(
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 thatacute 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 ofinvestiga-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 intravenouschem-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
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 patientsare 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 continuationchemo-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
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 dosagecon-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
---
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 ‘71ARTICLES
I00
9o
8070
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)
. Onlythree 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
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 itseffects 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
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