BI-WEEKLY CHLORAMBUCIL TREATMENT OF

CHRONIC LYMPHOCYTIC LEUKEMIA

WILLIAMH. KNOSPE,MD, VIRGILLOEB,JR, MD,
AND CHARLESM. HUCULEY, J R , MD*

Because the lymphocytes of chronic lymphocytic leukemia (CLL) are known

to proliferate slowly, it was postulated that intermittent therapy might have
a cumulative inhibitory effect on tumor cells while permitting normal cells to
recuperate between doses. Sixty-two evaluable patients with CLL were treated
with chlorambucil given orally as a single pulse every 2 weeks. The initial dose
was 0.4 mgjkg; subsequent doses were increased by 0.1 mg/kg until toxicity or
disease control was achieved. Responses were obtained in 6 of 8 (75%) previ-
ously untreated patients with indolent disease, in 18 of 31 (61%) previously
untreated patients with active disease, in 7 of 14 (50%) previously treated
patients not shown to be resistant to alkylating agents, and in 2 of 9 (22%)
patients resistant to prolonged daily chlorambucil therapy. The over-all ef-
fectiveness in patients with CLL not previously resistant to chlorambucil was
31 of 53 (58%), with five complete remissions (9%). Hematologic toxicity
was usually mild and never life-threatening. Gastrointestinal toxicity, which oc-
curred in 28 of 62 patients, was usually mild and easily controlled with anti-
emetics. It is concluded that bi-weekly oral administration of chlorambucil is
effective therapy for CLL with response rates similar to daily continuous chlor-
ambucil. Hematologic toxicity is considerably less than with daily treatment.

C URRENTLY, THE

daily chlorambucil.3~~~*J2
USUAL THERAPY
chronic lymphocytic leukemia (CLL) is
Therapy with daily
FOR
Presented at the Ninth Annual Scientific Meeting,
American Society of Clinical Oncology, Inc., Atlantic
City, N. I., April 10, 1973.
From ihe Department of Medicine, Section of Hema-
tology, Rush-Presbyterian&. Luke’s Medical Center,
Chicago, Ill.; Department of Medicine, Washington
University School of Medicine, St. Louis, Mo.; and De-
partment of Medicine, Section of Hematology and On-
cology, Emory University School of Medicine, Atlanta,
Ga.
Supported by the followipg Public Health Service
Research Grants from the National Cancer Institute to
the following institutions: CA03013 to the University of
Alabama in Birmingham, Ala.; CA03177 to Duke Uni-
versity Medical Center, Durham, N.C.; C.405634 to Vet-
erans Administration Hospital, Durham, N.C.; CA03227
and CAI1263 to Emory University School of Medicine,
Atlanta, Ga.: CAM807 to Medical College of Georgia,
Augusta, Ga.: CA05641 to University of Miami School
of Medicine. Miami, Flor.; CAI2639 to Presbyterian-
University of Pennsylvania Medical Center, Philadel-
phia, Pa.; CAll504 to Medical University of South Car-
olina, Columbia, S.C.; CA07961 to Temple University
School of Medicine, Philadelphia, Pa.: CA03376 to
Washington University School of Medicine, St. Louis,
Mo.; (2.412223 to University of Puerto Rico School of
Medicine, San Juan, P.R.; CAI2640 to Rush-Presby-
terian-St. Luke’s Medical Center, Chicago, Ill.; and
C413237 to University of Tennessee Memorial Re-
seqrch Center. Knoxville, Tenn.
*Writing Committee for the Southeastern Cancer
Studv Group: Chicago, Illinois; St. Louis, Missouri;
and Atlanta, Georgia.
Address for reprints: William H. Knospe, MD, Chief,
Radiohematology Laboratory, Section of Hematology,
Presbyterian-% Luke’s Hospital, 1753 West Congress
555
clilorambucil is not ideal, and the evidence
that longevity of patients with CCL is pro-
longed by therapy is equivocal.3 Some patients
Parkway, Chicago, Ill. 60612.
T h e following members of the Southeastern Cancer
Study Group participated in this study: ,John R. Dur-
ant, MD, University of Alabama in Birmingham, Ala.;
Harold Silberman, MD, Duke University Medical Cen-
ter, Durham, N.C.; William B. Kremer, MD, Veterans
Administration Hospital, Durham, N.C.; Yick-Kwong
Chan, PhD, Charles M. Huguley, Jr, MD, and Julian
Jacobs, MD, Emory University School of Medicine, At-
lanta, Ga.: Morton P. Berenson, MD, Russell R.
Moores, MD, and Claude Starr-Wright, MD, Medical
College of Georgia, Augusta, Ga.; Howard E. Lessner,
MD, University of Miami School of Medicine. Miami,
Flor.; Peter A . Cassileth. MD, and Scott Murphy, MD.
Presbyterian-University of Pennsylvabia Medical Cen-
ter, Philadelphia, Pa.; Karl Tornyos, MD, Medical Uni-
versity of South Carolina, Columbia, S.C. and Veterans
Administration Hospital, Charleston, S.C.: William E.
Barry. MD, and Richard V. Smalley, MD, Temple Uni-
versity School of Medicine, Philadelphia, Pa.; Virgil
Loeb, Jr, MD, and Shabbir H. Safdar, MD, Washington
University School of Medicine, St. Louis, Mo.: Enrique
Velez-Garcia, MD, and Norman Maldonado, MD, Uni-
versity of PuerLo Rico School of Medicine, San Juan,
P.R.; William H . Knospe, MD, Rush-Presbyterian-St.
Luke’s Medical Center, Chicago. 111.: Stephen Krauss,
MD, University of Tennessee Memorial Research Cen-
ter, Knoxville. Tenn.; add Sureyya Arkun. MD, Veter-
ans Administration Hospital, Brooklyn, N.Y.
T h e authors gratefully acknowledge the contribu-
tions of Tudith Stredronsky, RN, who rendered invalu-
able assistance in collating and analyzing data, and
Yick-Kwong Chan, PhD, Statistician, Southeastern Can-
cer Study Group, who performed the statistical analy-
sis.
Received for publication October 19, 1973.

556 February 1974
CANCER
fail to be benefitted by treatment, others may
be made worse. A major limitation in the use
of daily chlorambucil therapy is hematopoi-
etic toxicity, which often prevents the admin-
istration of sufficient quantities of the drug
to control the leukemia.
Perry and his associates have studied the ki-
netics of leukemic lymphocytes in CLL“ and
have shown that in this disease there is a slow
accumulation of long-lived, non-dividing lym-
phocytes. T h e agents commonly used in the
treatment of CLL are non-cycle-specific
agents: radiotherapy, chlorambucil, and pred-
nisone. Lymphocytes are particularly suscepti-
ble to these agents. Although other normal
hematopoietic cells may be affected, their re-
covery is rapid, whereas the leukemic lympho-
cytes are slow to regenerate. Perry et al. sug-
gested that intermittent therapy with an
alkylating agent might be therapeutically more
effective with less hematopoietic toxicity than
has been the usual experience with continu-
ous treatment.
Intermittent therapy has not been tried sys-
tematically in the treatment of CLL. dntermit-
tent regimens have been particularly effective
in the treatment of lymphocytic lymphoma
and plasma cell myeloma, which are character-
ized by slow growth rates similar to CLL.l.I1
Livingston and Carter reviewed the treat-
ment of CLL and of lymphosarcoma with sin-
gle agents.lO Their results are shown in Table
1. These data indicate a superiority of chlor-
ambucil in the treatment of CLL and an
efficacy comparable to other good agents for
lymphocytic lymphoma. I n all of these studies
chlorambucil was given on a daily basis. Some
of the therapeutic trials with cyclophos-
phamide involved pulsatile administration of
the drug, although most utilized a daily sched-
ule, but there did not appear to be any differ-
ence in the response rates for CLL or for lym-
phocytic lymphoma.
T h e Southeastern Cancer Study Group
(SEG) developed a protocol to determine the
response rate of CLL to an intermittent alkyl-
ating agent regimen. We chose chlorambucil
because of its demonstrated effectiveness in
CLL, its ease of administration, and because it
TABLE1 . Response Rates to Single Agents, Tabulated from Livingston and Carterlo
Nitrogen mustard
Chronic lympkocytic leukemia 39% of 82
“L y mphosarcoma” 49% of 154
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Vol. 33
was less toxic than other widely used alkylat-
ing agents. On the basis of preliminary studies
we chose to administer a single dose at inter-
vals of 2 weeks. Statistical considerations sug-
gested that an accurate estimate of response
rate and of toxicity would require at least 25
evaluable patients with previously untreated
active disease. At the same time we planned to
enter patients into the study with untreated
indolent disease, patients who had been pre-
viously treated and were not unresponsive to
alkylating agents, and patients who were
known to be resistant to chlorambucil admin-
istered daily over a period of 6 months.
MATERIALS
AND METHODS
Criteria for patient selection: Patients were
required to meet generally accepted diagnostic
criteria for CLL with at least 15,000
lymphocytes/cu mm of blood at the initiation
of study, and a bone marrow aspirate o r a
biopsy compatible with CLL.5 “Indolent” or
asymptomatic disease was defined by: 1) ab-
sence of symptoms attributable to CLL; 2) ab-
sence of anemia or thrombocytopenia; and 3)
no progression of disease during the 12 weeks
preceding onset of study. A patient failing to
meet any of these criteria was classified as hav-
ing “active” disease.
Four types of patients were entered into the
study and grouped as follows:
Group I-Previously untreated patients
with “indolent” disease.
Group 11-Previously untreated patients
with “active” disease.
Group 111-Previously treated patients with
“active” disease who had not been shown to
be resistant to treatment with an alkylating
agent, and who had no treatment for the pre-
ceding 3 months.
Group IV-Previously treated patients with
“active” disease who had received an alkylat-
ing agent daily for at least 6 months without
obtaining a response of “fair” or better.
Pre-treatment studies: Medical history and
physical examination were done with special
emphasis on symptoms relevant to CLL, plus
presence of fever, weight loss, enlargement of
Cyclophosphamide Chlorambucil
42% of 142 61y0 of 367
65% of 276 68% of 90

No. 2 CHLORAMBUCIL LYMPHOCYTIC
IN CHRONIC LEUKEMIA
* Knospe et al.
lymph nodes, liver, and/or spleen. Complete
blood counts, including platelet and reticulo-
cyte counts, were obtained, as well as appro-
priate chemical and serologic studies. A bone
marrow specimen was obtained by aspiration
or biopsy prior to therapy.
Studies during therapy and followup: Dur-
ing the first 4 weeks of treatment, the patient
was seen at least weekly. Once stabilization
occurred, the patient was seen every 2 weeks
for a period of 3 months, and thereafter every
4 weeks. If evidence of toxicity or progression
of the disease became apparent, the patient
was seen as often as necessary to assure maxi-
mum quality of patient care and complete
documentation of changes in status. Complete
blood counts were obtained on each visit, and
bone marrow aspirates obtained at 12, 26, and
52 weeks. Appropriate monitoring for toxicity
was maintained during the study period.
Criteria of yesponse: Measurable parameters
of disease activity included fever, weight loss,
performance status, the sum of the products of
diameters of up to five lymph nodes, the ex-
tent of the spleen or liver below costal mar-
gin, the hemoglobin concentration or hemato-
crit, the platelet count, the total white blood
cell count, and the percentage of lymphocytes
in blood and in marrow. A response was con-
sidered to be “excellent” (complete remission)
i f there was complete disappearance of all
signs and symptoms of disease, including less
than 30% lymphocytes in the bone marrow
and normal values for the peripheral blood
counts. A “good” response required an im-
provement of 50-99f7, in all measurable para-
meters of disease. A “fair” response required
an improvement of 2549y0 in all measurable
parameters of disease. A “questionable” re-
sponse indicated definite improvement not
qualifying as “fair.” Patients achieving a sta-
tus of “Fair” or better were classified as res-
ponders for the purpose of this study.
T o x i c eoects: T h e well-known toxic effects
TABLE 2. Method of Grading Hematolorric Toxicitv
Platelets Grade 1 Grade 2
I00,000
50,000
10,000
* Absolute bands + absolute segs.
Grade 3 or “Life-threatening” granulocyte toxicity = Grade 2 fall with serious infection.
Grade 3 or “Life-threatening” platelet toxicity = Grade 2 fall with serious bleeding.
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557
of chlorambucil given daily are primarily he-
matologic. It was expected that the toxicity of
the bi-weekly regimen would be similar. Toxic-
ity was graded as: 1 (moderate), 2 (severe), or
3 (life-threatening). Because anemia, neutro-
penia, and thrombocytopenia are so common
in CLL, we used a relative scale for defining
hematologic toxicity in terms of dropping
from one level to a lower level of count (see
Table 2). Grade 3 or “life-threatening” granu-
locytopenia was defined as a Grade 2 fall in
neutrophils with serious infection, and Grade
3 or “life-threatening” thrombocytopenia as a
Grade 2 fall in platelets with serious bleeding.
Evaluability: Study patients were consid-
ered “evaluable” if they met protocol stipula-
tions for selection, were treated according to
the protocol regimen, and remained under ob-
servation for at least 6 months unless dropped
as treatment failures because of excessive tox-
icity, progression of disease, or death.
Trealment regimen: Chlorambucil was ad-
ministered orally with an initial single dose of
0.4 mg/kg. Doses were repeated every 2 weeks
and increased by 0.1 mg/kg until control of
lymphocytosis or toxicity was observed. Subse-
quent doses were modified u p or down to pro-
duce mild hematologic toxicity. Treatment
was maintained for 6 months. If treatment
produced nausea, patients were instructed to
take the chlorambucil just before bed, to-
gether with an anti-emetic agent.
Those patients who achieved a response of
“fair” or better at the end of 6 months of ther-
apy were continued for another 6 months, and
a second evaluation was made.
RESULTS
This study of chlorambucil therapy of
chronic lymphocytic leukemia is part of a
larger study, not yet completed, which in-
cluded patients with well-differentiated and
poorly-differentiated lymphocytic lymphoma.
Granulocytes* Hemoglobin
3,000 Grade 1 = 3 gin fall
1,500
Grade 2 = 5 gin fall
750
200
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558 February 1974
CANCER VOl. 33

Ninety-six patients with CLL were entered on
study prior to the cut-off date for this analysis.
Of these, 34 were excluded as being “inevalua-
ble” (see below). Sixty-two patients completed
the study and were evaluable. These included
patients who were removed from study early
because of progression or intolerable toxicity.
There were 13 females and 49 males. Me-
dian age was 62 years, with an age range of 37
to 84 years. Responses are tabulated in Table
3.
Group 1. “PreviousZy untreated patients
with ‘indolent’ disease”: Six of eight evaluable
patients showed a response during the first 6
months of therapy (Table 3). Two patients
showed further improvement during the sec-
ond 6 months of therapy, progressing from
“good” to “excellent” (complete remission).
An over-all response rate of 75% was observed
in this group of patients.
Group IZ. “Previously untreated patients
with ‘active’ disease”: Eighteen of 31 evalua-
ble patients responded during the first 6
months of therapy (Table 3). Three patients
showed further improvement during the sec-
ond 6 months of therapy, one progressing
from “good” to “excellent” (complete remis-
sion), and two progressing from “fair” to
“good”. One patient progressed from “good”
to “excellent” between 12 and 16 months. One
patient who achieved only a “questionable”
response at 6 motnhs was continued and
achieved a “good” response during the next 6
months. An over-all response rate of 61% was
observed in this group of untreated patients
with “active” disease.
Group I I I . “Previously treated patients with
‘active’ disease, still responsive t o alkylating
agents”: Seven of 14 evaluable patients re-
sponded during the first 6 months of therapy
(Table 3). One patient showed further im-
provement after 12 months of therapy, pro-
gressing from “good” to “excellent” after 20
months of therapy. An over-all response rate
of 50% was observed in this group of pre-
viously treated patients with “active” disease
who were not resistant to alkylating agents.
Group ZV. “Previously treated patients with
‘active disease, tinresponsive to alkylating
agents”: T w o of nine evaluable patients pre-
viously resistant to daily chlorambucil re-
sponded to bi-weekly therapy during the first
6 months of treatment (Table 3). There was
no improvement in response status during the
second 6 months. It is of interest that one of
the patients who achieved a response status of
“fair” had complete disappearance of an au-
toimmune hemoIytic anemia which appeared
while on daily chlorambucil and had re-
sponded poorly to prednisone. T h e observa-
tion that one patient had a “fair” response and
one had a “good” response to bi-weekly chlor-
ambucil after a failure to improve on 6 months
of daily chlorambucil therapy suggests strongly
that in at least some patients bi-weekly treat-
ment is superior to daily administration of
drug.
If we omit the nine patients who were re-
sistant to daily chlorambucil at the time of
entry into the study, we have an over-all re-
sponse rate of 32 of 53 evaluable patients or
65%. All but one of the responsive patients
achieved a status of “fair” or better by 6
months after the initiation of therapy. A num-
ber of responding patients improved their re-
sponse status during the second 6 months of
therapy, and one patient in Group I1 who
only had “questionable improvement” at 6
months showed a “good” response after 12
months of therapy.
Of the five patients achieving a complete re-
mission, two had chlorambucil therapy discon-
tinued after 12 months. Both subsequently re-
lapsed at 42 months. Three patients were

TABLE
3. Best Response Attained during Course of Study*
No.
evaluable Response at 6 months Best response obtained*
Group patients Excellent Good Fair Excellent Good Fair Total %
I 8 0 5 I 2 3 1 6 75%
I1 31 1 11 6 2t 13 4 19 61%
111 14 0 6 1 1: .i 1 7 50%
IV 9 0 1 1 0 1 1 2 22%
__ - - - ~ - - ~-
62 1 23 9 5 22 7 34 55%
* With one exception, best response was obtained before 12 months.
t One at 16 months.
* One a t 20 months.
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No. 2 LYMPHOCYTIC
CHLORAMBUCIL I N C H R O N I C LEUKEMIA Knospe et al. - 559
maintained on bi-weekly chlorambucil and re- spite which one had a good response. Five
main in complete remission at 18, 30, and 55 were given prednisone, three of whom
months after starting therapy. Twenty-two achieved a good response.
other patients have been continued on bi- T e n were “lost to followup,” three after
weekly chlorambucil for periods of 5-29 only one dose. T h e other seven were experi-
months after a response was achieved. Two encing varying degrees of improvement after
patients died of progressive disease while on four to seven doses.
study. Two died of other causes. One was mur-
Survival: T h e current status of the patients dered, and the other was thought to have died
is shown in Table 4. A majority of the pa- of pre-existing heart disease. Essentially, these
tients entered on study were newly diagnosed, were “lost-to-followup.”
but some of the Group I and I1 patients and Eight were removed from study before com-
many of the Group I11 and IV patients had pletion because intercurrent disease either de-
been diagnosed some time before entering the manded stopping the study o r adding predni-
study. This skews a life-table curve of survival sone. Two developed evidence of metastatic
from time of diagnosis. Nevertheless, such a carcinoma. One required surgery for a benign
curve was made for the previously untreated tumor. One developed pneumonia, Four had
patients and is presented in Fig. 1. T h e ap- progression of pre-existing hemolytic anemia
parent survival is unusually good but depends and continued on chlorambucil with the addi-
to some extent on long survival prior to tion of prednisone. All of these latter had a
treatment. good response to the combination.
Inatahable patients: Thirty-four patients Toxicity: Hematologic toxicity was mild in
were excluded from analysis as being “ineval- almost all instances and in no case life-threat-
uable.” This requires explanation. It is inevi- ening. Five patients had depressed red blood
table that a study of treatment of a chronic cell levels, three patients had depressed granu-
disease with frequent complications per- locyte levels, and 15 patients had mild to mod-
formed by many investigators and extending erate reduction of platelets (Table 5 ) .
over 6 months will contain some patients who Nausea occasionally accompanied by vomit-
for various reasons do not receive the stipu- ing was the most common toxicity. Symptoms
lated treatment and therefore cannot be evalu- usually lasted only 24 hours after the inges-
ated. Such patients should be detailed in a re- tion of the chlorambucil, although several pa-
port but seldom axe. tients complained of nausea and weakness for
Four patients were “ineligible” because 3 to 4 days. These side effects were usually re-
they did not meet protocol requirements for lieved or reduced by anti-emetic agents. In
diagnosis. only two patients was gastrointestinal toxicity
T e n patients were “invalid” because proto- sufficiently severe to necessitate discontinua-
col stipulations for treatment were not fol- tion of therapy. Unfortunately, chlorambucil
lowed. In two the dose was not escalated de- is only available in two mg tablets, so that bi-

TABLE
4. Current Status of Patients
Responders Non- Responders

In. Living with

Total rernis- active
patients No. sion disease Dead No. Living Dead
No prior therapy
Group I 8 6 0 5(33,37,37, l(55) 2 0
44.96)
Group I1 31 19 2(18,55) 15(11-71)* 2(26,27) 12 9(17-84)* 3( 1,26,26)
Prior therapy
Group 111- 14 7 l(30) 6(27-145)* 0 7 5(17,31,41, 2(8,50)
156.300)
. ,
Group IV 9 2 0 1(28) ~ 4 1 ) 7 4(11,36,122, 3(34,44,59)
225)
TOTALS 62 34 3 27 4 28 18 10
( )-Months after diagnosis.
* -Range of Survival.
 10970142, 1974, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197402)33:2<555::AID-CNCR2820330234>3.0.CO;2-I by Nigeria Hinari NPL, Wiley Online Library on [15/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
560 CANCERFebruary 1974 VOl. 33

I .o IV) in terms of the total amount of chloram-

bucil administered.
n=39
DISCUSSION
Our results indicate that bi-weekly adminis-
k
v,

0
=>
0.6
& 0.2
0.0
0 20 40 60 80
Months after diagnosis
FIG. 1. Life-table survival curve for Group I, pre-
viously untreated indolent patients, and Group 11,
previously untreated active patients.
weekly dosage requires the ingestion of a large
volume of medication and inert filler at one
time.
One patient developed a skin rash requiring
termination of chlorambucil; three others had
minor cutaneous reactions.
Dosages: A median total dose of chlorambu-
cil of 564 mg (range: 119-1 177) or 8.3 mg/kg
(range: 1.6-15.3) was administered during the
first 6 months of therapy. T h e median average
single dose at 6 months was 45.7 mg with a
range of 20.7-83.3 mg. T h e median maximum
dose was 58 mg with a range of 20-132 mg or
0.90 mg/kg with a range of 0.40-1.83 mg/kg.
After control of the disease was achieved, a re-
duction in dosage was almost always required.
T h e median final dose was 0.71 mg/kg with a
range of 0.30-1.83 mg/kg. There was virtually
no difference between the various groups (I-
tration of chlorambucil can provide effective
therapeutic control of CLL. T h e toxicity en-
countered is mild and predominantly gastroin-
testinal. Usually the nausea or vomiting can
be prevented or reduced by anti-emetic agents.
Some patients will manifest weakness and
nausea for as long as a week after the large
oral dose of chlorambucil, but this is uncom-
mon. T h e hematologic toxicity is minimal,
with infrequent mild reversible depression of
platelets. Undesirable effects upon the formed
100
elements of the blood have been considerably
less than that encountered in previous studies
using daily chlorambucil.~~~3 An advantage
to the patient with bi-weekly therapy is the re-
lief from the burden of taking medication
each day. We believe that a bi-weekly schedule
provides more reliable regulation of projected
dosage with less opportunity for missed doses.
One problem related to the schedule used
in the present study was the long treatment
program usually required to achieve a remis-
sion. U p to 6 months were required before a
maximal response was observed, with a
range of 2 to 20 months. It is of interest that
the average total amount of chlorambucil in-
gested during the bi-weekly treatment regimen
of 6 months is equivalent to 3.1 mg daily.
T h e best response rates were observed in
untreated patients with either “indolent” or
“active” disease. However, response rates ex-
ceeded 50y0 in all treatment groups, except
those in Group IV where significant remis-
sions were not expected. Complete remissions
were observed in 5 of the 62 evaluable pa-
tients (8%) included in the study. These res-
ponses are comparable to previous studies of

5 . Toxicity
TABLE
No.
evaluable Hemoglobin Granulocytes* Plateletst Gastrointestinal CNS Skin
Group patients It 2z 1 2 1 2 1 2 1 2 1 2
I 8 1 2 1
I1 31 2 3 7 1 11 1 2 1
I11 14 2 2 7 1 1
IV 9 2 1 1 1 1
TOTALS 62 4 1 3 11 4 20 3 1 3 1
* I n no instance was granulocyte toxicity associated with severe complications or infections.
t I n no instance was thrombocytopenia associated with serious hemorrhage.
* 1 = moderate, 2 = severe (see text for definition).
 10970142, 1974, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197402)33:2<555::AID-CNCR2820330234>3.0.CO;2-I by Nigeria Hinari NPL, Wiley Online Library on [15/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
No. 2 CHLORAMBUCIL
IN CHRONIC LEUKEMIA Knospe et al.
LYMPHOCYTIC - 56 1
TABLE
6. Chlorambucil Dosage During First 6 Months
Totals ( a n
Group I Group I1 Group I11 Group I V patients)
Total dose
Median (mg) 448 583 492 602 564
Median (mg/kg) 5.9 8.4 6.8 10.1 8.3
Range (mg) 119-1,000 150-1,114 210-1,177 125-926 119-1,177
Range (mg/kg) 1.6-11.9 2.3-14.7 3.2-15.3 2.2-1 2 . 9 1.6-15.3
Average single dose
Median (mg) 43.0 43.9 49.4 47.7 45.7
Range (mg) 20.7-83,3 22.2-82.9 24.0-73.5 29.4-55.5 20.7-83.3
Maximum dose
Median (rng/kg) 0.65 0.90 0.95 1 .oo 0.90
Range ( m g / W 0.40-1.63 0.45-1 .83 0.45-1.30 0.48-1.64 0.40-1.83
Final dose
Median (mg/kg) 0.60 0.73 0.78 0.50 0.71
Range ( m g / k d 0.36-1.73 0.30-1.83 0.37-1.17 0.32-1.11 0.30-1 .83

the Southeastern Cancer Study Group in which weekly administration of chlorambucil is an

patients with CLL were treated with daily effective well-tolerated regimen for CLL with
chlorambucil. In previous SEG studies, the minimal toxicity and a therapeutic efficacy
over-all response was 69%, with a 10% com- similar to previous experience with daily
plete response rate (12 of 111 patients).8~”~3 chlor am buci 1.
T h e observation that 36% of the patients Future studies of the Southeastern Cancer
continued to respond on bi-weekly chlorambu- Study Group of CLL will exploit the low tox-
cil for periods u p to 29+ months indicates icity inherent in a bi-weekly schedule of oral
that the regimen is effective for long-term chlorambucil. We plan to increase the initial
maintenance. Two patients remained in a dose to 0.8 mg/kg which appears reasonable
complete remission for 30 months after treat- in view of the minimal toxicity observed be-
ment was discontinued, indicating a gratifying tween 0.4-1 .O mg/kg. A larger initial dose may
reduction in the body burden of leukemic permit a more rapid response to the bi-weekly
cells. Data are too few as yet to indicate regimen.
whether survival may be prolonged with this
bi-weekly treatment schedule.
Intermittent regimens of the type used in CONCLUSIONS
the present study have not been used pre-
viously in the therapy of CLL, although sev- 1. T h e response rate of CLL to large bi-
eral studies have recently been reported indi- weekly doses of chlorambucil is similar to that
cating the efficacy of pulsatile schedules in the reparted with daily treatment.
chemotherapy of Burkitt’s lymphoma, cancer 2 . Responses may be obtained in patients
of the lung, malignant lymphoma, and multi- refractory to long-term daily chlorambucil
ple myeloma.B~7~13J4 Our present experience therapy .
extends these studies, indicating that bi- 3. Toxicity is minimal.

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