, .53 inn 58-59 mo

ing meningeal leukemia as the initial site of

relapse.

COMPARISON OF FULL DOSAGE

VERSUS HALF DOSAGE

CON-TINUATION CHEMOTHERAPY3

(1965-67)

In study III intercurrent infection during remission was a frequent problem. The

pur-‘PABLE II

ToTI ‘E’11EuA1y 01’ ACUTE LYMI’ILOCYTI(

LEUKEMIA STUDY I\, I 96.5-67

Nunsber patients

Number complete reinissioli Number ran(lonhized

Median complete remission

1e(Iia!i heiiiatologic remission Number initial relapse (‘NS Patients surviving (tnile)

After hemnatological relapse

(time)

In lieniatologic remission

(tinie)

In (omnpkte renhission

(tinme)

‘I’imeoff therapy

* One (1111(1 (leveloped spinal fluid pleocytosis with leukeinic C(’llS in October, 1963. She was treate(l with

(3)

248 THERAPY OF LEUKEMIA

TABLE III

TOTAL THERAPY OF ACUTE LYMPHOCYTIC

LEUKEMIA STUDY V, 1967-68

Number patients 35

Number complete remission marrow 32

Number complete remission 31

Number completing initial phases

of therapy 30

Number initial relapse CXS 3(last 20mo ago)

Number initial relapse marrow 6 (last 4 mo ago)

Number died during complete

remission 3 (last 10 mo ago)

Number patients surviving (time) 22 (39-46 mo)

Number in continuous complete

remission (time) 19 (38-45 mo)

Time off therapy 2 to 16 mo

pose of study IV was to determine whether this hazard could be reduced without loss

of therapeutic effects by decreasing the dosage of continuation chemotherapy. Remission induction and a 1-week course of intravenous chemotherapy were carried out as in study III. Then the patients were randomized into

two

groups, one to receive full dosage of methotrexate,

mercaptopu-rine, cyclophosphamide and vincristine as in study III, the other to receive one-half dosage of the same agents. No “prophylac-tic” central nervous system irradiation was administered.

Of 50 consecutive patients, 45 developed complete remission, 42 of whom were avail-able for randomization

(

Table II ). For the 21 patients who received full dosage

con-tinuation chemotherapy, median duration of

complete remission was 15 months and of hematological remission 33 months. Eight of the 21 full dosage patients are surviving for 5 years or more. Three are in complete remission and have been off all therapy for

2 years. One is in hematological remission and four are surviving after hematological relapse. For the 21 patients who received one-half dosage continuation chemother-apy, the median duration of complete

re-mission was 6 months and of hematological

remission 16 months. One survives for 5

years after hematological relapse. In 10 of the full dosage and 15 of the one-half dos-age patients, initial relapse occurred in the central nervous system.

From this study we concluded that: (1) full dosage multiple agent continuation

chemotherapy is superior to one-half dos-age with regard to duration of complete remission, duration of hematological remis-sion, and frequency of 5-year survival; (2) in patients receiving multiple agent contin-uation chemotherapy meningeal relapse

rather than hematological relapse is the

TABLE IV

TOTAL THERAPY OF ACUTE LYMPHOCYTIC LEUKEMIA STUDY ‘91, 1968-70

Randomizaiion for 2,400 rads craniospinal irradiation and 1 -week inten3ire chemotherapy

Number Paiients-IlO

Number Complete Remission-104

Number Randomized-94

ilad Rod No Rad No 11w!

In! Chemo No lint (‘hemo fat Chemo ?‘o Jut (‘hiemo

Number patients 22 23 23 26

Number initial relapse CNS 2 (1 12 17

Number initial relapse marrow 5 5 ‘3 1

Number died in comitinuous complete remission I I I 1

Number patients in continuous complete remission 14 17 7 7

I)uration 17-38 ‘no 15-37 mo 18-30 mo 13-37 1110

Number patients in continuous hematologic remission 15 17 15 16

Duration 17-38 mo 15-37 1310 18-33 mio 15-37 mo

Number patients surviving 16 17 16 19

(4)

---

Ian

--- 111

- & HD WED

Year

t962-3

t964-5

965-7 965-7

1967-8 Pts.

3 24 21

21

3’

CNS Therapy

500 rods CrSp

200 rods CrSp

NONE

NONE

2400 rods Cr + Intrathecal MIX

12

24

36

48

60

72

84

96

108

MONTHS

‘5 AUG ‘71

ARTICLES

I00

9o

80

70

60

50

40

30

20

10

0

0

FIG. 1. Acute lyrnphocytic leukemia of childhood. Complete remission

duration.

most frequent event terminating complete remission status.

INCREASED INTENSITY OF “PROPHY..

LACTIC” CENTRAL NERVOUS

SYS-TEM THERAPY4 (1967-68)

In study V greater emphasis was placed on central nervous systenl therapy. After

remission induction with prednisone and

vincristine and the 1-week course of

inten-sive intravenous chemotherapy, all patients

were given 2,400 to 2,500 rads cranial ir-radiation and five doses of intrathecal

methotrexate. Continuation chemotherapy

consisted of oral mercaptopurine daily, in-travenous methotrexate and cyclophos-phamide weekly, and a 2-week course of

prednisone and vincristine every 10 weeks.

Of 35 consecutive patients, 32 developed

complete remission marrows, 31 developed complete remission, and 30 completed all

initial phases of therapy

(

Table III

)

. Only

three have developed initial relapse in the central nervous system, the last 20 months

ago. Six have had initial relapse in the

mar-row, the last 4 months ago. Three died of

infection during complete remission, the

last 10 months ago. At present 19 patients

are in continuous complete remission for 3 years or more. All 19 have been off all

ther-apy for 2 to 16 months. With almost

two-thirds of the patients who developed com-plete remission remaining in continuous

complete remission for over three years,

the results of this plan are the best ever to be achieved in the treatment of this

dis-ease.

Figure 1 illustrates the complete

remLs-sion duration curves of patients who

devel-oped complete remission in these five stud-ies. The abscissa represents duration of

complete remiesion in months; the ordinate

represents the percentage of patients re-maining in complete remission. For the first four studies the curves tended to level off after 3 years. If the patients in study V follow this pattern it is reasonable to expect

that one-half or more of them will

expeni-ence having a prolonged leukemia-free

(5)

250 THERAPY OF LEUKEMIA

A CONTROLLED STUDY OF CRANIO..

SPINAL RADIOTHERAPY AND

SHORT-TERM INTENSIVE

CHEMOTHERAPY5

(

I 968-70)

The purpose of study VI was to define the usefulness of two features of total ther-apy: the “prophylactic” central nervous sys-tern therapy and the 1-week course of

in-tensive chemotherapy. After induction of complete remission with vinscristine, pred-nisone and daunorubicia patients were randomized to receive or not the 1-week course of intravenous chemotherapy. They were randomized a second time to receive

or not 2,400 rads craniospinal irradiation. Continuation chemotherapy was similar to

that administered in study V. The weekly methotrexate and cyclophosphamide were administered orally instead of intravenously.

Of 110 patients entered into the study, 104 developed complete remission, 94 of whom were available for both randomiza-tions

(

Table IV). Seven of the 104 patients had evidence of central nervous system leu-kemia at diagnosis or before randomization and thus had to be treated with central ner-vous system therapy, not randomized for it.

The 94 patients were randomized for

2,400 rads craniospinal irradiation and for

the 1-week intensive chemotherapy. Of 45 patients who received central nervous sys-tem irradiation, only two have had initial relapse in the central nervous system; 31 of

the 45 continue in complete remission for 15 to 38 months. Of the two who had initial relapse in the central nervous system, one had received only 1,200 rads of irradiation because of severe leukopenia and infection.

Of 49 patients who did not receive

cen-tral nervous system irradiation, 29 have had initial relapse in the central nervous system and 14 are in complete remission for 15 to

37 months. These data indicate that

ade-quate craniospinal irradiation is effective in inhibiting central nervous system relapse and prolonging complete remission.

Thirty-two of the 45 patients who

re-ceived irradiation and 31 of the 49 who did

not are in continuous hematological remis-sion. This indicates that the influence of

central

nervous system irradiation in pro-longing complete remission is due to its

effects on the central nervous system and

not on the bone marrow.

Twenty-one of 45 patients who received 1 week of intensive chemotherapy and 24 of 49 who did not receive it remain in com-plete remission. This indicates that so far

the 1 week of intensive chemotherapy does not appear to influence complete remission duration of patients subsequently receiving combination chemotherapy and probably is

of no benefit within our treatment scheme. The 29 patients who developed central nervous system leukemia were treated with 2,400 rads craniospinal irradiation. Six of the 29 have already developed recurrent

re-lapse in the central nervous system. This

in-dicates that 2,400 rads is not sufficient for

eradication of central nervous system leuke-mia once it has become evident.

SUMMARY AND CONCLUSION OF

TOTAL THERAPY STUDIES

Multiple agent continuation chemother-apy of ALL in remission results in superior durations of complete remission and hema-tological remission and a significant fre-quency of long-term leukemia-free survival.

Full dosage multiple agent continuation chemotherapy is superior to half dosage with regard to durations of complete

remis-sion and hematological remission and fre-quency of long-term survival.

In patients receiving multiple agent

chemotherapy the central nervous system is

the most frequent site for initial relapse and this is the prime reason for termination of complete remission.

Craniospinal irradiation, 2,400 rads, or

(6)

ARTICLES 251

Brief, intensive chemotherapy early dur-ing remission has no apparent benefit for patients subsequently receiving the same

agents during continuation chemotherapy.

One cannot be certain that the long-term leukemia-free survivors will not eventually develop recurrence or relapse. However, the high frequency of long-term complete remission achieved with total therapy mdi-cates that at this point in time ALL in

chil-dren cannot be considered an incurable disease. Palliation is not an acceptable ap-proach to its initial treatment. Every child with ALL deserves an opportunity for pro-longed leukemia-free survival and possible

cure.

REFERENCES

1. George, P., Hernandez, K., Hustu, 0., Borella,

L., Holton, C., and Pinkel, D. : A study of

“total therapy” of acute lymphocytic leuke-mia in children. J. Pediat., 72:399, 1968.

2. Pinkel, D. : Five year follow-up of “total

ther-apy” of childhood lymphocytic leukemia.

J.A.M.A., 216:648, 1971.

3. Pinkel, D., Hernandez, K., Borella, L., Holton,

C., Aur, R., Samoy, C., and Pratt, C. : Drug dosage and remission duration in childhood lymphocvtic leukemia. Cancer, 27:247, 1971.

4. Aur, R. J. A., Simone, J., Hustu, H. 0., Walters,

T., Borella, L., Pratt, C., and Pinkel, D.: Cen-tral nervous system therapy and combination

chemotherapy of childhood lymphocytic

leu-kernia. Blood, 37:272, 1971.

.5. Aur, 11. J. A., Simone, J. V., Hustim, H. 0., and

Vergosa, Jlf : A comparative study of central

nervous system irradiation and intensive

chemotherapy early in remission of childhood

acute lymphocytic leukemia. Cancer, 29:381,

1972.

Few beginners can realize how little editorial

refusal of a manuscript really means. Editors are

beset by all kinds of conditions and limitations as to space, as to what they have on hand already, as to the particular type of story (apart from merit)

that the propose to use-or that their proprietors

propose to use-as to scenes, settings, as to Cod

knows what-things that a young aspirant towards

writing would never dream of. He thinks that if

his story is good, the editor muct take it. He doesn’t

know that the editor may have decided that they

have accepted enough stories about love to last six

months, that they can’t use rich widows for a year,

have definitely decided never to use negro dialect,

and can’t run anything more that has to do with

the sea-or with the land-or with religion-till

they’ve used all the sea and the land and the

re-ligion they’ve bought already. But of course no one

beginning literary work has any idea of this.

STEPHEN LEACOCIC

How to Write

London, John Lane, 1944

(

EDIToR’s NOTE : Frequently applicable to

(7)

1972;50;246

Pediatrics

Donald Pinkel, Joseph Simone, H. Omar Hustu and Rhomes J. A. Aur

ACUTE LYMPHOCYTIC LEUKEMIA

NINE YEARS' EXPERIENCE WITH "TOTAL THERAPY" OF CHILDHOOD

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(8)

1972;50;246

Pediatrics

Donald Pinkel, Joseph Simone, H. Omar Hustu and Rhomes J. A. Aur

ACUTE LYMPHOCYTIC LEUKEMIA

NINE YEARS' EXPERIENCE WITH "TOTAL THERAPY" OF CHILDHOOD

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the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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