ARTICLE
INTRODUCTION
The limiting toxicity of the majority of cytostatic drugs used in the
chemotherapy of malignant tumors reveals itself as development of myelodepression,
primarily leukopenia, caused by a decrease in the neutrophil count. Toxic
myelodepression impedes the continuation chemotherapy at the necessary
intensity and intervals planned, with the result that the therapeutic
effect is reduced. Several growth factors (different colony-stimulating
factors, IL-1, IL-3, IL-6, IL-11, TPO and others) have been studied in
animal experiments and clinical trials, to identify any bone marrow reconstitution
following chemotherapy. Of these, only colony-stimulating factor (CSF)
has been successfully introduced into clinical practice.
IL-1 is one of the main mediators of the development of host defense
reactions to invading pathogens [1, 2]. The important component of IL-1's
versatile biological activity is its ability to stimulate hematopoiesis.
IL-1-induced hematopoiesis stimulation is expressed as an increase in
the numbers of neutrophils, lymphocytes, eosinophils, and, to some extent,
platelets, due to induction of thrombocyte growth factor synthesis [3-5].
IL-1 induces production of colony stimulating factors (G-CSF, M-CSF, GM-CSF),
IL-3, IL-6 and, cooperatively with these cytokines, directly or indirectly
stimulate leukopoiesis in vivo, increasing subpopulations of premature
myeloid line cells [6-10]. IL-1alpha and IL-1beta restore the neutrophil
count in animals after administration of 5-fluorouracil [7, 11], cyclophosphamide
[12-14], and doxorubicin [15].
Both members of the IL-1 family (IL-1alpha and IL-1beta) have been studied
in several clinical trials, for the reconstitution of bone marrow in cancer
patients after high dose chemotherapy, and have been shown to have dose-dependent
leukostimulatory activity [16-22]. Unfortunately, at very high doses (100-200
ng/kg)
IL-1 induced several adverse effects, including hypotonia, and almost
30% of patients needed particular treatment for these [23-26]. Bearing
in mind that IL-1 has a great capacity for stimulating bone marrow hematopoiesis,
we decided to investigate its leukostimulatory activity under different
regimens and administration routes, at relatively low doses. In this paper,
we report the results of clinical trials where human recombinant IL-1beta
was used for reconstitution of bone marrow after chemotherapy in cancer
patients.
MATERIALS AND METHODS
The human recombinant IL-1beta [27] was produced in the State Research
Institute of Highly Pure Biopreparations (St. Petersburg, Russia). The
recombinant
IL-1beta appeared to be identical to the natural human IL-1beta in terms
of its physical, chemical and biological properties [28]. This preparation
was approved for clinical use by the Russian Ministry of Health (registration
number 97/51/6).
IL-1beta was administered as a stimulator of leukopoiesis over 30-90
min by i.v. drop infusion in 500 ml of isotonic (0.9%) sodium chloride
solution, at a dose of 10-20 ng/kg daily for 5 days. Paracetamol, noramidopyrin-methansulfonate-natrium,
diphenhydramine hydrochloride and chlorpyramine were used in some patients
to prevent or reduce pyrogenic reactions.
Subcutaneous IL-1beta administration was performed over 10 days according
to the following schedule: 100 ng in 1.0 ml of physiological saline on
the first day; 200 ng in 2.0 ml of physiological saline on the second
day and 300 ng in 3.0 ml of physiological saline on the third day and
every day thereafter. The total dose of IL-1beta was 2,700 ng per course.
Clinical study of human recombinant IL-1beta as a stimulator of leukopoiesis
was conducted at the N.N. Petrov Research Institute of Oncology (St. Petersburg),
in a group of 93 patients with morphologically verified, disseminated
forms of solid tumors and malignant lymphomas, who were receiving combined
chemotherapy. Clinical trials were started in phase I studies, with escalating
doses of IL-1beta administered by i.v. drop infusion in 23 patients (6
males and 17 females, age range from 17 to 67 years, average - 42 years).
IL-1beta doses were as follows: 0.1-0.4 ng/kg (6 patients), 0.5-1.2 (2
patients), 1.6-4.0 (6 patients), 4.5-10.0 (9 patients). Among these patients
16 were with disseminated melanoma, 3 with breast cancer, 2 with Hodgkin's
disease, 1 with lung cancer and 1 with Ewing's sarcoma.
The activity of IL-1beta as a stimulator of leukopoiesis was studied
in a group of 67 patients (17 males and 50 females) (group A). The mean
age was 41 years (ranging from 17 to 69 years). These patients received
IL-1beta by intravenous drop infusion. The patients were suffering from
generalized forms of Hodgkin's disease (38 patients), non-Hodgkin's lymphomas
(18 patients) and solid tumors (11 patients). Fifty-one patients out of
67 (76%) had grade III and IV leukopenia (according to WHO criteria, 1979),
and 16 patients (24%) had grade IV toxic leukopenia with decreased peripheral
blood leukocyte numbers (M ± m = 1.5 ± 0.1 x 109/L).
Leukopenia was caused by repeated standard cycles of combined chemotherapy
according to programs MOPP, CCNU-OPP, ABVD, DOPP-ABV, BEACOPP, BMV, EVAP,
CHOP, CCNU-COP, CVAMP, CHOEP, CAF, DBCT. In 9 patients (13%), myelodepression
had been induced by prior, combined chemotherapy and radiation therapy.
The leukostimulatory effect of human recombinant IL-1beta on s.c. administration
was studied in a group of 16 patients (5 males and 11 females). Their
mean age was 39 years (ranging from 23 to 68). They were suffering from
Hodgkin's disease (7 patients), non-Hodgkin's lymphomas (5 patients),
disseminated breast cancer (3 patients), teratoblastoma (1 patient). All
patients had grade II-III leukopenia (M ± SD = 1.6 ± 0.2 x
109/L) and neutropenia (M ± m = 0.9 ± 0.1 x
109/L) caused by combination chemotherapy according to the
programs MOPP, LOPP, ELOP, CVAMP, CHOP, CCNU-COP, CMP, ACE and combined
chemotherapy and radiation therapy.
The results obtained have been compared to another similar group (group
C) of patients ("historical" control group), consisting of 30 patients
(4 males and 26 females). The mean age was 40 years (ranging from 16 to
64), and they were not receiving any leukostimulatory treatment. They
were suffering from non-Hodgkin's lymphoma, Hodgkin's disease and breast
carcinoma - 11, 17 and 2 patients respectively. All patients of this group
had grade III toxic leukopenia caused by combined chemotherapy and, in
some cases, by chemotherapy and radiation therapy. The detailed characteristics
of patients by gender, age, diagnoses and details of previous treatment
are shown in Table 1.
In addition, a comparative pilot study of the leukopoiesis stimulatory
effect of GM-CSF (Leucomax) and IL-1beta was conducted. Twenty patients
were enrolled in this study (4 males and 16 females). Their mean age was
42 ± 3.5 years (ranging from 21 to 69). These patients were suffering
from Hodgkin's disease and non-Hodgkin's lymphoma (12 and 8 respectively).
All patients had grade III and IV leukopenia (according to WHO criteria,
1979).
Initial leukopenia before the administration of leukostimulants was
at 1.2 ± 0.1 x 109/L in group L receiving Leucomax,
and 1.4 ± 0.1 x 109/L in group I receiving IL-1beta.
Initial absolute granulocyte counts in peripheral blood were 0.6 ±
0.1 x 109/L and 0.7 ± 0.1 x 109/L
respectively. Myelosuppression was caused by several programs of combined
chemotherapy (MOPP, CVAMP, CCNU-OPP, CHOP, CHOEP, BACOD-E). Leucomax was
administered s.c. at a dose of 5 mkg/kg daily for 5 days. IL-1beta was
administered by i.v. drop infusion at a dose of 15 ng/kg in 500 ml of
physiological saline once a day for 5 days. The effectiveness of hemostimulation
was determined by the leukocyte count and absolute granulocyte count dynamic
in peripheral blood, and by the time taken for their restoration to normal
levels.
Informed consent was obtained from all patients.
The reliability of any differences observed during data processing was
determined using Student's test,
C-square and Wilkinson-Mann-Whitney test.
RESULTS AND DISCUSSION
Leukostimulatory activity of human recombinant
IL-1beta administered by intravenous drop infusion
The leukostimulatory effect of recombinant human IL-1beta administered
by i.v. drop infusion was studied and confirmed in patients with grade
III and IV toxic leukopenia. Study group A consisted of 67 patients with
disseminated forms of malignant lymphoma and solid tumors; the great majority
of them (76%) had profound grade III and IV leukopenia. The leukocyte
counts in peripheral blood of patients in group A after chemotherapy but
before administration of IL-1beta was 1.5 ± 0.1 x 109/L,
with a minimum level of 0.3 x 109/L. The leukopenia
in these patients, confirmed by repeated investigation, had continued
for 8 ± 1 days (with a maximum of 60 days), prior to administration
of the cytokine.
The administration of IL-1beta at doses of 10-20 ng/kg caused an increase
in leukocyte levels to 4.7 ± 0.3 x 109/L over 8
± 1 days, starting from the first administration. The leukostimulatory
effect of IL-1beta was registered from day 3 to day 5 of its administration
and was confirmed by statistically significant (p > 0.001) leukocyte
count increases up to 3.4 ± 0.3 x 109/L (see Table
2).
The same changes were seen in the absolute granulocyte count restoration
in peripheral blood of group A patients (see Table
2). The granulocyte counts increased to 3.2 ± 0.2 x 109/L
within 8 ± 1 days after the first administration of IL-1beta (p <
0.001), while the initial granulocytopenia had been 0.9 ± 0.1 x
109/L. The absolute peripheral blood granulocyte count restoration
to normal levels of 2.3 ± 0.1 x 109/L on average
(increment equal to 256 ± 50%) was observed even during IL-1beta
administration, i.e. within a short time frame.
This considerable effect of IL-1beta administration was not registered
in 7 patients with malignant lymphoma with specific liver damage, nor
in 9 patients who had undergone combined chemotherapy and radiation treatment
(all of them in group A). These patients displayed longer period of leukopoiesis
restoration lasting up to 27-32 days. However, 9 patients with malignant
lymphoma and specific bone marrow damage without blast transformation,
had no statistical differences compared to group A for all parameters.
The study did not reveal any statistical difference between the therapeutic
effect of IL-1beta at doses ranging from 10 to 20 ng/kg. The dose of 15
ng/kg was therefore selected as effective.
The patients in group A were divided into three subgroups, depending
on the degree of bone marrow suppression, for the differential analysis
of the therapeutic effect of IL-1beta. There were 16 patients with grade
II leukopenia prior to leukostimulation (the peripheral blood leukocyte
count was 2.4 ± 0.1 x 109/L) in the first subgroup,
38 patients with grade III leukopenia (1.4 ± 0.1 x 109/L)
in the second subgroup, and 13 patients with grade IV leukopenia (0.7
± 0.1 x 109/L) in the third group. The complete
peripheral blood leukocyte counts and absolute granulocyte count restoration
were registered in all subgroups. The leukocyte counts in these subgroups
of patients reached 5.0 ± 0.4 x 109/L, 4.4 ±
0.3 x 109/L, 5.2 ± 1.4 x 109/L,
and absolute granulocyte counts reached 2.9 ± 0.4 x 109/L,
3.0 ± 0.2 x 109/L, 4.4 ± 1.3 x 109/L
in the first, second and third subgroups, respectively, without statistically
significant differences between the subgroups (p > 0.05). However,
the most rapid restoration of leukopoiesis was recorded in patients with
initial grade II leukopenia already during IL-1beta administration (M
± m = 5 ± 1 days), and the longest leukopoiesis restoration
period (M ± m = 12 ± 1 days) was registered in patients with
the most profound initial myelopoiesis suppression (grade IV leukopenia,
p < 0.001).
The leukostimulatory effect of IL-1beta in group A was compared to in
the control group C of 30 patients with toxic grade III leukopenia who
had independent (spontaneous) myelopoiesis restoration without additional
administration of leukostimulants. The statistical analysis conducted
in both groups revealed statistically significant (p < 0.001), 3-fold
more rapid leukopoiesis restoration after stimulation with IL-1beta in
group A as compared with group C (see Table
2). Patients in group A, who had been receiving IL-1beta, appeared to
have total peripheral blood leukocyte count restoration prior to the next
chemotherapy treatment course (M ± m = 8 ± 1 days) while patients
in group C achieved the same result in 25 ± 2 days.
Leukostimulatory activity of human recombinant
IL-1beta administered by subcutaneous
injection
One of the most important aspects of the study was the investigation
of the therapeutic effect of IL-1beta after changing the way of administration
from i.v. to s.c. for the purpose of extending the cytokine administration
under out-patient conditions and reduction of side effects. In this set
of clinical trials, the group of 16 patients with malignant lymphoma and
solid tumors received IL-1beta s.c. at a total dose of 2,700 ng per course.
A statistically significant (p < 0.001) increase in peripheral blood
leukocyte counts from 1.6 ± 0.2 x 109/L to 5.5
± 0.5 x 109/L in 9 ± 1 days was found in this
group of patients, which demonstrated almost complete (up to 92%) leukocyte
count restoration. The initial level (prior to chemotherapy) in these
patients was 6.0 ± 0.8 x 109/L. A significant leukocyte
count increase (p < 0.001) by 219% on average, up to 3.5 ± 0.4
x 109/L was shown within 3-5 days from the start of
s.c. IL-1beta administration, and, more importantly, the absolute peripheral
blood granulocyte counts were restored to normal levels (M ± m =
2.2 ± 0.4 x 109/L) at the same time (Table
2).
The granulocyte counts (see Table
2) fluctuated between 0.9 ± 0.1 x 109/L as the
initial level of neutropenia and 3.7 ± 0.4 x 109/L
after 9-10 days of IL-1beta administration (p < 0.001). The granulocyte
count after IL-1beta administration was not statistically different in
absolute values from the initial level (M ± SD = 4.6 ± 0.7 x
109/L) before chemotherapy (p > 0.2).
The data on the therapeutic effect of IL-1beta after s.c. administration
in a group of 16 patients are shown in Tables
3 and 4. The previous specific chemotherapy treatment had induced grade
II (2.5 x 109/L), grade III (1.4 x 109/L)
and grade IV (0.7 x 109/L) toxic leukopenia in 5, 7
and 4 patients of this group respectively. The therapeutic effect of IL-1beta
administered s.c. was registered in all patients, independent of the level
of bone marrow suppression. These patients demonstrated complete restoration
of the peripheral blood leukocyte count to 5.4 ± 1.0 x 109/L,
5.0 ± 0.9 x 109/L, 6.5 ± 0.7 x 109/L
and restoration of absolute granulocyte counts to 3.4 ± 0.7 x
109/L, 3.6 ± 0.7 x 109/L, 4.3 ±
1.0 x 109/L respectively. There were no statistically
difference between the subgroups after leukopoiesis stimulation. The time
periods of the bone marrow restoration in the subgroups were similar (p
> 0.05). It is important to mention that patients with grade II and
IV leukopenia demonstrated a complete leukocyte count restoration to normal
levels in the same period of time: 7 ± 1.5 and 8 ± 1 days respectively.
It is also important to note that the effect of IL-1beta after s.c.
administration was obvious even in patients with grade IV leukopenia and
neutropenia caused by previous combination chemotherapy (4 patients out
of 16). In these patients, the initial peripheral blood leukocyte counts
were 0.7 ± 0.1 x 109/L and the absolute granulocyte
counts were 0.2 ± 0.1 x 109/L. During the 5 days
of IL-1beta administration, we observed a stable increase in leukocyte
counts up to 3.9 ± 0.9 x 109/L and granulocyte
counts to 1.5 ± 0.9 x 109/L. After the course,
complete restoration of the leukocyte counts to 6.5 ± 0.7 x
109/L and granulocyte counts to 4.3 ± 0.1 x 109/L
was registered.
The results presented (Table
2) allow us to compare the IL-1beta leukostimulatory effect in patients
receiving IL-1beta s.c. as a single dose of 4.3 ± 0.3 ng/kg (n =
16) and i.v. drop infusions at a dose of 10-20 ng/kg of (n = 67). They
also allow us to compare the results obtained from the patients in the
"historical" control group who had spontaneous restoration of leukopoiesis
(without hemostimulation). The therapeutic effect of IL-1beta administered
subcutaneously, manifested itself similarly to that in patients receiving
i.v. drop infusions of the drug. Myelopoiesis restoration in the s.c.
and i.v. groups was observed within a very similar time interval i.e.
8 ± 1 and 9 ± 1 days (p > 0.2) from the beginning of hemostimulation,
respectively. The leukocyte and granulocyte counts reached a normal level
to 4.7 ± 0.3 x 109/L and to 3.2 ± 0.2 x
109/L respectively after i.v. drop infusions of the cytokine.
The leukocyte and granulocyte counts increased to 5.5 ± 0.5 x
109/L and 3.7 ± 0.4 x 109/L respectively
after s.c. administration. There was no statistical difference between
i.v. and s.c. IL-1beta administration. The great leukostimulatory effect
of subcutaneously administered IL-1beta was seen despite the lower single
dose (4.6 ± 0.3 ng/kg) and total (2,700 ng) doses, as compared to
the i.v. drop infusions of the cytokine.
The comparative analysis of the leukostimulatory
effect of Leucomax (Molgramostim) and recombinant IL-1beta in
patients with malignant lymphoma and myelodepression induced by administration
of cytostatics (pilot study data)
The comparative analysis of the leukostimulatory effect of the GM-CSF
preparation - Leucomax (molgramostim) and recombinant IL-1beta was conducted
as an open, randomized clinical pilot phase III study in 20 patients with
malignant lymphoma and with grade III and IV leukopenia caused by combined
chemotherapy. The leukopenia level prior to administration of hematopoiesis
stimulators was on average 1.2 ± 0.1 x 109/L in
group L, receiving Leucomax (10 patients), and 1.4 ± 0.1 x
109/L in group I, receiving IL-1beta (10 patients). The initial
numbers of peripheral blood granulocytes were 0.6 ± 0.1 x
109/L and 0.7 ± 0.1 x 109/L respectively
(pU > 0.05). Myelosuppression continued for 5.5 ± 2.5
days on average in group L and 4 ± 2 days in group I (pU
> 0.05) and was caused by a variety of chemotherapy programs (MOPP,
CVAMP, CCNU-OPP, CHOP, CHOEP, BACOD-E).
The peripheral blood leukocyte counts increased from 1.2 ± 0.1
x 109/L prior to administration of Leucomax, to 7.8
± 2.6 x 109/L after the end of its administration
(pu < 0.001), the level of leukocytes reached the normal
value (4.8 ± 1.2 x 109/L) during the leukostimulation
treatment. The absolute peripheral blood granulocyte numbers also were
rising from 3.2 ± 0.9 x 109/L (pu <
0.001) before Leucomax administration and reached 5.6 ± 2.1 x
109/L (pu < 0.001) after its termination, i.e.
a nearly complete restoration of absolute granulocyte counts compared
to the initial level before chemotherapy (6.2 ± 1.1 x 109/L
pu > 0.05).
Very similar results were obtained in the second group (I) receiving
IL-1beta as a leukopoiesis stimulator. IL-1beta caused an increase in
the leukocyte counts in peripheral blood from 1.4 ± 0.1 x
109/L to 4.2 ± 0.5 x 109/L that reached
the normal value within 8 ± 1 days, i.e. the same as in group
L (pu > 0.05).
Some differences between mean values of leukocyte counts (7.8 ±
2.6 x 109/L versus 4.2 ± 0.5 x 109/L)
after leukopoiesis stimulation in both groups turned out to be not significant
according to the Wilkinson-Mann-Whitney criterion and were very likely
linked to the ability of Leucomax to cause hyper-stimulation of leukopoiesis.
As in group L, the granulocyte level was restored to the normal value
2.4 ± 0.6 x 109/L during the administration of
IL-1beta. The absolute count was to 3.0 ± 0.4 x 109/L
after stimulation, and the differences between the initial level before
chemotherapy and final values were not significant (pU >
0.05).
All patients were examined for cortisol levels prior to administration
of cytokines, and on day 7 after the start of leukostimulation with Leucomax
and IL-1beta. The cortisol levels before and after administration of cytokines
changed from 702 ± 117 nmol/L to 665 ± 99 nmol/L and from 647
± 95 nmol/L to 781 ± 89 nmol/L respectively in groups L and
I (pU > 0.05). According to the data obtained, Leucomax
and IL-1beta at the doses used, did not induce significant changes in
corticosteroid production. Also, neither preparation induced changes in
peripheral blood neutrophil functional activity: phagocytosis and oxygen
radical production (data not shown).
Both Leucomax and IL-1beta, at the doses used, were well tolerated by
the patients. The distinctive and characteristic feature of IL-1beta treatment
was moderate fever, in 80% of patients in group I. The other side effects
were not important. Preliminary results indicate that Leucomax and IL-1beta
are probably similar as regards their leukostimulatory effects when administered
during combined chemotherapy for malignant lymphoma, and that they do
not increase corticosteroid levels.
Side effects of recombinant human IL-1beta
IL-1beta at doses of 0.1-20 ng/kg (including phase I studies) were well
tolerated, the side effects regressed spontaneously without special treatment,
and allowed leukostimulatory or protective treatment with IL-1beta to
be continued without limiting toxicity (Table
5). IL-1beta administered i.v. at doses of 0.1-1.2 ng/kg did not cause
any side effect. The most frequent adverse effect during administration
of IL-1beta at the higher therapeutic doses administered by i.v. drop
infusions and s.c., was grade I-III fever in 67.9 and 62.5% of patients
respectively (p < 0.05). The fever manifestations were easily reduced
by paracetamol tablets or noramidopyrin-methansulfonate-natrium with diphenhydramine
hydrochloride injections. The grade I hyperthermia (43.8%) was registered
more frequently in patients receiving IL-1beta s.c. than in those receiving
it i.v. (26.9%), grade II hyperthermia was registered more rarely - 18.8%
and 35.9% respectively (p > 0.05).
IL-1beta administered by i.v. drop infusion at a single dose of 15 ng/kg
IL-1beta caused a transitory decrease in arterial blood pressure to 100/70
mm in only 1 patient. This decrease did not require any specific treatment.
S.c. injections of IL-1beta were accompanied by moderate local reactions:
hyperemia in 31.2% of patients, soreness at the injection site in 25.0%,
fever and chill were less severe and were of shorter duration. IL-1beta
did not cause any clinically side effects in 20.5% of patients receiving
i.v. drop infusion or in 18.8% of patients receiving s.c IL-1beta.
CONCLUSION
The clinical data obtained suggest that IL-1beta is an effective leukopoiesis
stimulator in patients with myelodepression receiving combined chemotherapy,
and combined chemotherapy plus radiation treatment for malignant tumors.
The ability of human recombinant IL-1beta to re-establish bone marrow
hematopoiesis after chemotherapy has been shown previously in other clinical
studies [16, 17, 19].
The subcutaneous route of administration of IL-1beta seems to be the
rational and optimal route from the point of view of simplicity and convenience
of administration, without the loss of leukostimulatory and protective
effects in cancer patients requiring intensive combined chemotherapy and
radiation treatment. It is particularly appropriate for out-patient clinics.
A study of the therapeutic effects of higher doses of subcutaneously
administered IL-1beta (10-15-20 ng/kg) is planned in the light of the
minimal side effects and the possibility of increasing the leukostimulatory
and protective effects of this drug.
Acknowledgements. We would like to thank the medical staff of
the Chemotherapy Department, N.N. Petrov Research Institute of Oncology,
St. Petersburg who helped us with the enrollment of patients and with
the clinical study.
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