Intensive chemotherapy with mitoxantrone and high-dose cytosine

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1992 79: 876-881
Intensive chemotherapy with mitoxantrone and high-dose cytosine
arabinoside followed by granulocyte-macrophage colony-stimulating
factor in the treatment of patients with acute lymphocytic leukemia
HM Kantarjian, EH Estey, S O'Brien, E Anaissie, M Beran, MB Rios, MJ Keating and J Gutterman
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Intensive Chemotherapy With Mitoxantrone and High-Dose Cytosine
Arabinoside Followed by Granulocyte-Macrophage Colony-Stimulating Factor in
the Treatment of Patients With Acute Lymphocytic Leukemia
By Hagop M. Kantarjian, Elihu H. Estey, Susan O‘Brien, Elias Anaissie, Miloslav Beran, Mary Beth Rios,
Michael J. Keating, and Jordan Gutterman
Thirty-four adults with refractory acute lymphocytic leukemia received salvage therapy with mitoxantrone 5 mg/m2
intravenously over 1 hour daily for 5 days and cytosine
arabinoside (ara-C) 3 g/m2 intravenously over 2 hours every
12 hours for six doses, followed by granulocyte-macrophage
colony-stimulating factor (GM-CSF) 125 pg/m2intravenously
over 4 hours daily until recovery of granulocytes above 2.0 x
10a/pL.Their outcome was compared with 29 prognostically
similar historical control patients treated with the identical
chemotherapy without GM-CSF. Overall, the complete response rates were similar in the treatment and control
groups (13 of 34 [38%] v 11 of 29 [38%]). There was a trend for
less remission induction mortality in the GM-CSF-treated
patients (2 of 34 [6%] Y 6 of 29 [21%]; P = .08), but, con-
versely, a higher rate of resistant disease (19 of 34 [56%] v 10
of 29 [34%]; P = .09). Recovery of granulocyte counts above
500/pL was significantlyfaster in the GM-CSF-treated group
(25 days Y 33 days; P < .Ol), but there was no reduction in
the incidence of febrile episodes (91% v 93%) or of documented infections (59% v 59%). Survival was prolonged in
the GM-CSF-treated patients but was not of clinical relevance (31 Y 20 weeks; P = .05). In summary, the addition of
GM-CSF to intensive chemotherapy in refractory adult ALL
was associated with a reduction in the remission induction
mortality, probably secondary to a shorter duration of granulocytopenia, but not with an improvement in complete
response rates.
0 1992 by The American Society of Hematology.
I
cyte-macrophage colony-stimulating factor (GM-CSF)
after mitoxantrone and high-dose ara-C intensive chemotherapy in adult ALL would achieve reductions in myelosuppression and its associated complications. Our findings are
summarized in this report.
MPROVEMENT in the prognosis of patients with acute
lymphocytic leukemia (ALL) has resulted from the
introduction of chemotherapeutic agents with different
mechanisms of actions, and from the use of these agents in
intensification regimens.’.’ Intensification therapies have
included high doses of cytosine arabinoside (ara-C), etoposide, cyclophosphamide, and asparaginase?s829
In pediatric
ALL’,* and, to a lesser extent, in adult ALL, such approaches have improved the cure fractions in different
subsets of patients?.’ These programs are generally tested
in the salvage setting to assess efficacy and toxicity before
their incorporation into the frontline induction-maintenance programs.
We have previously conducted serial studies of high-dose
ara-C and mitoxantrone, first alone and later in combination, in adults with refractory ALL,’’-’’ and observed complete response (CR) rates of 20% to 40%. With the
high-dose ara-C-containing regimens, significant morbidity
and mortality related to myelosuppression were obThe addition of growth factors to intensive chemotherapy
regimens in patients with solid and hematologic malignancies13-19 has been reported to reduce the intensity and
duration of granulocytopenia, myelosuppression-related
morbidity and infections, and hospitalization.
In this study, we investigated whether the use of granulo-
From the Departments of Hematology, Infectious Diseases, and
Clinical Immunology and Biological Therapy, University of Texas
M.D. Anderson Cancer Center, Houston, TX 77030.
Submitted August 12,1991; accepted October 8,1991.
Address reprint requests to Hagop M. Kantajian, MD, M.D.
Anderson Cancer Center, Department of Hematology, Box 61, 1515
Holcombe Blvd, Houston, TX 77030.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C.section 1734 sole& to
indicate this fact.
Q 1992 by TheAmerican Society of Hematology.
0006-4971/92/7904-0008$3.00/0
876
MATERIALS AND METHODS
Study popularion. Thirty-four patients with refractory ALL
were treated between May 1989 and April 1991. Informed consent
was obtained according to institutional guidelines. Criteria for
entry were (1) the presence of 30% or more blasts in the bone
marrow or more than 10 x lo) circulating blasts/kL in the
peripheral blood; (2) a performance status of 0 to 2 on Zubrod
scale; and (3) normal hepatic and renal functions. Work-up at
presentation included history and physical examination; documentation of the extent of disease; complete blood counts (CBC),
platelet and differential; SMA12 with liver and renal function
studies; bone marrow aspiration and biopsy, morphology and
histochemical and enzymatic stains; and cytogenetic studiesm A
diagnosis of ALL required confirmation by morphology, negative
peroxidase, and positive terminal deoxynucleotidyl transferase
(TdT) and/or common acute lymphocytic leukemia antigen
(CALLA). Immunophenotyping and electron microscopic studies
were confirmatory and were used in the diagnostic evaluation of
difficult cases.
Therapy. Induction chemotherapy consisted of mitoxantrone 5
mglm’ intravenously over 1hour daily for 5 days, and ara-C 3 glm’
intravenously over 2 hours every 12 hours for 6 doses. GM-CSF was
started 24 hours after chemotherapy was completed at 125 pglm’
over 4 hours daily until the recovery of granulocytes above 2.0 x
lO’/pL. A second course was administered at the same dose
schedule in patients who did not obtain a CR after the first course,
and who did not have prohibitive toxicities. Timing of the second
course depended on the serial evaluation of marrow studies, and
on the general condition of the patient. Subsequent maintenance
therapy included one more consolidation course, followed by
maintenance with 6 mercaptopurine 50 mg orally three times daily
and methotrexate 20 mg/m2weekly.
Historical control population. The results of this study were
compared with those observed in 36 patients with refractory ALL
treated in the immediate previous period (March 1985 and April
1989) with the same mitoxantrone and high-dose ara-C schedule
but without GM-CSF. The entry criteria on both studies were the
Blood, Vol79, No 4 (February 15), 1992: pp 876-881
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CHEMOTHERAPY
+ GM-CSF IN ALL
877
same, except for the inclusion of patients with any performance
status. Seven patients with Zubrod performance 3 or 4 who were
treated in the historical control group were excluded from this
analysis. Thus, 29 patients from the historical control group were
included in the comparative analysis.
Patients in the historical control group received similar supportive care therapy (platelets, red cells, antibiotic regimens) as the
study population. Data on both studies were collected and evaluated by the same investigators (H.M.K. and M.B.R.). Techniques
for the evaluation of febrile episodes and documenting infections
were identical and reviewed by the same investigators (H.M.K.,
E.A., and M.B.R.). A febrile episode was defined as a temperature
of 3S3”Cor above, uncorrelated to transfusions and lasting for at
least 2 hours.
Response criferia. CR was defined as 5% or less blasts in a
normocellular or hypercellular bone marrow with normal peripheral and differential counts, including a granulocyte count greater
than 1,50O/p,L and a platelet count greater than 100 x 103/p,Lfor
at least 1 month.’l Partial remission (PR) required similar criteria
except for the presence of 6% to 25% marrow blasts. Patients
failing induction therapy were categorized as (1) early death if they
expired within 2 weeks from the start of therapy; (2) death during
induction if they expired 2 weeks or later while receiving induction
therapy; or (3) resistant if they survived induction but regrew with
resistant leukemia. Primary resistance was defined as persistence
of a marrow leukemic infiltrate (MLI = marrow blast percent X
cellularity) of 20% or more during therapy. Secondary resistance
was defined as a reduction of the MLI to less than 20% with
subsequent leukemia regrowth.
Statistical methods. The x2 test was used to compare differences
among variables in the two groups. Survival after salvage therapy
was measured from the date of start of treatment and CR duration
was measured from the date of remission until documented
relapse. Survival and remission duration curves were plotted by the
method of Kaplan and Meier.” Differences among curves were
compared by the modified Wilcoxon testU and by the log-rank
test.” For the times to recovery of granulocytes and platelet counts,
patients dying or changed to alternative therapy because of
leukemic growth before attaining the desired counts were censored
at the time of death or initiation of alternative therapy.
RESULTS
The characteristics of the 34 patients entered on study
and of the 29 patients in the historical control group are
detailed in Table 1. Patients in the treatment group were
older, but other characteristics were similar among the two
populations (Table 1).
Response. Overall, 13 patients (38%) achieved CR with
intensive chemotherapy followed by GM-CSF, two (6%)
died during remission induction with hypoplastic marrows,
and 19 (56%) had resistant disease. The CR rates were the
same in the treatment and historical control groups (Table
2). However, patients receiving chemotherapy and GMCSF had a lower incidence of induction mortality (excluding early deaths) compared with those receiving chemotherapy alone (6% v 21%;P = .08), but had a higher incidence
of resistant disease (56% v 34%; P = .09).
The CR durations were not significantly different (median CR durations 31 weeks in the study population versus
17 weeks in the historical control group; P = .9; Fig 1).
Short-term survival was significantly longer in the study
population (31 weeks v 20 weeks; P = .05 by modified
Wilcoxon test), although the difference was not significantly
relevant from the clinical standpoint and in terms of overall
survival (P= .3 by log-rank test; Fig 2).
To test if there were imbalances in prognostic factors
between the two groups, we first investigated whether any
variable affected CR rate or survival in the combined study
and historical groups and then checked whether that
variable was similarly distributed in the two groups. Only
performance status was associated with significantly different CR rates (P= .05) and a trend for different survivals
Table 1. Characteristicsof the Study Population and of the Historical Control Group
No. of Patients (%)
Characteristic
Age (yr)
Median age (yr)
Performance status (Zubrod scale)
Hemoglobin (g/dL)
WBC ( X ~ O ~ / ~ L )
Platelet count ( x 103/bL)
Albumin (g/dL)
Lactic dehydrogenase (U/L)
Karyotype
Salvage status
Diagnosis to therapy (mo)
Duration of first remission (mo)
Category
t 40
0-1
2
5 10
> 20
I50
53.5
t 450
Diploid
Ph
IM
Other
First
Second
Third or more
s6
26
<6
>6
Study Population
(N = 34)
Historical Control
(N = 29)
11 (32)
31
27 (79)
3 (10)
24
23 (79)
7 (21)
19 (56)
6 (18)
16 (47)
17 (50)
18 (53)
10 (30)
7 (21)
7 (21)
10 (30)
19 (56)
9 (26)
6 (18)
17 (50)
17 (50)
11 (32)
23 (68)
6 (21)
14 (48)
6 (21)
12 (41)
8 (28)
17 (59)
7 (24)
4 (14)
5 (17)
13 (45)
16 (55)
7 (24)
6 (21)
9 (31)
20 (69)
12 (41)
17 (49)
PValue
Abbreviations: Ph, Philadelphiachromosome-positive; IM, insufficient metaphases; NS, not significant; WBC, white blood cell count.
.04
NS
NS
NS
NS
.07
NS
NS
NS
.13
NS
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878
KANTARJIAN ET AL
I nn
Table 2. Responseto Mitoxantrone and High-Dose ara-C With or
Without GM-CSF in the Treatment and Historical Control Groups
No. of Patients (%)
Study
Population
(N = 34)
Response
CR
13 (38)
-
Early death
Aplastic death
Historical
Control
(N = 29)
1 1 (38)
2 (7)
] 6%
al
PValue
NS
$
-
60
al
E
n
(”)) 21%
3 (10)
Death > 20% leukemia infiltrate Secondary resistance
l8 (53)156% 10 (34))34%
1 (3)
Primary resistance
2(6)
80
40
.08
.09
20
0
(P = .08), and this variable was equally distributed between
the two groups. Age, on the other hand, had no significant
associations with either response rate or survival (Table 3).
Hematologic recovery after chemotheramand myelosuppression-associated complications. Hematologic recovery was
compared after the first course of therapy in both groups.
All 63 patients in both the study population and historical
control had a lowest granulocyte count of less than 1OO/pL
after therapy. Recovery of the granulocytic series was
significantly faster among patients treated with GM-CSF
after intensive chemotherapy. In the study population, the
number of days to recovery of granulocytes above 0.5 x
103/pL was 25 days, compared with 33 days for the
historical control group (Fig 3; P = .005). However, the
number of days to recovery of platelets was not significantly
different (Fig 4; P = .17).
Febrile episodes and documented infections during the
first course occurred with similar frequency in both groups,
despite the shorter duration of granulocytopenia among
patients treated with GM-CSF after intensive chemotherapy. Table 4 lists the distribution of the most serious febrile
events during chemotherapy. Eleven patients (32%) in the
study group and seven patients (24%) in the historical
control group developed more than one febrile episode
(mean number of febrile episodes per course 1.26 and 1.17,
respectively). All 10 patients who died during remission
induction had major infectious episodes causing death:
disseminated fungal infections in seven patients (Candida,
0
26
DISCUSSION
In this study, adults with refractory ALL received GMCSF as a supportive care measure after intensive chemotherapy with mitoxantrone and high-dose ara-C. The results,
compared with those of a historical control group of
patients who received the identical chemotherapy regimen
Table 3. Factors Influencing Responseand Survival (63 Patients)
No.of CR/
Total
Patients
Characteristic
Performance (Zubrod)
Hemoglobin (g/dL)
Category
<40
240
0
1-2
110
I
b3
a
WBC ( x 1 0 3 / ~ ~ )
60
.-c
s
c
Platelet count (x103/pL)
40
E
Albumin (g/dL)
n
20
Lactic dehydrogenase (U/L)
First CR duration (mo)
0
0
26
52
78
104
130
Remission Duration (Weeks)
Fig 1. Durationof CR in the (---) study population (7 of 13 relapsed)
and the (-) historical control group (8 of 11 relapsed) (P = .91).
130
5 patients; candida and aspergillus, one patient; Rhodotorula rubra, one patient) and bacterial infections or pneumonia in three patients.
other side-effects. The incidence of nonhematologic sideeffects was similar among patients receiving intensive chemotherapy alone or followed by GM-CSF (Table 5). In
particular, in this population of patients with adult ALL,
the development of complications such as hypotension,
cardiopulmonary complications, fluid retention, and hypoalbuminemia with GM-CSF therapy was rare.
Age (yr)
80
104
Fig 2. Survival duration in the (---) study population (26 of 34
failed) and the I-) historical control group (25 of 29 failed). P = .05
(Gehan = Breslow); P = .31 (log-rank).
100
s
78
52
Survival from Start of Therapy (Weeks)
Salvage attempt
>10
120
>20
150
>50
1 3.5
> 3.5
<450
2450
<6
26
(%)
PValue
16/49(33) .30
8/14(57)
8/13(61) .05
16/50(32)
12/33(36) .76
12/30(40)
21/51 (41) .30
3/12(25)
9/28(32) .38
15/35(43)
9/25(36) .78
15/38(39)
14/28(50) .08
10/35(29)
14/35(40) .73
10/28(36)
11/35(31) .22
First
Second
or more 13/28(46)
Median
Survival
P
(wk)
Value
21
30
33
17
24
20
26
.27
.08
.77
.52
20
22
24
.78
20
.41
30
19
.16
20
18
29
19
23
.48
25
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CHEMOTHERAPY
100
+ GM-CSF IN ALL
a79
Table 4. Incidence of Febrile Episodes and of Documented Infections
During the First Course of Chemotherapy With or Without GM-CSF
--I
No. of Patients (%)
dO
nl
c
5
I
60
n
Episode
c
Febrile episodes
Fever of unknown origin
Documented infection
Bacterial
Pneumonia
Pneumonia sepsis
Fungal
Viral
Bleeding
c
5
:
40
n
20
, !
,
without subsequent GM-CSF therapy, showed (1) a significantly decreased duration of granulocytopenia without a
reduction in the incidence of febrile episodes and documented infections; (2) a trend for a lower induction
mortality rate but, conversely, a higher incidence of resistant disease which (3) led to similar CR rates and (4) a
statistically significant prolonged short-term survival.
GM-CSF therapy was associated with a reduction in the
incidence of induction mortality, but not with an increased
CR rate. Thus, patients at high risk of induction mortality
may also have a more resistant disease that would manifest
itself if they recover from their myelosuppression. Prolonged myelosuppression and consequent induction mortality in such patients may be from the leukemia-inhibitory
effect exerted by the residual leukemia on the normal stem
cells. GM-CSF therapy, by enhancing normal hematopoietic recovery and preventing mortality, unmasks the natural
course of these patients, ie, recovery with leukemia. This
would thus produce, as seen in this study, improved
short-term survival, but little effect on CR duration or
long-term prognosis.
nn
I vv
80
m
c
-al
5
P
Historical
Control
(N = 34)
(N = 29)
31 (91)
1 1 (32)
20 (59)
14 (41)
27 (93)
+
---I
4
Study
Population
60
2 (6)
While the duration of granulocytopenia was reduced, this
did not translate into a lower incidence of febrile episodes
or documented infections. This observation is not peculiar
to this study but has also been noted in the setting of
patients with solid tumors receiving very intensive chemotherapy followed by GM-CSF with or without autologous
stem cell infusions.25Most febrile episodes and infections
occur early in the period of granulocytopenia, and are as
related to the intensity of granulocytopenia as to its
duration. By shortening the duration of granulocytopenia,
GM-CSF therapy was not capable of reducing the incidence
of febrile episodes or infections (possibly an indication of
the intensity of granulocytopenia), but reduced their severity as measured by the mortality rate (possibly more related
to the duration of severe granulocytopenia).
The effects of growth factors as a supportive treatment
after intensive chemotherapy depend on the intensity and
the duration of myelosuppression. Factors affecting these
two variables are (1) the tumor type (solid versus hematologic malignancies); (2) the quality of the bone marrow or
normal stem cell pool (prior chemotherapy or irradiation or
marrow involvement by tumor, particularly in leukemia);
(3) the intensity of chemotherapy (marrow suppressive
versus ablative); and (4) whether normal (autologous or
allogeneic) stem cells are reinfused after chemotherapy/
irradiation. Better results with growth factors may be
achieved with less intensive regimens, with intact bone
marrow, and with reinfusion (of large amounts) of stem
cells after high-intensity chemotherapy. Studies that have
shown reductions in the incidence of febrile episodes and of
Table 5. Other Side-Effects Associated With Intensive
Chemotherapy With or Without GM-CSF Supportive Care
c
5
No. of Patients
40
g
Historical
Diarrhea
Mucositis
Neurotoxicity
5 (15)
5 (17)
3 (10)
1 (3)
Cardiotoxicity
Pulmonary toxicity
Chest pain
Lowest albumin level less than 2 g/dL
l(3)
2 (6)
1 (3)
1 (3)
20
Toxicity
0
14
28
42
56
Days to Platelets Recovery Above 30x1Oa/pl
Fig 4. Days to recovery of platelets above 30 x lO'/pL in the (---)
study population (n = 34) and the (-)historical control group (n = 29)
(P = .17).
(Oh)
Study
Population
(N = 34)
n
3 (9)
-
Control
(N = 29)
-
1(3)
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KANTARJIAN ET AL
documented infections have generally also shown reduction
in the intensity as well as the duration of granulocytopenia.
These studies have used less intensive regimens compared
with those used in hematologic neoplasms, and were
generally in the setting of patients with solid tumors and/or
normal bone marrows.’6~17~26
A concern with the introduction of growth factors as
supportive measures in patients with cancer was the possible potentiation of tumor growth. This was particularly
important in the setting of myeloid leukemia, in which
leukemic cells may share properties with normal stem cells.
In our study in patients with ALL, the achievement of a
favorable response rate and lowering of induction mortality
suggests that the use of GM-CSF is safe in this tumor, and
that a beneficial effect may be achieved with its addition to
chemotherapy in earlier stages such as remission induction
of newly diagnosed ALL, or as part of maintenance-
intensification in remission, when significant morbidity
and/or mortality is expected.
Finally, some of the side-effects of growth factor therapy
may be disease associated. In a parallel study in patients
with transformed phases of chronic myelogenous leukemia
(CML) treated with a similar intensive chemotherapy
regimen followed by the same dose schedule of GM-CSF,
we observed a higher incidence of complications. Among 48
patients treated, the incidences of hypotension (21% v O%),
cardiopulmonary problems (19% v 9%), fluid retention
(19% v O%), and development of hypoalbuminemia less
than 2 g/dL (19% v 3%) were drastically different from
those observed in this ALL study. CML transformation has
been associated with the production of cytokines such as
interleukin-1, interleukin-6, and others” that could synergize with GM-CSF (or other growth factors) to enhance the
development of certain toxicities.
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