VINCRISTINE IN THE TREATMENT OF

ACUTE LEUKEMIA IN CHILDREN

Ruth M. Heyn, M.D., Chairman, Writing Committee; E. C. Beatty, Jr., M.D.,
D. Hammond, M.D., J. Louis, M.D., M. Pierce, M.D., M. L. Murphy, M.D.,
and N. Severo, Ph.D.
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School,
Ann Arbor, Michigan (R.M.H.); Childrens Hospital of Denver, Denver, Colorado (E.C.B., Jr.);
The Division of Hematology, Childrens Hospital of Los Angeles, Los Angeles, California
(D.H.); University, of Illinois, Chicago, Ill. (IL.); Bobs Roberts Hospital, University of
Chicago, Chicago, Ill. (M.P.); Memorial Hospital, Sloan-Kettering In.stitute for Cancer
Research, New York, N.Y. (M.L.M.); and Department of Statistics, State University
of New York at Buffalo (N.S.)

V INQIISTINE SULFATE* (hereafter referred mice treated with Vcr. The inhibition of
to as Vcr) is a dimenic alkaboidal RNA synthesis caused by Vcr was partially
drug which is prepared from the plant prevented by pretreatment with large doses
Vinca rosea Linn. The observation by of glutamic acid.
Cutts, Beer, and Noble in 1957, that cer- The present report deals with the re-
tam crude fractions of this plant induced a suits of a cooperative study conducted by
peripheral granulocytopenia and depression Leukemia Group A, designed to evaluate
of bone marrow in rats led to the separation the response of children with acute leuke-
of a purified compound, vinblastine mia to a constant weekly dose of Vcr and to
sulfate,2 which inhibited the growth of a determine the effect of maintenance, versus
number of animal tumors, and prolonged no maintenance therapy during remission.
the survival time of mice in several of the The incidence, quality, and duration of
mouse leukemias.3 In 1959, the studies of remissions, and the associated toxic effects
Johnson, Wright, and Svoboda4 led to the of the drug were measured.
purification of other active alkaloids from
MATERIAL AND METHODS
the plant, one of which was Vcr.5 Clinical
studies have shown that vinblastine sulfate Children under 15 years of age with
is effective in the lymphomas and chonioepi- acute leukemia were eligible for study
theliomas with relatively little effect in the when they had become resistant to previous
acute leukemias, whereas Vcr has proved to anti-leukemic treatment and examination of
be effective against the acute leukemias and the bone marrow revealed that the percent-
certain other neoplasms as well.#{176} age of leukemic cells was greater than 25%.
The biochemical pathway of action of The status of disease at the onset of treat-
Vcr has not been determined although tis- ment and at periodic intervals through-
sue culture studies suggest that Vcr may in- out the study was determined by evalua-
hibit the de novo synthesis of nucleic acids.6 tion in four categories-bone marrow,
Creasey and Markiw7 demonstrated an in- blood, physical findings, and symptoms-ac-
hibition of the incorporation of uridine into cording to the criteria adopted by Leuke-
soluble RNA in Ehrlich ascites carcinoma in mia Group A (see Appendix). Physical and
neurological examinations and a complete
a Oncovin (Vincristine sulfate, Lilly) was gen-
blood count were required weekly while on
erously supplied by Dr. J. C. Armstrong of the Eli
Lilly Company. study. Bone marrow examinations were

(Received December 7, 1965; accepted for publication February 2, 1966.)

PRESENT ADDRESS: (J.L.) Loyola University, Stnitch School of Medicine, Chicago, Illinois.
ADDRESS FOR REPRINTS: (R.M.H.) Department of Pediatrics and Communicable Diseases, University
Hospital, Ann Arbor, Michigan 48104.
PEDIATRICS, Vol. 38, No. 1, July 1966

82

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 ARTICLES 83

quired on the fourteenth and twenty-eighth Removal from study and estimation of
days of study and at 4-week intervals dur- response were based on the criteria for
ing remission. evaluation. Statistical analysis was done by
Vcr was provided in vials of 1 mg and the Department of Statistics of the State
dissolved in five ml of distilled water. The University of New York at Buffalo.
solution was used for a period not exceed-
RESULTS
ing 1 week. The dose employed was 0.075
mg/kg given intravenously on days 0, 7, 14, One hundred and sixty-three children
and 21 of study. When a patient was in with acute leukemia were entered on the
complete remission as determined by the \Tcr study from 14 contributing pediatric
criteria for evaluation on either day 14 or centers (Table I). The following analysis is
28, the maintenance regimen was deter- based on results obtained in 149 patients,
mined by a constrained randomized proce- 121 of whom received an adequate drug
dure. One group received no therapy while trial and 28 of whom received an made-
in remission and the other continued on Vcr quate trial or less than four injections of the
at the same weekly dose until relapse to drug. Twenty-six children expired while on
disease status 3 (moderate) or 4 (advanced). study; only two of these had received ade-
If a remission had not been attained by quate trials of drug.
day 28 and signs of serious drug toxicity
were not present, the dose was increased to
General Characteristics of the
Patients Studied
0.1 mg/kg for two doses. At 42 days, an-
other marrow was done and a decision re- The morphological diagnosis, sex, age,
garding subsequent therapy made. If the and race of the patients studied is given in
child entered a complete remission on day Table II. The morphological diagnosis was
42, or any time thereafter, he was eligible either acute lymphocytic or undifferentiated
for the randomization program of mainte- cell leukemia in 90%, acute granulocytic len-
nance vs. no maintenance therapy and was kemia in 7%, and acute monocytic leukemia
followed accordingly. Treatment was con- in 3% of the children treated. The age group
tinued at 0.075 mg/kg once weekly if the of 3 to 6 years predominated, the distribu-
patient was status quo or still showing im- tion of sexes was approximately equal, and
provement without limiting toxicity. If the the large majority were of Caucasian ex-
patient showed deterioration in any cat- traction.
egory at 42 days, he was removed from The median duration of leukemia, from
study. onset of symptoms to treatment with \Tcr,
Dose adjustments were made for toxicity was 13.5 months (range 2 to 53 months) in
on a weekly basis by either halving or omit- this group of children. The distribution of
ting the dose. Symptoms of muscle weak- children who were moderately, or more se-
ness, paralysis, severe neuritic pain, or par- verely ill at onset of therapy was roughly
esthesias not due to central nervous system equal; 71 patients entered the study in sta-
leukemia, or severe constipation not con- tus 3, and 78 patients entered in status 4.
trolled by stool softeners were indications The initial leukocyte count in all children
for lowering the dose. treated ranged from 300 to 343,000/cu mm
A period of 28 days was arbitrarily se- with a median of 3,950/cu mm. The median
lected as an adequate trial of therapy. The percentage of blasts in the bone marrow at
patients received no other chemotherapy or the onset of therapy in all patients was
x-ray treatment while on study except that 84.5% with a range from 24 to 100%.
allowed to the skull for the treatment of
Remissions
central nervous system leukemia. When in-
trathecal methotrexate was used, the pa- Complete remissions (CR) were attained
tient was removed from study. in 14, or 11.6% of adequate trial cases. The

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84 VINCRISTINE IN LEUKEMIA

TABLE I
CONTRIBUTING INSTITUTIONS AND INVESTIGATORS

. . Principal .
Instztutwns . As8ociate Investigators
Investigators

University of Michigan. Ann Arbor R. Heyri J. Kastelic, I. Ertel, R. holland

Memorial Hospital M. L. Murphy M. Haghbin, J. howard, It. Alberto

Sloan-Kettering Institute. New York City

University of Wisconsin, Madison N. Smith P. Joo, L. Thatcher

University of Washington, Seattle J. I-Iartmann M. Origenes

University of Chicago, Chicago M. Pierce S. Smith

Childrens Hospital, Washington, D. C. S. Leikin ..

Childrens Hospital Los Angeles D. Hammond N. Movassaghi, N. Shore, K. Williams

C. Brubaker

Ohio State University, Columbus IV. Newton, Jr. D. Kmetz, N. Nagi, L. Sinks

Babies Hospital, New York City J. Wolff A. Sitarz

University of Pittsburgh, Pittsburgh V. Albo W. Irin, P. Gaffney

University of Illinois, Chicago J. Louis .

Childrens hospital, Denver E. Beatty, .Jr. C. Iteiquain

University of Minnesota Minneapolis W. Krivit .

St. Christophers Hospital, Philadelphia A. McElfresh .

TABLE II median time required for induction of CR

SUMMARY OF PATIENT CIIAIIAcTEuISTICs was 46.5 days. The median duration of CR
in children who received maintenance drug
Charactsristies No. therapy 63.5 days,
was with a range from 34
to 112 days. A similar duration of remission
Morphologic diagnosis
Acute lymphocytic leukemia 76
was noted in patients who did not receive
Acute undifferentiated leukemia 57 maintenance therapy, with a median dura-
Acute granulocytic leukemia II tion of 59 days (range 28 to 84 days).
Acute inonocytic leukemia 5
A larger number of patients achieved
Sex
partial remissions. Forty-three, or 35.5% of
Male 83
Female 66 adequately treated patients, had good par-
Age tial remissions (GPR) which lasted a mcdi-
o- years 16 an of 35 days. Twenty-two (18.1%) achieved
3-6 years 94
fair partial remissions (FPR), and 25
7-15 years 39
(20.6), minimal remissions (MR). The ac-
Race
Caucasian 139 tual amount of drug received by the various
Negro 9 remission groups is given as the median of
Oriental I
the average weekly dose of drug received
prior to remission. These findings are sum-

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 ARTICLES 85

TABLE III
RESPONSE TO VINCESISTINE

% of . Median of
% of Median .
Type of adeqnate . Median duration average weekly
. . 1\o. . trial day of . .
remtssion trial and range sn days dose to remission
cases onset
cases (mg/kg)

Complete

vitIi main. Ii 63.5 (34-1H)

- 11.6 9.4 46.5 - .061
without main. 3 59 (8-84)

Goodpartial 43 35.5 28.8 8 35(6-111) .071

Fairpartial 2l 18.2 14.8 15 28(13-63) .07

Minimal 15 20.7 16.8 II 19(2-66) .073

Failures 17 14.0 11.4 .067

Inadequate trials 28 18.8 .073

Total 149 100.0% 100.0%

marized in Table III, which gives data for period without therapy. Both had GPR fol-
the best response obtained by each patient. lowing retreatment and one had a GPR after
The number of adequately treated pa- a third course of Vcr.
tients achieving an A, marrow (less than 8% Eleven children with acute granulocytic
blasts) was 52, or 42.9%. The marrow remis- leukemia achieved one CR, three GPR, and
siOn rate for the acute lymphocytic and three MR. Four had inadequate trials of
acute undifferentiated leukemias was 44%. drug. One child with acute monocytic
The majority of these occurred in the CR leukemia achieved a GPR. Two others had
and GPR groups. The median day for at- MR and two were failures.
tainment of an A, marrow for all groups The age, race, sex, duration of disease,
was 28 days. The pattern of response of eel- previous drug therapy, initial peripheral
lular elements in the marrow in those pa- leukocyte count, and disease status at onset
tients achieving an A, rating is shown in
Figure 1, which illustrates the percentage Median
%of
of blasts, erythroid precursors, and granulo- celia

cytic elements during the first 6 weeks of o__.__o Blasts

100
therapy. An erythroid hyperplasia of 32%
a- . -x Erythrocyte precursors

. - - . - I Granu.locytic elements
was present by 14 days and greater than
75
40% by 28 days. This hyperplasia persisted
throughout remission, accompanied in a
50
large number of patients by persistent low .-.--.-K

hemoglobin values. The percentage of gran- ..s

25 ,--.
ulocytic cells remained relatively low . . ..
,.:-
throughout remission and many of the pa-
-?
0 . -9
0
tients had mild leukopenias in the periph- lit 28 1t2
era! blood. Dars on study
Only two of the three patients who had Fic. 1. Bone marrow response to vincristine in 52
CR were retreated following a maintenance patients achieving complete marrow remission.

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86 VINCRISTINE IN LEUKEMIA

TABLE IV TABLE V
PRE-TREATMENT BLASTS IN MARROW IN VARIOUS MEAN NUMBER OF DISuG \VITIIDRAWAIS PER

RESPONSE GROUPS PATIENT BEFORE REMISSION IN THE \ARIOUS

RESIoNsE Guoucs
. made-
Fazl-
%
blast..
CR GFR FPR MR
ore
quate
.
Total made-
trial Cause/or drug
CR GPR FPR JSR Failure quate
withdrawal .
trial
Q5.-49 Q 8 1 4 19
50-74 8 I 1 9 3 3 56 Leukopenia . 64 . 44 . 68 . 04 . 47 .56
75-100 4 3 O 14 I 1 94 GI toxicity . 36 . I9 . 09 . . . 18 .04
Neurotoxicity .64 .0l .09 .04 . iS .07
Total 1$ 43 l 5 17 58 149

S CR -complete remission; GRP =good partial remission; FPR

dren who received 0.1 mg/kg weekly on one
-fair partial remission; MR -minimal remission.
or more occasions. The patients were di-
vided retrospectively into those who re-
of therapy did not influence the response to ceived the increased doses before their best
Vcr. The marrow picture prior to treatment, status was obtained and those who received
however, revealed a significantly greater (X them subsequent to this. Of those who re-
= 23.9, p < 0.01) number of complete and ceived them before, there was one GPR
good partial remissions in those children which became a CR and one FPR which
who had less than 75% blasts in their mar- became a GPR. One patient with a GPR
row at the onset of therapy than in those and one with a FPR improved their marrow
with more than 75%. This is shown in Table category but not their disease status, and 11
Iv. patients showed no improvement. This was
Toxicity altered the total amount of drug also true of those patients receiving the in-
given. Table V shows the mean number of creased doses after their best status. Four
drug alterations per patient for the various improved their marrow category rating
response groups prior to remission for the without changing status, and 19 had no fur-
three categories of toxicity. The change in ther improvement.
drug dose is also reflected in the median of
the average weekly dose of Vcr to remis- Toxicity
sion. The CR group received 0.061 mg/kg The symptoms and signs of toxicity were
weekly, whereas all other groups received divided into four major groups-alopecia,
.067 mg/kg/wk or more (Table III). leukopenia, gastrointestinal, and neuro-
The opportunity of increasing the dose to muscular. The number of patients who
0.1 mg/kg/wk if there was no response by demonstrated these signs is shown in Table
the twenty-eighth day was used in 40 pa- VII. Alopecia developed in 72 patients
tients, but in only two was it associated with (48.3%) at a median of 28 days (range 4 to
changing the type of response to Vcr. Table 118 days). The median total dose of drug
VI demonstrates the changes seen in chil- preceding alopecia was 0.27 mg/kg.

TABLE VI

OUTCOME OF PATIENTS WHO RECEIVED 0 . 1 MG/KG VINCRISTINE ON ONE OR MORE OCCASIONS BEF0IIF
AND AFTER BEST STATUS

Inadequate
Tinw CR GPR FPR MR Failure
trial

Q*
Before best status I A2 to A, 1 A2 to A1 I A3 to A2 - 5*
1A,toA2 1*
3*

After best status - 4 A2 to A, I 7*

C No improvement.

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 ARTICLES 87

Signs and symptoms of neuromuscular TABLE VIII

and gastrointestinal toxicity are tabulated GASTROINTESTINAL AND NEUROTOXICITY ASSOCIATED

in Table VIII. The median day of onset and WITH VINCRISTINE

the median total dose of drug to onset are

Num- Median
given. Sixty-five children (43.6%) developed
bet % of Median day total
gastrointestinal toxicity including nausea of I 49 of onset dose to
pa- patients and tang. onset
and vomiting, stomatitis, abdominal pain, tients (mg/kg)
and constipation. Nausea and vomiting,
Gastrointestinal
which occurred in 17 patients, were usually Nau,eaand vomiting 17 11.4 14 (1-39) .13
transient and followed the injection of drug Anorexia 10 6.7 14(3-98) .15
Constipation 48 SI 14(1-lOS) .15
within 24 hours, whereas the other signs Abdominal pain 0 13.4 13.5 (0-76) .13
could occur at any time and be persist- Neurotoxicity
Neuritic pain 17 11.4 14 (1-77) .15
ent. Constipation occurred in 48 patients Paresthesias 17 11.4 1 (-56) .Q
(32.2%) and abdominal pain in 20 (13.4%). I orabsentDTRa 49 3.8 31 (6-197) .6
Muacleweakneu 34 S6. 41.3 (1-160) .S
The median day of onset for all gastrointes-
tinal symptoms was 14 days, following a
total dose of 0.15 mg/kg. The most common jection. It usually subsided within 1 or 2
sign of neuromuscular toxicity was diminu- days but tended to recur after subsequent
tion or absence of deep tendon reflexes doses. Hoarseness, muscle atrophy, insom-
which developed in 49 (32.8%) patients nia, and skin rash occurred in a few chil-
after a median of 31 days, following a total dren. Anorexia was present in 10 children.
dose of 0.26 mg/kg Vcr. Neuritic pain de- Seven patients were removed from study
veloped in 17 patients (11.4%), subsequent because of severe Vcr toxicity. The total
to a total dose of .15 mg/kg. A distressing
dose of drug and the duration of treatment
sign of neuritic involvement was jaw pain
before removal were variable. In two pa-
which was noted in six patients, occurring
tients, the presence of severe central ner-
usually within 24 hours after the injection
vous system leukemia made drug toxicity
of drug. The jaw pain tended to be tran- difficult to evaluate. A third child de-
sient, but to recur when another injection veloped severe liver damage and general-
was given. Mild paresthesias, which oc- ized muscle weakness following 161 days
curred in 17 children (11.4%) after a median on study and subsequently succumbed with
of 21 days, followed a median total dose of liver failure. At autopsy this child showed
0.22 mg/kg. Muscle weakness occurred in
diffuse parenchymal cell degeneration and
54 children (36.2%), preceded by a median
necrosis of the liver, and extensive demyel-
total dose of 0.32 mg/kg. Convulsions oc-
inization of the brain and spinal cord. An-
curred in two children who had signs and
other child had marked anorexia, weight
spinal fluid evidence of uncontrolled leu-
loss, depression, and constipation. The re-
kemic infiltration of the central nervous sys-
maining three patients demonstrated a
tern.
combination of moderately severe gastroin-
Fever to 102 to 103#{176}Fdeveloped in 31
testinal and nervous system symptoms si-
children (20.8%) within 24 hours of drug in-
multaneously. Only one of the seven pa-
tients did not receive an adequate trial of
TABLE VII
drug-demonstrating moderately severe con-
INCIDENCE OF TOXICITY TO VINcRIsTINv.
stipation and neuromuscular toxicity after
only two doses of drug.
Number of % of 19
patients cases DISCUSSION

Alopecia 72 48.3 Reports of early clinical trials with Vcr in

WBC<1000 65 43.6 acute leukemia involved a small number of
GI 65 43.6
patients. Karon,8 Rohn,#{176} Selawry,10 and
Neurotoxicity 80 53.6
Tan presented a total of 35 patients, of

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88 VINCRISTINE IN LEUKEMIA

whom 5 achieved complete and 9 partial had cyclophosphamide. Although more pa-
remissions. The doses used varied widely tients who achieved CR entered study in
from 0.01 to 0.2 mg/kg/wk, with adjust- disease status 3 (moderate), there were 4 of
ments in the weekly dose based on toxicity. 14 who entered in disease status 4 (ad-
There was fairly general agreement that vanced). Among the GPR, there were 26
toxocity was innocuous at doses of 0.05 who entered in disease status 3, and 17 in
mg/kg/wk, or less. Karon2 later reported disease status 4. This is in contrast to the
that complete remissions were obtained in findings of Leukemia Group A with cyclo-
54% of 13 adequately treated children who phosphamide, in which no patients in ad-
had become refractory to 6-mercaptopurine vanced disease status achieved a complete
and methotrexate. In Karons study a com- remission.4 These findings suggest that Vcr
plete remission began when an A, marrow can be used in the more seriously ill pa-
was obtained, provided the other categories tient.
achieved a one rating before the marrow Vcr gave complete or good partial remis-
relapsed. sions in 4 of the 7 adequately treated cases
The largest series of adequately treated of acute granulocytic leukemia. Although
children was reported by Evans, et this number is small, it compares favorably
who treated 35 patients resistant to pre- with the remission rate from steroids#{176} or
vious therapy and 17 previously untreated antimetabolitesl6 in previously untreated
patients. The usual dose of Vcr was 0.1 patients with acute granulocytic leukemia.
mg/kg/wk with subsequent changes in dose One of the aims of this study was to use a
for leukopenia. When Vcr was used without constant dose of \7cr for the induction of
steroids, the marrow remission rate in stem remission. The attendant high rate of toxici-
cell leukemia was 85% for the 13 previously ty altered this to a certain extent but the
untreated patients, and 57% for 21 resistant decrease in dose was not detrimental since
patients. The mean duration of remission in the number of dose alterations was greater
the latter group was 55 days when no further in the CR group than in any other category
treatment was given, and 60 days when of response.
maintenance therapy was given every 2 Eleven of the patients who developed CR
weeks. When all morphological types of received maintenance therapy in contrast to
acute leukemia were considered, the mar- 3 who did not.* In this small number of pa-
row remission rate for patients resistant to tients, there was no difference in the dura-
other therapy was 40%. tion of CR (63.5 vs. 59 days, respectively).
In the Leukemia A study involving 149 These figures are similar to those reported
children with all types of acute leukemia in by Evans, et al. (f3 vs. 55 days).
relapse to previous therapy, the CR rate for Of the three patients who achieved a CR
adequately treated children was 11.6%, and and had no maintenance therapy, two were
the GPR rate was 35.5%. The criteria for a retreated after relapse. Both developed
CR were more rigid than in previously re- good partial remissions, and had total pen-
ported studies, since normality was re- ods on study of 159 and 218 days, respec-
quired simultaneously in all four parame- 0 The apparent lack of randomization suggested
ters of clinical and hematological evalua- by these figures can be explained by the fact that
tion. Using the marrow response, the 43% several of the cases early in the study were put
into the second phase by certain investigators when
remission rate compares favorably with
the marrow attained a one rating and before the
other studies.
other categories of evaluation were normal. 5ev-
Previous therapy did not influence the eral of these patients were subsequently accepted
response to Vcr, suggesting a lack of cross- as GPR since they never achieved normality in all
resistance between this agent and other categories, leaving the imbalance shown by these
figures. There were originally 15 patients in the
effective antileukemic drugs. All patients
maintenance program of whom four became GPR;
had been previously treated with steroids there were 1 1 in the non-maintenance plan of
and antimetabolites, and two-thirds had whom eight became GPR.

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 ARTICLES 89

tively. Since there were only five patients esthesias were noted, these signs were apt
whose total time on study exceeded 150 to worsen.
days, it might suggest that intermittent Gastrointestinal symptoms of toxicity
therapy with Vcr deserves further trial. In were common and are probably due to neti-
order to investigate this further, Leukemia romuscular effects of the drug. Constipation
Group A is presently using Vcr as part of a developed in one third of the group treated,
cyclic therapy program to determine wheth- although prophylactic measures, such as
er short term use will prevent early resis- stool softeners and lubricants, were pre-
tance to the drug. scnibed. In spite of these precautions, many
The effect of Vcr on the marrow in those patients developed abdominal pain or ohs-
patients achieving an A1rating was a rapid tipation which necessitated alterations in
clearance of blasts concomitant with the de- drug dose or other therapy for relief.
velopment of an erythroid hyperplasia and The alopecia which developed in a high
a reversal of the myeloid/erythroid ratio percentage (48.3%) of the patients treated
which persisted throughout remission. A pe- was distressing to the children, many of
nipheral neutropenia, anemia, or both were whom appreciated wigs. Regrowth of hair
noted in 13 (23%) of the patients who at- began soon after the drug was discon-
tamed complete or good partial remissions. tinued, and a few patients developed re-
The mechanism of the anemia induced by growth of hair while Vcr was continued
Vcr is not clear; all stages of erythrocytic without interruption over long periods of
precursors are found in the marrow and a time.
maturation arrest is not apparent. Further Vcr did not prevent the occurrence of
information regarding the effect of Vcr on leukemic invasion of the central nervous
the life span and metabolism of erythro- system. Of the 40 patients who developed
cytes is needed. meningeal leukemia while on study, 26
Vcr has a greater degree of toxicity asso- were given intrathecal methotrexate either
ciated with its use than have steroids, an- as initial treatment or subsequent to recur-
timetabolites, or cyclophosphamide. The his- rence of nervous system leukemia after x-
topathology induced by Vcr was studied in ray treatment to the skull. Twelve patients
monkeys by Adamson, et al.,17 who noted were kept on Vcr along with intrathecal
peripheral neuropathy and demyelinization methotrexate therapy. In these patients
in the dorsolateral columns of the sacral cord there was no accentuation of neurological
in animals who were given 0.3 mg/kg at symptoms or findings while receiving both
weekly intervals. In the only patient who drugs on the same day.
expired with signs of neurotoxicity and
hepatic failure in this study, demyeliniza- SUMMARY
tion was noted in the lateral funiculi of the Vcr induced complete marrow remission
cord. Muscle weakness and loss of deep in 43% of children with all types of acute
tendon reflexes were the most common leukemia who were refractory to other an-
signs of neurotoxicity. The muscle weakness tileukemic therapy. The median duration of
was either generalized, localized, or both. disease before Vcr treatment was 13.5
Specific sites of involvement included pto- months. The marrow response in those pa-
sis, facial palsy, foot drop, thenar weakness, tients achieving an A1 marrow was rapid
and hoarseness. Loss of deep tendon with a marked clearing of the blasts by 14
reflexes persisted in many patients through- days and a complete remission by 28 days.
out the study without attendant weakness The median duration of complete remission
or the development of other neurologic with and without maintenance therapy was
signs. Recovery from signs of mild neuro- 63.5 and 59 days, respectively.
toxicity after the drug was discontinued Drug toxicity occurred in about half the
progressed over several weeks. If the drug patients, limiting the total dose of drug that
was continued after weakness, pain, or par- could be given. Leukopenia, alopecia, gas-

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90 VINCRISTINE IN LEUKEMIA

trointestinal symptoms, and neurotoxicity children. (Abst.). Proc. Amer. Ass. Cancer
Res., 3:367, 1962.
were the most common problems seen.
12. Karon, M. R., Freireich, E. J., and Frei, E.,
These were reversible on withdrawal of the
III.: A preliminary report on vincristine sul-
drug. fate-a new active agent for the treatment of
Remissions were not improved by in- acute leukemia. PEDIATRICS, 30:791, 1962.
creasing the dose of Vcr to 0.1 mg/kg for 13. Evans, A. E., Farber, S., Brunet, S., and Man-

two or more doses after 4 doses of 0.075 ano, P. J. : Vincristine in the treatment of
acute leukemia in children. Cancer, 16:1302,
mg/kg. The reduction in dose necessitated
1963.
by drug toxicity was not detrimental to a 14. Pierce, M. I., Murphy, M. L., Shore, N. A.,
good response since the children attaining and Sitarz, A. : Comparison of cytoxan ther-
complete remissions experienced the great- apy administered orally or intravenously in
2 groups of children with acute leukemia.
est number of alterations in dose prior to
(Abst.). Proc. Amer. Ass. Cancer Res., 6:51,
the onset of remission. 1965.
15. Wolff, J. A., Brubaker, C., Murphy, M. L.,
REFERENCES Pierce, M., and Severo, N. : Prognostic fac-
1. Cutts, J. H., Beer, C. T., and Noble, R. L.: tors in the response of acute childhood leu-
Effects on hematopoiesis in rats of extracts kemia to prednisone. (Abst.). Proc. Amer.
of Virica rosea. Rev. Canad. Biol., 18:476, Ass. Cancer Res., 5:69, 1964.
1957. 16. Carter, R. E., Brubaker, C. A., Leikin, S. L.,
2. Noble, R. L., Beer, C. T., and Cutts, J. H.: Louis, J., Severo, N., and Wolff, J. A. : The
Role of chance observations in chemother- frequency of the various morphologic types
apy: Vinca rosea. Ann. N.Y. Acad. Sci., of childhood leukemia and their response to
76:882, 1958. certain chemotherapeutic agents. Cancer
3. Noble, R. L., Beer, C. T., and Culls, J. H.: Chemother. Rep., 16: 155, 1962.
Further biological activities of vincaleuko- 17. Adamson, R. H., Crews, L., and Ben, M.:
blastine-an alkaloid isolated from Vinca Some aspects of the pharmacology of yin-
rosea (L.). Biochem. Pharm., 1:347, 1958. cristine. (Abst.). Fed. Proc., 23: 106, 1964.
4. Johnson, I. S., Wright, H. F., and Svoboda,
C. H. : Experimental basis for clinical evalu- Acknowledgments
ation of anti-tumor principles derived from This study was supported by the following
Virica rosea Lmn. (Abst.). J. Lab. Clin. Med., grants from the National Cancer Institute, National
54:830, 1959. Institutes of Health, United States Public Health
5. Svoboda, C. H.: Alkaloids of Vinca rosea Service: CA-0315, CA-06262, and CA-05826, Me-
(Catharanthu roseus). IX. Extraction and morial Hospital, New York City; CA-03526, Babies
characterization of leurosidine and leurocris- Hospital, New York City; CA-01300, Bobs Roberts
tine. Lloydia, 1961. 24: 173, Hospital, Chicago; CA-04937, University of Wash-
6. Johnson, I. S., Armstrong, J. C., Gorman, M., ington, Seattle; CYP-4985-C7, University of Illinois,
and Burnett, J. P., Jr.: The ymca alkaloids: Chicago; CA-05436, University of Wisconsin, Mad-
A new class of oncolytic agents. Cancer ison; CA-07439, University of Pittsburgh, Pitts-
Res., 23:1390, 1963. burgh; CA-03750, Ohio State University, Columbus;
7. Creasey, W. A., and Markiw, M. E.: Bio-
CA-04179, Childrens Hospital of Denver, Denver;
chemical effects of the ymca alkaloids. II. CA-03888, Childrens Hospital, Washington, D.C.;
A comparison of the effects of colchicine, CA-02971, University of Michigan, Ann Arbor;
vmblastine and vincristine on the synthesis
CA-02649, Los Angeles Childrens Hospital, Los
of ribonucleic acids in Ehrlich ascites car- Angeles; and contract PH 43-63-1147 (Cancer
cinoma cells. Biochim. Biophys. Acta, Chemotherapy National Service Center), State
87:601, 1964.
University of New York at Buffalo.
8. Karon, M. : Leurocristine sulfate in the treat-
ment of acute leukemia. (Abst.). Proc. Amer.
Ass. Cancer Res., 3:333, 1962. APPENDIX
9. Rohn, R. J., and Hodes, M. E.: Some effects of
CRITERIA FOR EVALUATION OF RESPONSE TO
intravenously given leurocristine. (Abst.).
CHEMOTHERAPY IN ACUTE LEUKEMIA-ADOPTED
Proc. Amer. Ass. Cancer Res., 3:355, 1962.
BY LEUKEMIA GROUP A, 1962
10. Selawry, 0. S., and Delta, B. C. : Leurocris-
tine in cancer of children (Abst.). Proc. I. Criteria for rating categories.
Amer. Ass. Cancer. Res., 3:360, 1962. A. Category A-bone marrow
11. Tan, C. T. C., and Aduna, N. S.: Preliminary 1. A1-blasts less than 8%. Blasts, lympho-
clinical experience with leurocristine in cytes and pathologic cells less than 40%

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 ARTICLES 91

under 2 years of age and less than 30% D. Category D-symptoms

over 2 years. 1. D1-asymptomatic and normally active.
2. As-values between A, and A2. 2. D2-mild symptoms ascribable to leu-
3. A,-blasts and pathologic cells 25% or kemia; ambulatory or limited activity.
greater. Blasts, pathologic cells and 3. D,-marked symptoms and bed rest.
lymphocytes 60% or greater, or percen- II. Criteria for rating disease status.
tage of lymphocytes greater than 70%. A. Disease status based on category ratings.
B. Category B-blood 1. No apparent disease (1), A,, B,, C1, D1.
1 . B1-following subcategory values must 2. Mild disease (2), rating of 2 in one or
be met: more categories (no 3 rating).
a. Hemoglobin: 10 gm % or more 3. Moderate disease (3), rating of 3 in one
under 2 years of age; 11 gm % or categories.
or two
more over 2 years of age. 4. Advanced disease (4), rating of 3 in
b. Granulocytes: absolute count 1500- more than two categories.
8500/cu mm. III. Indications for removing patient from study.
C. Lymphocytes: absolute count should A. Change from disease status 1 or 2 to 3 or 4.
not exceed 10,000/cu mm under 2 B. Change from disease status 3 to 4.
years of age or 7000/cu mm over 2 C. Patient in disease status 3 or 4 can be re-
years of age. moved from study when there is deteriora-
d. Platelets : within normal range for tion in category C or D with no improve-
technique used. ment in category A or B.
e. Morphology: no blasts or pathologic D. Progressive local leukemic infiltration for
cells. which other therapy is necessary.
2. B,-abnormalities in one or two sub- E. Special provision described in protocol.
categories. F. Death.
3. B3-abnormalities in three or more sub- IV. Terms describing response to therapy.
categories. A. Complete remission-improvement to dis-
C. Category C-physical signs ease status 1.
1. Each physical finding constitutes a sub- B. Good partial remission-improvement to
category. The degree of abnormality disease status 2.
for each subcategory is rated 0 (no de- C. Fair partial remission-improvement to dis-
fect). 2 (definite abnormality present), ease status 3.
and 3 (marked abnormality present). D. Minimal remission-improvement in any
a. C1-0. category without change in status.
b. Cs-greater than 0 but less than 4. E. Failure-deterioration after adequate trial
C. C-greater than 4. period.

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VINCRISTINE IN THE TREATMENT OF ACUTE LEUKEMIA IN CHILDREN
Ruth M. Heyn, E. C. Beatty, Jr., D. Hammond, J. Louis, M. Pierce, M. L. Murphy and N.
Severo
Pediatrics 1966;38;82
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007.
Copyright 1966 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005.
Online ISSN: 1098-4275.

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 VINCRISTINE IN THE TREATMENT OF ACUTE LEUKEMIA IN CHILDREN
Ruth M. Heyn, E. C. Beatty, Jr., D. Hammond, J. Louis, M. Pierce, M. L. Murphy and N.
Severo
Pediatrics 1966;38;82

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
/content/38/1/82

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication,
it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked
by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,
Illinois, 60007. Copyright 1966 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: 0031-4005. Online ISSN: 1098-4275.

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