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Sequential Administration of Recombinant Human Interleukin-3 and
Granulocyte-Macrophage Colony-Stimulating Factor After AutologousBone
Marrow Transplantation for Malignant Lymphoma:
A Phase 1/11 Multicenter Study
By Joseph W. Fay, Hillard Lazarus, Roger Herzig, Ruben Saez, Don A. Stevens, Robert H. Collins, Jr, Luis A. PiAeiro,
Brenda W. Cooper, Joseph DiCesare, Marilyn Campion, James M. Felser, Geoffrey Herzig, and Steven H. Bernstein
Preclinical studies of recombinant human interleukin-3
(rhlL3) and granulocyte-macrophage colony-stimulating factor
(rhGM-CSF) have shown enhancement of multilineage hematopoiesis when administered sequentiatly. This study
was designed t o evaluate the safety, tolerability, and biologic effects of sequential administration of rhlL-3 and rhGMCSF after marrow ablative cytotoxic therapy and autologous
bone marrow transplantation (ABMT) for patients with malignant lymphoma. Thirty-seven patients (20 patients with
non-Hodgkin’s lymphoma and 17 patients with Hodgkin’s
disease) received one of four different treatment regimens
before ABMT. Patients were entered in one of four study
groups t o receive rhlL-3 (2.5 or 5.0 pglkglday) administered
by subcutaneous injection for either 5 or 10 days starting 4
hours after the marrow infusion. Twenty-four hours after
the last dose of rhlL-3, rhGM-CSF (250pg/mz/d as a 2-hour
intravenous infusion) administration was initiated. rhGMCSF was administered daily until the absolute neutrophil
count (ANC) was =1,5OO/pL for 3 consecutive days or until
day 21 posttransplant. The most frequent adverse events in
the trial included nausea, fever, diarrhea, mucositis, vomiting, rash, edema, chills, abdominal pain, and tachycardia.
Three patients were removed from the study because of
chest, skeletal, and abdominal pain felt t o be probably related t o study drug. Four patients died during the study
period because of complications unrelated t o either rhlL-3
or rhGM-CSF. The median time to recovery of neutrophils
(ANC =500/pL) and platelets (platelet count 220,0001pL)
was 14 and 15 days, respectively. There were fewer days of
platelet transfusions than seen in historical control groups
using rhGM-CSF, rhG-CSF,or rhlL-3 alone. In addition, there
were fewer days of red blood cell transfusions compared
with historical controls using no cytokines or rhGM-CSF.
These data indicate that the sequential administration of
rhlL-3 and rhGM-CSF after ABMT is safe and generally welltolerated and resultsin rapid recovery of multilineage hematopoiesis.
0 1994 by The American Societyof Hematology.
I
rhIL-3 has been evaluated as a single agent after ABMT
for lymphoid malignanciestwo
in
In both trials,
there was a modest acceleration of neutrophil and platelet
recovery compared with that found in patients who received
no growth factor after transplantation. However, in comparison to patients who received rhGM-CSF in a phase 111 trial,
there appeared to be no improvement in neutrophil or platelet
recovery.’
Based on these observations, we conducted the first clinical trial to evaluate the safety, tolerability, and biologic effect
of sequential rhIL-3 and rhGM-CSF administered to patients
with malignant lymphoma treated with intensive cytotoxic
therapy and ABMT.
NTENSIVE CYTOTOXIC treatment combined with autologous bone marrow transplantation (ABMT) has been
shown to result in prolonged relapse-free survival for a significant fraction of patients with non-Hodgkin’s lymphoma
(NHL) and Hodgkin’s disease (HD) who fail to respond
to standard therapy.’.’ Infection and bleeding complications
associated with marrowablative transplant therapy are major
causes of morbidity and mortality for these patients. A recent
clinical trial showed that recombinant human granulocytemacrophage colony-stimulating factor (rhGM-CSF) administered after ABMT significantly reduced the duration of
profound granulocytopenia compared with p l a ~ e b oPatients
.~
treated with rhGM-CSF had fewer infections, a reduced requirement for antibiotics, and a shorter duration of hospitalization. However, rhGM-CSF did not affect platelet or red
blood cell (RBC) recovery.
Recombinant human interleukin-3 (rhIL-3) is a multilineage hematopoietic growth factor that plays an important
role in the activation, differentiation, and proliferation of
hematopoietic progenitor cells. Several studies using cultured humanbonemarrow (BM) have shown that rhIL-3
alone or combined either sequentially or simultaneously with
rhGM-CSF stimulated the growth of both myeloid andmegakaryocytic lineage^.^.^ In nonhuman primate studies, rhIL-3
enhanced myeloid and platelet recovery, reducing chemotherapy-induced severe neutropenia.’ In other preclinical
studies, the combination of rhIL-3 and rhGM-CSF was synergistic in stimulating both neutrophil and platelet production. The sequential administration of rhIL-3 followed by
rhGM-CSF had the greatest effect on increasing peripheral
leukocyte counts.8”‘ These observations suggest that rhIL-3
may expand anearly hematopoietic progenitor cellpopulation, enabling more effective differentiation into mature
cells with rhGM-CSF, a ‘later-acting’’ hematopoietic
growth factor.”.”
Blood, Vol 84, No 7 (October l ) , 1994: pp 2151-2157
From The Charles A.Sammons Cancer Center, Baylor University
Medical Center, Dallas, T X ; the University Ireland Cancer Center,
Case Western Reserve University, Cleveland, OH; the University of
Louisville, Louisville, KY; Oklahoma Memorial Hospital, Oklahoma
City, OK; The Cytokine Development Unit, Sandoz Pharmaceuticals,
East Hanover, NJ; and Roswell Park Cancer Institute, Buffalo, NY.
Submitted February 23, 1994; accepted June 2, 1994.
Supported in part by The Tri Delta Cancer Fund Dallas Chapter,
Dallas, T X ; by National Institutes of Health, US Public Health Services, National Cancer Institute GrantNo. P3OCA43703; by The
Coleman Leukemia Research Fund; and by American Cancer Society
Career Development Award No. 85801228.
Address reprint requests to JosephW. Fay, MD, Baylor University
MedicalCenter,3500GastonAve,
Sammons Tower, Suite #410,
Dallas, TX 75246.
The publication costsof this article were defrayedi n part by page
chargepayment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
0 1994 by The American Society of Hematology.
0006-4971/94/8407-0031$3.00/0
2151
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2152
FAY ET AL
higher rhIL-3 doses (groups 2 through 4). depending on safety and
tolerability. Subsequently, additional patients were entered into
Patients. Patients enrolled in this study had either NHL or HD
groups 1 through 3 to further assess safety, tolerability, and biologic
determined by the investigator tobe incurable with conventional
activity.
treatment regimens. The following five centers participated in this
Initially, 3 patients in group 1, 1 in group 2, and 1 in group
trial: the Sammons Cancer Center, Baylor University Medical Center
4 received rhIL-3 as a 2-hour intravenous infusion. To facilitate
(Dallas, TX); University Ireland Cancer Center, Case Western Readministration of rhIL-3, the protocol was subsequently amended
serve University (Cleveland, OH); J. G. Brown Cancer Center, Uniand all additional patients received rhIL-3 subcutaneously.
versity of Louisville (Louisville, KY); Roswell Park Cancer Institute
Twenty-four hours after the last dose of rhIL-3, all patients re(Buffalo, NY); and Oklahoma Memorial Hospital (Oklahoma City,
ceived their first dose of rhGM-CSF (250 ,ugh2). rhGM-CSF was
OK).
administered daily until the ANC was 2 1500/pL for 3 consecutive
Eligible patients included male and female patients 18 years of
days or until day 27, whichever occurred first.
age or older whohad Kamofsky Performance Scores of >60%,
RBC transfusions were administered to maintain the hematocrit
anticipated life expectancies of 8 weeks or longer, no significant
between 22 and 30. Platelet transfusions were administered to mainorgan system dysfunction, and a BM biopsy with 225% cellularity
tain a platelet count of 22O,OOO/pL. Patients were treated with broad
and no histologic evidence of malignant cells at the time of marrow
spectrum antimicrobials when fever developed and theANC deharvest. In addition, patients had adequate cardiovascular, pulmocreased to less than 500/pL. Amphotericin B (0.5 to 1.0 pg/kg/d)
nary, hepatic, and renal function before participation in the trial.
was added if patients had persistent fever after 4 to 7 days of broad
Patients were excluded from the trial for the following reasons:
spectrum antimicrobial therapy.
previous treatment with rhIL-3 or GM-CSFnL-3 fusion protein; a
Treatment monitoring. To assess toxicity and biologic activity
platelet count less than100,O00/pL or absolute neutrophil count
of sequential rhIL-3 and rhGM-CSF, patients underwent daily as(ANC) less than 1,2OO/pL at thetime of marrow harvest; a neoplastic
sessments of symptoms and physical examinations while hospitaldisease requiring treatment within the last 5 years other than NHL,
ized andweekly after discharge. Laboratory studies, including a
HD, non-melanoma skin cancer, or cervical cancer; myelosupprescomplete blood cell count (CBC), a white blood cell differential, a
sive chemotherapy within 4 weeks of BM harvest; pelvic radiation
platelet count, and a reticulocyte count, were obtained at baseline,
before the marrow harvest; administration of hematopoietic growth
daily while inthe hospital, and 2 or 3 times per week after discharge.
Serum chemistries, a urinalysis, and a coagulation profile were perfactor within 2 weeks before theBM harvest or within 2 weeks
formed at baseline and 2 or 3 times per week thereafter. Assessment
before the marrow transplant. Patients who had acquired immunodeof tumor response to treatment was generally performed 30 days
ficiency syndrome (AIDS), a positive test for human immunodefiafter the BMT and was planned every 3 to 4 months thereafter for
ciency virus (HIV), any form of active hepatitis, required treatment
1 year after transplant.
with systemic corticosteroids, or who hadpreviously undergone marAdverseevents. All adverse events, whether or not considered
row transplantation therapy were also excluded. All patients prorelated to the administration of rhIL-3 and/or rhGM-CSF, were evalvided written informed consent and protocols were approved by the
uated throughout the study. Adverse events included any new signs,
Institutional Review Board for human investigation at each institusymptoms, physical findings, or changes in baseline concurrent contion.
ditions. The severity of the adverse event and its relationship to the
Marrow harvest. BM cells were obtained using standard proceadministration of rhIL-3 and/or GM-CSF were evaluated. Adverse
dures and frozen in 10% dimeythyl sulfoxide using controlled-rate
events were graded by the clinical investigator as mild, moderate,
liquid nitrogen freezing.I4 Marrow cells were not purged in vitro.
or severe using toxicity parameters pooled from Eastern Cancer
The minimal number of marrow cells in the marrow graft was 0.9
Oncology Group (ECOG), Northern California Oncology Group
X 10’ nucleated cellskg actual patient weight.
(NCOG), Southwest Oncology Group (SWOG), and National Cancer
Cytokines. The rhIL-3 and rhGM-CSF (Leucomax) used in this
Insitute (NCI) toxicity parameters.
study were provided by the Cytokine Development Unit of Sandoz
Statistical analysis. All reported adverse events were included
Pharmaceuticals Corp (East Hanover, NJ). Both cytokines are nonin the overall incidence estimates, regardless of any relationship or
causality assigned to the cytokines by the investigator.
glycosylated proteins produced in Escherichia coli. rhIL-3 was reTime-to-event outcomes were evaluated using life table techconstituted with sterile water and administered intravenously or subniques (Kaplan-Meier estimate). Because of the small number of
cutaneously. rhGM-CSF was mixed with 50 mL of normal saline and
patients in each rhIL-3 study group and because the treatment out0.1% human serum albumin and administered as a 2-hour infusion.
comes were similar among the study groups, data were pooled to
Study design. This trial was a multicenter phase VI1 open-label
estimate median times to platelet and neutrophil engraftment and
dose-finding study. Patients underwent complete baseline evaluatime to hospital discharge. For the engraftment parameters, patients
tions before receiving treatment with one of the following treatment
who did not have an ANC 2 1,50O/pLor a platelet count of >20,000/
regimens: ( l ) etoposide (1,800 to 2,400 mglm’), cyclophosphamide
pL during the period of observation were censored on the last day
,’~;
(6,000 to 7,200 mglm’), and BCNU (400 to 600 ~ n g / m ~ ) ’ ~(2)
an ANC or platelet count was available. Patients who died were
etoposide (1,800 mg/m’), cyclophosphamide (6,840 mglm’), and tocensored on the study day of their death for each of the time-total body radiation (1,000 cGy)”; ( 3 ) etoposide (2,400 mg/m’), cisevent outcomes. There were too few patients to statistically compare
platin (200 mg/m’),andBCNU (600 mg/m’)18; or (4) carboplatin
the biologic activity of rhIL-3 and rhGM-CSF treatment among the
(1,600 mg/m2) and thiotepa (900 m g / ~ n ~ ) . ’ ~
study groups.
After completion of the treatment regimen, patients received an
Medians and ranges were determined for the number of transfuinfusion of autologous marrow cells (day 0). Four hours later, pasion events and the number of units transfused. To meaningfully
evaluate the total number of platelet units transfused, the number
tients received their first dose of rhIL-3. Patients received rhIL-3 in
of units of apheresed platelets was converted to standard units by
the following four study groups: group 1 received rhIL-3 at 2.5 pg/
multiplying the number of apheresed units by 6.4.20
kg/day for 5 days; group 2 received rhIL-3 at 2.5 pg/kg/d for 10
days; group 3 received rhIL-3 at 5.0 pgkg/d for 5 days; and group
RESULTS
4 received rhIL-3 at 5.0 pg/kg/d for 10 days.
From
April
1992
to
January
1993, a totalof 37 patients
Three patients were initially treated with the lowest dose of rhILwith refractory lymphomawereenrolled.Twentypatients
3 (group 1). Subsequent groups of 3 patients were treated with the
MATERIALS AND METHODS
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SEQUENTIAL IL-3IGMCSF IN ABMT
2153
Table 1. Demographics and Disease Characterirtics
~
~~
Treatment Group
IL-3 dose, no. of days (n)
Age (yr)
Median
Range
Sex (no.)
Male
Female
Primary diagnosis (no.)
NHL
HD
KPS (no.)
100
90
80
70
60
50
Unknown
Total cells/kg reinfused
(x108/kg)
Median
Range
Preparative regimen by
diagnosis in)
VP-16, cytoxan, BCNU
VP-16, cytoxan, TB1
VP-16, cisplatin. BCNU
Carboplatin, thiotepa
No. of days of GM-CSF
Median
Range
Overall
35
17-64
1
2
3
4
2.5 rg/kg/d, 5 d (11)
2.5 pg/kg/d, 10 d (12)
39
27-64
39
2 1-57
32
17-55
33
25-54
27
10
11
0
6
6
7
4
3
0
20
5
6
7
5
5
6
3
0
2.0
0.9-3.5
1.9
0.9-3.3
2.2
1.l-3.5
2.0
1.1-2.8
1.4
1.2-1.4
HD (11) NHL (5)
HD ( 0 ) NHL (10)
HD (5) NHL (4)
HD (1) NHL (1)
HD ( 6 )NHL (2)
HD ( 0 ) NHL (3)
0
HD (2) NHL (1)
HD ( 0 ) NHL (1)
HD (3) NHL (3)
HD (1) NHL ( 0 )
0
HD ( 0 ) NHL (2)
HD ( 0 ) NHL (1)
0
12
0-24
12
5-23
15
3-24
12
0-15
17
0
had NHL and 17 patients had HD. A summary of patient
demographic and disease characteristics by rhIL-3 study
group is shown in Table 1. The Karnofsky performance score
(KPS) listed in Table 1 was determined on day 0 after the
cytotoxic treatment regimen was administered and ranged
from 50% to 100%. Treatment regimens consisting of either
high-dose etoposide, cyclophosphamide and BCNU; highdose etoposide, cyclophosphamide, and total body irradiation(TBI); high-dose etoposide, cisplatin, and BCNU; or
high-dose carboplatin and thiotepa were administered to 16,
10, 9, and 2 patients, respectively.
Safety and tolerability. Overall, the most common
( 2 5 0 % of patients) adverse events in the study were nausea
(97%), fever (97%), diarrhea (92%), mucositis (83%), vomiting (78%), rash (75%), edema (72%), chills (a%),
abdominal pain @g%),and tachycardia (50%). It was difficult to
determine in every instance whether these events were related to underlying disease, to the transplantation procedure,
or to the drugs used in the study. To assess the safety and
tolerability of sequential rhIL-3 and rhGM-CSF and to determine dose-limiting toxicities, if any, the number and percentage of patients with at least one severe adverse event considered to be related or remotely related to study drug was
examined. Overall, 22 patients (59%) had at least one severe
adverse event secondary to any attribution. Eleven of 37
patients (30%) had at least one severe event considered by
11
0-19
the investigator to be possibly or probably related to rhIL-3
and/or rhGM-CSF. Six of 14 patients (43%) in groups 3 and
4 (rhL-3 at 5.0 pgfkgfd for 5 or 10 days, respectively)
had severe adverse events possibly or probably related to
cytokines, in contrast to 5 of 23 patients (22%)in groups 1
and 2 (rhIL-3 at 2.5 pg/kg/d for 5 or 10 days, respectively).
There was a total of 15 severe adverse events in the 11
patients; these events are listed in Table 2.
Frequencies of unique severe events were also tabulated.
For this evaluation, ifa given event occurred more than
once, it was counted as only one unique event. The highest
frequency of severe events both overall and possibly or probably related to cytokines occurred in group 4 (rhIL-3 at 5.0
pgkgld for 10 days).
Table 2. Savore Adv.ru Event. "Possibly" or "Probablr
Attributnble to rhlL-3 or rhGM-CSF
Event
Fever
Musculoskeletal pain
Rash
Chills
Chest pain
Pulmonary edema
Abdominal Dain
No. of Patients (%l
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2154
FAY ET AL
Table 3. Reasonsfor Early Withdrawal (Before Day 42)
IL-3
Treatment
Group
2.5 pgRg,
5d
2.5 &kg.
10 d
5.0 pgikg.
5d
5.0 d w ,
10 d
Days of
Days of
11-3
GM-CSF
Study Day
Withdrawn
5
5
9
HD
NHL
5
10
0
9
12
19
HD
HD
NHL
5
5
5
8
8
4
13 pain Skeletal
13
Chest pain
8
Death
NHL
7
0
Primary
Diagnosis
HD
6
Reason for
Withdrawal
Death
Death
Abdominal
pain
Death
Seven patients were removed from the study before day
42 post-ABMT because of a severe adverse event (3 patients)
or death (4 patients). The 3 patients removed from the study
because ofan adverse event possibly related to cytokines
had chest, skeletal, or abdominal pain at days 13, 13, and
19 post-ABMT, respectively. These 3 patients are among
those listed in Table 2. All 3 patients were receiving rhGMCSF at the time they were removed from the study. Among
the 4 patients who died during the study period, 1 patient
died on day 6 because of sepsis associated with lymphomatous intestinal wall perforation; 1 patient died on day 8 because of respiratory distress and pseudomembranous enterocolitis; 1 patient died on day 9 because of multiorgan failure
secondary to tumor lysis syndrome; and 1 patient died on
day 12 secondary to cardiac and renal failure related to the
cytotoxic treatment regimen. Table 3 lists the reasons for
early patient withdrawal from the study. The patient who
developed cardiac and renal failure had symptoms and signs
of pulmonary edema before ABMT. However, the rhIL-3
was felt possibly to be responsible for the pulmonary edema
by the clinician; consequently, pulmonary edema is listed in
Table 2.
An additional 7 patients died after ABMT. Six patients,
all with advanced lymphoma before transplant, died of progressive lymphoma between 78 and 287 days after transplantation. One patient died of BCNU-related pulmonary
fibrosis at day 88.
Biologic activity. The biologic activity of sequential
rhIL-3 and rhGM-CSF after ABMT wasassessed by examining granulocyte and platelet recovery, as well as platelet
transfusion requirements. There were no differences in granulocyte and platelet recovery after ABMT for HD or NHL
(data not shown). Therefore, blood count recovery data were
pooled for analysis. The median day to engraftment of neutrophils after transplant, defined as a sustained ANC 2 100,
500, and l,OOO/pL, was 11, 14, and 16 days, respectively.
The data for neutrophil recovery to =500/pL are shown in
Fig 1. All patients experienced neutrophil recovery, except
the 4 patients who died during the study period.
The day of platelet engraftment was defined as the first
of 5 consecutive days of an untransfused platelet count that
was 220,OoO/pL. The median time for a sustained platelet
count 22O,OOO/pL was 15 days (Fig 1).
At the end of the study (day 42), 8 patients hadnot
achieved a sustained platelet count 220,0OO/pL; this includes the 4 patients who died during the study period and
4 additional patients who remained dependent on platelet
transfusions beyond day 42. For the remaining 29 patients,
the median number of days that platelet transfusions were
administered was 5 days, with a range of l to 25 days. A
median of 30 U of platelets was transfused (range, 6 to 174)
over the course of the study. Thirty-three patients were alive
and RBC transfusion-independent by day 42. The median
number of days that RBC transfusions were administered
was 4. The median number of packed RBC units transfused
was 6.
The median number of days of hospitalization for all patients (n = 37) was 22.
Excluding the 4 patients who died before day 42, 33 patients were evaluated for serious infectious complications
after transplantation. Five patients (15%) experienced bacteremia betweenday -5 and day 22. Four of these patients
had bacteremia with gram-positive cocci and 1 patient had
gram-negative bacteremia. There were no serious fungal or
viral infections.
Twenty-one patients (57%) experienced a complete (12
patients) or partial (9 patients) response after transplantation
when restaged by day 42. Seven patients had stable disease
and 3 patients had progressive disease. Staging studies were
not available on 2 patients and 4 patients died early, so their
disease status was unknown. Currently, there are 26 patients
(70%) who are alive between 10 and 19 months after transplantation.
DISCUSSION
The primary objective of this trial was to estimate the
optimal dose and schedule of rhIL-3 and rhGM-CSF after
ABMT. We selected four different rhIL-3 dose schedules
followed by rhGM-CSF that were felt likely to be safe and
tolerable for patients undergoing marrow transplantation.
The dose and route of administration of rhGM-CSF in our
trial was the same as that reported by others in ABMT for
lymphoma except it was administered after an initial treatment with rhIL-3.3
There are abundant in vitro marrow culture and preclinical
animal data indicating substantial enhancement of multilineage hematopoiesis with the sequential administration of
rhIL-3 and rhGM-CSF.4311
The hematopoietic effect of the
sequential combination of these cytokines presumably is related to enhanced proliferation of cellular elements early in
the hematopoietic lineage by rhIL-3, followed by further
proliferation and differentiation of hematopoietic progenitors
by rhGM-CSF. The design of this trial attempts to take advantage of the hematologic effects of sequential rhIL-3 and
rhGM-CSF.
Preliminary data are emerging from clinical studies of
rhIL-3 administered to patients alone or in combination with
rhGM-CSF after cytotoxic chemotherapy for neoplastic diseases. These studies suggest enhanced recovery of both neutrophil and platelet production without serious adverse ef-
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2155
SEQUENTIALIL-3/GM-CSF IN ABMT
100
75
r'
_ ...................
ANC
"
..........
500
.......................
25
Fig 1. Time to neutrophil and
platelet recovery (n = 37). The
median number of daysto recovery for ANCand platelets was 14
and 15, respectively.*Transfusion-independent.
1-J
.......................................................
B
4
ANC: 14days
.............................................................................................
"
0
0
10
fects from either rhIL-3 or the sequential combination of
rhIL-3 and rhGM-CSF.21-26
All four regimens of rhIL-3 followed by rhGM-CSF were
reasonably well-tolerated, with noconsistent toxicities attributable to rhIL-3. Only 3 patients were removed early from
the trial because of skeletal, chest, or abdominal pain. These
patients were receiving rhGM-CSF at the time these symptoms developed. Other clinical trials using rhIL-3 or rhGMCSF after ABMT have reported such toxicities as low-grade
fever, myalgias, headaches, skeletal pain, nausea, and diarrhea.'2.'3'27Patients who receive high-dose cytotoxic therapy
and ABMT commonly have similar symptoms and assigning
a relationship to rhIL-3 and rhGM-CSF may not be possible.
Nevertheless, 6 of 14 patients (43%) who received 5.0 pg/
kg/d of rhIL-3 had at least one severe adverse event considered by the investigator to be probably or possibly related
to rhIL-3 and/or rhGM-CSF. However, this was true for only
5 of 23 patients (22%) who received the 2.5 pg/kg/d dose of
rhIL-3. There were too few patients in the trial to determine
statistical differences in frequency of severe adverse events
between the rhIL-3 groups.
BM recovery after ABMT was similar in all four sequential cytokine study groups. No patients have developed marrow failure with follow-up ranging between 9 and 16 months
from transplant. Too few patients in this study were entered
in each rhIL-3 study group to show statistically significant
differences in hematopoietic recovery. However, to estimate
the potential benefit of sequential rhIL-3hhGM-CSF after
ABMT, marrow recovery data were pooled from all four
rhIL-3 subgroups for purposes of comparison to published
experience without cytokines and with rhGM-CSF, rhGCSF, or rhIL-3 a10ne.3.'2*28.29
Table 4 compares the median
37
studv)
day of neutrophil and platelet recovery after intensive
cytotoxic therapy, ABMT, and treatment with sequential rhIL-3
20
30
50
40
Study Day
and rhGM-CSF with the median day of neutrophil and platelet recovery when nocytokines are administered or treatment
with rhGM-CSF, rhG-CSF or rhIL-3 alone is administered.
In our study, the median day to an ANC 2500/pL was
14, and to an ANC 2 l,OOO/pL was 16. This finding is similar
to the granulocyte recovery after ABMT and rhG-CSF monotherapy and may be faster than that seen after rhGM-CSF
or rhIL-3 alone. In addition, serious bacterial infections were
uncommon in our trial and there were no systemic fungal
or viral infections.
Platelet recovery after transplantation and combination cytokine therapy was prompt. The median time for a sustained
platelet count 220,0OO/pL was 15 days after transplantation.
Patients required a median of five platelet transfusions after
marrow transplant. These data indicate substantial enhancement of thrombopoiesis after ABMT using sequential rhIL3 and rhGM-CSF and represent significant hastening of
platelet recovery compared with ABMT followed by rhGMCSF, rhG-CSF, or rhIL-3 m ~ n o t h e r a p y . ~ ~ 'Indeed,
~*~**~~
platelet recovery after ABMT and sequential rhIL-3 and
Table 4. Median Neutrophil and Platelet Recovery Altar ABMT and
Cytokine Therapy for Lymphoid Malignancies
Cytokine Therapy
None3
33
GM-CSF3
G-CSFB
lL-3'2
IL-3 GM-CSF
(current
No. of
Patients
63
65
15*
30
Median Day
to ANC
2 1.000/pL
Median Day
to Platelets
~2o.ooo/pL
26
13
24
29
26
33
27
16
15
+
* Two patients had germ cell tumors.
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2156
FAY ET AL
rhGM-CSF in this trial is comparable to that reported with
rhG-CSF-primed peripheral blood progenitor cell transplantation after similar intensive cytotoxic therapy for
lymph~ma.’~~’’
Given that the number of hematopoietic progenitor cells in an autologous marrow graft are substantially
fewer on average than obtained with collections of cytokine
primed peripheral blood cells, platelet recovery after ABMT
and treatment with sequential rhIL-3 and rhGM-CSF is especially impressive.”
RBC recovery using sequential rhIL-3 and rhGM-CSF
may be enhanced compared with results seen with ABMT
and no cytokine or rhGM-CSF monotherapy. The median
number of units of RBCs transfused after transplantation in
our study was 6, compared with 8 U after rhGM-CSF or 10
U with placebo.’ However, more data with sequential rhIL3hhGM-CSF are necessary before final judgement on RBC
recovery can be made with certainty.
There has been no indication that the antitumor response
seen with the transplant therapy has been abrogated in any
way because of the administration of sequential rhIL-31
rhGM-CSF. However, further follow-up is necessary.
Sequential administration of rhIL-3 and rhGM-CSF after
BM ablative treatment for lymphoma and ABMT appears to
stimulate multilineage hematopoiesis. When compared with
historical control studies, granulocyte and platelet recovery
appear more rapid compared withABMT followed by
rhGM-CSF or rhIL-3 monotherapy. Platelet recovery appears more rapid compared with that seen with G-CSF after
ABMT. Indeed, the platelet recovery seen with sequential
rhIL-3 and rhGM-CSF is comparable to that reported after
cytokine-primed peripheral blood progenitor cell transplantati~n.~”’’
rhIL-3 treatment at 2.5 pgkgld may be better
tolerated than 5.0 pg/kg/d; too few patients were treated
for determination of statistical differences. It is likely that
additional patients treated with adose of 5.0 pg/kg/d of rhIL3 sequentially with rhGM-CSF would result in significant
unacceptable toxicity. Although there were no apparent differences in patient tolerability between the 5- and 10-day
schedule of rhIL-3 at 2.5 pg/kg/d, we feel that the longer
rhIL-3 schedule may have greater potential to enhance trilineage hematopoiesis when combined with rhGM-CSF after
ABMT. Longer follow-up will be required for assessment
of the effects of sequential rhIL-3 and rhGM-CSF on the
overall survival of patients who receive ABMT therapy for
refractory lymphoma. A prospective randomized clinical
trial to determine whether sequential rhL-3 and rhGM-CSF
is better than rhGM-CSF alone after marrow transplantation
is ongoing.
ACKNOWLEDGMENT
The authors thank Betty Webb, Aggie Mejia, and Betsy Stein for
their expert assistance in preparation of the manuscript; Diana Wilson for data collection; and Laura Connolly, Katie Harding, Jules
Howell, and Norma Sasso for data monitoring.
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1994 84: 2151-2157
Sequential administration of recombinant human interleukin-3 and
granulocyte-macrophage colony-stimulating factor after autologous
bone marrow transplantation for malignant lymphoma: a phase I/II
multicenter study
JW Fay, H Lazarus, R Herzig, R Saez, DA Stevens, RH Jr Collins, LA Pineiro, BW Cooper, J
DiCesare and M Campion
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