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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2471-2477
Filgrastim for Cladribine-Induced Neutropenic Fever in Patients
With Hairy Cell Leukemia
By
Alan Saven,
Carol Burian,
Jasvant Adusumalli, and
James A. Koziol
From the Division of Hematology/Oncology, Ida M. and Cecil H. Green
Cancer Center, Scripps Clinic, La Jolla, CA; and The Scripps Research
Institute, La Jolla, CA.
 |
ABSTRACT |
Cladribine treatment of hairy cell leukemia (HCL) is complicated by
neutropenic fever in 42% of patients despite documented infections
being relatively uncommon. We performed a study of priming filgrastim
followed by cladribine and then filgrastim again to determine if
filgrastim would lead to a reduction of neutropenia and febrile
episodes. Thirty-five patients received filgrastim and cladribine and
were compared with 105 historic controls treated with cladribine alone.
Cladribine was administered at 0.1 mg/kg/d by continuous infusion for 7 days. Filgrastim was administered at 5 µg/kg/d subcutaneously on days
 3, 2, and 1 and then again after the completion of cladribine
until the absolute neutrophil count (ANC) was  2 × 109/L on 2 consecutive days (days +8, +9, etc). After
filgrastim priming, the median ANC increased from 0.9 × 109/L to 2.26 × 109/L (2.5-fold
increase), and after cladribine, the median nadir ANC in the
filgrastim-treated group was 0.53 × 109/L compared with
0.29 × 109/L among historic controls (P = .04). The median number of days to an ANC greater than 1.0 × 109/L was 9 days in the filgrastim-treated group
versus 22 days among historic controls (P < 10 5). The percentage of febrile patients, number of
febrile days, and frequency of admissions for antibiotics were not
statistically different in the two groups. Filgrastim regularly
increases the ANC in patients with HCL and shortens the duration of
severe neutropenia after cladribine. This phase II study, with
comparison to historical controls, failed to detect any clinical
advantage from the use of filgrastim and cladribine in the treatment of
HCL. Accordingly, the routine adjunctive use of filgrastim with
cladribine in the treatment of HCL cannot be recommended.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HAIRY CELL LEUKEMIA (HCL) is an uncommon
chronic B-cell lymphoproliferative disorder whose defining features are
the presence of mononuclear cells displaying cytoplasmic projections and the typical pattern of infiltration both in the bone marrow and
spleen.1 Single courses of cladribine
(2-chlorodeoxyadenosine [2-CdA]; Leustatin; Ortho Biotech, Raritan,
NJ), a purine nucleoside analog, induce complete and long-lasting
remissions in the vast majority of HCL patients.2-5 Of 349 evaluable patients treated at Scripps Clinic with a single course of
cladribine administered at 0.1 mg/kg/d by continuous infusion for 7 days, the overall response rate was 98%, with 91% complete
responses.4 In this report from Scripps Clinic, the
administration of cladribine to patients with HCL resulted in a high
frequency of drug-induced severe neutropenia and neutropenic fever,
although documented infections were relatively uncommon. After the
administration of cladribine, 71% of patients experienced grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 × 109/L), and 42% of patients developed neutropenic fever
that frequently resulted in the need for hospitalization, because these
febrile patients are often ill-appearing, with chills, headache,
myalgias, anorexia, and malaise. Nevertheless, only 13% of patients
had documented viral or bacterial infections, and there were no acute fungal infections. The fever generally responded well to antipyretics such as acetaminophen and usually resolved within 3 to 5 days. A
similar incidence of neutropenic fever has been documented in studies
conducted with cladribine in patients with HCL at other institutions.6-8
The empiric institution of broad-spectrum antibiotics is the
cornerstone of the initial management of chemotherapy-induced febrile
neutropenic cancer patients. An ANC less than 0.5 × 109/L is considered the single most significant risk factor
for infection.9 The other factors that alter this risk
include the magnitude of neutropenia, the duration of neutropenia,
phagocyte function, the status of the patient's cellular and humoral
immune system, alterations of physical defense barriers, and the
patient's endogenous microflora.10 There is a striking
decrease in the incidence of infection when the neutrophil count
increases from less than 0.1 × 109/L to greater than
0.5 × 109/L.11
Although documented infections in HCL patients after cladribine
treatment are relatively infrequent, given the severity of the
neutropenia and the pyrexia the standard of care in such patients is to
initiate empiric broad spectrum intravenous antibiotics while extensive
efforts are made to exclude infection. Considerable expense and
inconvenience are thus incurred by these patients. Antibiotic-induced
toxicity and nosocomial disease are potential risks. Although the
precise mechanism of the neutropenic fever has not been defined, the
release of interleukin-1, tumor necrosis factor- , and other
cytokines into the circulation during cell lysis or even occult
infections may possibly play a significant role.
Recombinant human granulocyte colony-stimulating factor (G-CSF;
filgrastim) has previously been shown to be safe in the treatment of
neutropenia accompanying HCL and to regularly increase neutrophil counts.12 Given that the fever universally occurs in the
presence of severe neutropenia, it is reasonable to postulate that an
agent capable of increasing granulocytes, such as filgrastim, would lead to a reduction in the number of these febrile episodes and thereby
prevent unnecessary hospitalization, expense, and iatrogenic disease.
Also, if the fever occurred in the absence of profound neutropenia, it
would potentially mitigate against hospitalizing these patients.
Accordingly, we performed a study of priming filgrastim followed by
cladribine, and thereafter filgrastim, to evaluate this hypothesis and
compared the results with those of historic controls.
| |
MATERIALS AND METHODS |
Eligibility criteria.
Patients required a diagnosis of HCL based on the peripheral blood
smear and bone marrow as reviewed by the hematopathologist at Scripps
Clinic. In addition, they underwent a confirmatory peripheral blood
immunophenotypic analysis (monoclonal antibodies against the B-cell
antigens CD19, CD20, and CD22 were applied, and coexpression of CD11c,
CD25, and CD103 was evaluated). Neutropenia (ANC <1.0 × 109/L), anemia (hemoglobin <10 g/dL), thrombocytopenia
(platelets <100 × 109/L), symptomatic splenomegaly,
rapidly progressive lymphocytosis, or repeated infections was required
before administering cladribine treatment. There were no age
restrictions. Patients were excluded if they had received treatment
within 4 weeks of cladribine therapy, if they had an active infection,
or if they had abnormal renal or hepatic functions. The study was
approved by the Scripps Clinic Institutional Review Board and written
informed consent was obtained.
Treatment plan.
Patients were treated as outpatients using a computerized ambulatory
drug delivery (CADD) portable infusion pump (Pharmacia Deltec, St Paul,
MN) to deliver the cladribine after insertion of a peripherally
inserted central venous (PICC) catheter. Cladribine was administered at
a dose of 0.1 mg/kg/d by continuous intravenous infusion for 7 days.
Filgrastim (Neupogen; Amgen, Thousand Oaks, CA) was administered to all
patients at 5 µg/kg/d subcutaneously on days 3, 2, and
1 and then again after the completion of cladribine until an ANC
2 × 109/L was achieved on 2 consecutive days (days
+8, +9, etc). Upon discontinuation of the filgrastim, if the ANC
decreased to less than 1.0 × 109/L, then filgrastim
treatment was restarted until the ANC was again 2 × 109/L on 2 consecutive days.
Acetaminophen (650 mg orally every 4 hours) could be taken by patients
in the filgrastim-treated and historic control groups for a temperature
greater than 38.5°C. Acetaminophen could not be taken on a
prophylactic basis or when the temperature was less than 38.5°C.
The use of aspirin or nonsteroidal anti-inflammatory agents was prohibited.
Patients were hospitalized to exclude infection and to receive broad
spectrum intravenous antibiotics when fever (temperature >38.5°C)
occurred in association with an ANC less than 1.0 × 109/L. Antibiotic selection was deferred to the treating
physician. Antibiotics were discontinued if the cultures drawn remained
negative, the patient had been afebrile for 24 hours, and the ANC was
0.5 × 109/L. If the patient remained afebrile off
antibiotics, hospital discharge occurred after a further 24 hours of
observation as an inpatient.
Patient evaluations.
Before the initiation of filgrastim and cladribine, patients underwent
a history and physical examination; a complete blood count with
differential including neutrophil, lymphocyte, monocyte, and hairy cell
counts; a 24-channel chemistry test, including renal and hepatic
functions; bone marrow aspirate and biopsy; peripheral blood
tartrate-resistant acid phosphatase (TRAP) stain; and a peripheral
blood immunophenotypic analysis.
During filgrastim priming on days 3, 2, and 1,
oral temperatures were taken three times daily at 8-hour intervals, and the complete blood count with differential was repeated on days 3 and 0. During cladribine therapy (days 0 to +7) and filgrastim (days +8, +9, etc) thereafter, the physical examination and oral temperature were recorded by the physician on days +3, +6, and +8 for
outpatients and daily for hospitalized patients. Oral temperatures were
recorded by the patient three times daily at 8-hour intervals and with
the onset of suspicious symptoms, eg, subjective fever, chills,
diaphoresis, etc. A complete blood count with differential was obtained
daily during cladribine and at least twice weekly during filgrastim
therapy in all patients. The 24-channel chemistry panel was repeated on
days +3, +6, +8, and +10.
Toxicity.
Toxicities were evaluated using standard criteria.13
Historical controls.
The historic controls underwent the same evaluations and identical
cladribine therapy as did the treated group, but received no neutrophil
colony-stimulating factors. The historic control patients selected were
consecutive patients with HCL treated with cladribine at the Scripps
Clinic between April 1986 and January 1993. The hospitalization
policies in the historic control patients and the filgrastim-treated
group were identical.
Statistical considerations.
Because HCL is a rare disease with only 600 new cases reported annually
in the United States,14 we accepted a phase II study design
that favored accrual of a substantial number of HCL patients to
expeditiously determine whether filgrastim, an expensive and potentially unnecessary intervention as an adjunct to cladribine treatment, results in clinical benefit. Because of the small number of
patients available for study, we asked whether outcomes in unmatched,
historical controls could provide a statistically valid comparison
despite being neither randomized nor blinded.
Only a limited number of patients (n = 35) were treated with filgrastim
in addition to cladribine; it was desired to compare outcomes in these
patients with those of unmatched controls treated solely with
cladribine, drawn consecutively from the Scripps Clinic database of HCL
patients. One method of increasing the power of the experiment for
detecting differences in outcomes is by increasing the number of
controls relative to the filgrastim-treated group. Accordingly, an
unbalanced design with unequal allocation of patients to the two
cohorts was adopted. A 3:1 ratio of controls to filgrastim patients was
chosen as the incremental gain in power that might have been realized
by using even a greater ratio of controls to patients than 3:1 seemed
marginal. Let e denote the effect size for any particular
parameter to be compared, that is, e= |µ1 µ2| / , where µ1 denotes the
mean of that parameter value in filgrastim + cladribine patients,
µ2 denotes the mean of that parameter value in cladribine
patients, and denotes the common standard deviation in the two
populations. Then, a sample size of 35 cladribine + filgrastim-treated
patients and 105 cladribine controls would be sufficient to detect a
clinically significant effect size of 0.4, 0.6, or 0.8 with a power of
0.53, 0.86, or 0.98, respectively, using a standard two-sided
t-test at conventional level = .05.15
Comparisons of univariate outcomes between the two groups were made
with standard (parametric) t-tests and (nonparametric) Mann-Whitney tests for continuous outcomes and Fisher's exact test for
discrete outcomes. Exploratory multivariate procedures were also
undertaken but did not establish any other meaningful differences
between the two groups. The results from the univariate nonparametric
procedures are reported here, because the parametric results were
quantitatively similar. Two-sided P values corresponding to the
observed test statistics are given without correction for the
multiplicity of tests performed.
| |
RESULTS |
Patient demographics.
Thirty-five patients received filgrastim and cladribine and are
compared with 105 historic control patients
(Table 1) who received cladribine alone.
The two groups were generally well balanced, with only spleen size and
prior treatment demonstrating significant differences. There were more
splenectomized patients among the historic controls (P = .03),
and no historic control patients had received prior cladribine
(P < 104).
Blood counts after filgrastim priming and cladribine administration.
The peripheral blood counts after filgrastim priming demonstrated that
the median total leukocyte count increased from 2.3 × 109/L to 3.9 × 109/L, corresponding to an
increase in the median ANC from 0.9 × 109/L to 2.26 × 109/L; this represents a 2.5-fold increase in the
ANC (Table 2). No significant differences
in the hemoglobin concentration or platelet counts were observed.
After the administration of cladribine in the filgrastim-treated group
and among the historical controls, the median nadir total leukocyte
count was 0.8 × 109/L and 0.6 × 109/L and the median nadir ANC was 0.53 × 109/L and 0.29 × 109/L (P = .04),
respectively (Table 2). Again, no significant differences were observed
in the median nadir hemoglobin concentration or platelet counts.
Toxicities Duration of neutropenia, febrile episodes, and
hospitalization.
The median number of days to achievement of an ANC greater than 1.0 × 109/L was 9 days in the filgrastim-treated group
versus 22 days among historic controls (P < 105; Table 3). The
median number of febrile days for all patients in the
filgrastim-treated group was 1 day and was 3 days for only the febrile
patients; the median number of febrile days for all patients in the
historic controls was 3 days and was 6 days for only the febrile
patients (P = .21 and P = .17, respectively). Additional information regarding the severity and duration of neutropenia observed and the proportion of febrile events that occurred
in association with the different levels of neutropenia is also shown
in Table 3. The number of patients at the different levels of nadir
neutropenia and the number of days at these levels of neutropenia were
statistically different between the filgrastim-treated group and the
historic controls. The median number of hospital days, number of
patients admitted, and number of days of intravenous and oral
antibiotics were not statistically different in both groups. The mean
number of admissions and the mean number of hospital days for
neutropenic fever were 0.26 and 3.1 per patient in the filgrastim-treated group and 0.35 and 3.9 per patient in the historic controls, respectively.
The median time for the onset of fever in the filgrastim-treated group
was on day +8 (range, day +1 to day +29) and in the historic controls
was on day +7 (range, day +3 to day +32). Of the 19 febrile patients in
the filgrastim-treated group, the median time for the onset of fever in
18 patients was on day +8 (range, day +1 to day +12); 1 patient
experienced fever on day +29. Of the 47 febrile patients in the
historic controls, the median time for the onset of fever in 44 patients was on day +7 (range, day +3 to day +13); 3 patients
experienced fevers on days +18, +28, and +32. Thus, the fevers tended
to occur early on after cladribine therapy, when patients in both
groups were at their neutrophil nadirs and were unaffected by the
shorter duration of neutropenia in the filgrastim-treated group. This
likely explains why the hospitalization rate was not significantly
different between the two groups, because the incidence of fevers was similar.
Among the 11 patients in the filgrastim-treated group requiring
hospitalization, 1 patient was admitted twice for fever and 2 patients
were admitted for PICC-related complications (1 with negative blood
cultures and 1 patient with Staphylococcus aureus bacteremia).
Among the 45 patients in the historic control group requiring
hospitalization, 1 patient was readmitted for fever and 8 patients were
admitted for nonfebrile indications (2 with dehydration, 1 with
vasovagal syncope, 1 with severe thrombocytopenia [platelets, 3 × 109/L], 1 with pneumonia, and 3 with PICC-related
coagulase-negative staphylococcus cellulitis in the absence of bacteremia).
The same peripheral blood and clinical parameters were evaluated for
patients with a pretreatment ANC less than 1.0 × 109/L and for patients with a pretreatment ANC less than
0.5 × 109/L. For patients with a pretreatment ANC
less than 1.0 × 109/L, the median nadir ANC after
cladribine was 0.45 × 109/L in the filgrastim-treated
group (n = 21) versus 0.14 × 109/L among historic
controls (n = 61; P = .024), and the median number of days to
achieve an ANC greater than 1.0 × 109/L in the
filgrastim-treated group was 9 days versus 27 days among historic
controls (P < 104). For patients with a
pretreatment ANC less than 0.5 × 109/L, the median
nadir ANC after cladribine was 0.04 × 109/L in the
filgrastim-treated group (n = 5) versus 0.06 × 109/L
among historic controls (n = 23; P = .47), and the
median number of days to achieve an ANC greater than 1.0 × 109/L in the filgrastim-treated group was 14 days versus 33 days among historic controls (P = .054). In both groups, the
ANC increased after filgrastim priming, but there was no clear
advantage compared with historic controls for both subgroups in terms
of number of febrile patients, febrile days, patients admitted, or
hospital days.
Responses.
Of the 35 patients in the filgrastim-treated group, 28 (80%) obtained
a complete response, 5 (14%) a partial response, 1 patient was a
nonresponder, and 1 patient had no follow-up data. Of the 105 historical controls, 94 (90%) achieved a complete response, 7 (7%)
achieved a partial response, 2 were nonresponders, and 2 were not
evaluated for response; these response rates are comparable to those
for the filgrastim-treated group (P = .27).
| |
DISCUSSION |
We have previously demonstrated that single courses of cladribine
administered to patients with HCL induced complete and long-lasting responses in the vast majority of patients treated.4 The
major acute toxicity, occurring in 42% of patients, is neutropenic
fever, with documented viral or bacterial infections occurring in 13%. Accordingly, we initiated this study to determine if filgrastim administered before (priming) and after cladribine would ameliorate the
incidence and severity of neutropenic fever. The rationale for the
incorporation of priming filgrastim was twofold: first to determine
what effect filgrastim would have on the absolute neutrophil counts in
patients with HCL, and second by increasing the neutrophil count before
the administration of cladribine it would potentially have a favorable
impact on nadir neutrophil counts. A potential hazard to this approach
is that filgrastim-induced cycling of hematopoietic progenitor cells
may increase their susceptibility to cytotoxic drugs, thus increasing
rather than reducing the myelotoxicity of the
cladribine.16,17 For example, granulocyte-macrophage colony-stimulating factor (GM-SCF; sargramostim) priming in acute myeloid leukemia may have slowed the speed of postchemotherapy neutrophil recovery.18,19
In this report, priming filgrastim regularly increased the neutrophil
count without stimulating the number of circulating hairy cells. The
median nadir ANC in the filgrastim-treated patients was statistically
greater than that of the historic control patients. After a median of
10 days of filgrastim administration (including priming filgrastim),
the time for the ANC to exceed 1.0 × 109/L was
decreased from 22 to 9 days; this advantage was greatest in patients
with a pretreatment ANC less than 1.0 × 109/L. However, the number of febrile days and duration of
fever in febrile patients, the number of patients hospitalized, and the
number of hospital days were not significantly different. It is
possible that the interpretation of results may have been weakened by
the lack of a concurrent, randomized control group and by the fact that
the number of study subjects and events were insufficient to detect
subtle differences. These results could also have been influenced by
there being more splenectomized patients among the historic controls
and only patients in the filgrastim group had received prior cladribine
therapy. In addition, the use of priming filgrastim could have had an
overall deleterious effect in the filgrastim-treated group of patients.
No Scripps Clinic patients have been treated only with post-cladribine
filgrastim, making comparisons impossible. Nevertheless, the data
support the conclusion that filgrastim use in HCL patients treated with cladribine has little or no effect on the febrile episodes, even though
the degree and duration of neutropenia was reduced.
Given these results, the routine use of filgrastim cannot be
recommended for all patients with HCL receiving cladribine. In those
patients with a precarious medical status, it might be reasonable to
consider the use of filgrastim so as to lessen the duration of severe
neutropenia exposure. Because the presence of active infection was an
exclusion criterion in this study, no conclusions can be drawn except
that filgrastim does improve neutrophil counts, which may be of benefit
in this clinical circumstance. Cladribine is generally not administered
in the presence of active infection given the myelosuppression and
potent immunosuppressive properties of this purine nucleoside
analog.20-22
It is indeed curious that multiple reports, with the exception of a
single study,7 have demonstrated a very low incidence of
opportunistic infections after cladribine treatment of HCL, despite the
severe neutropenia, monocytopenia, and T-cell immunosuppression that
accompanies cladribine treatment.4-6,8 Prior studies have demonstrated an association between failure of interferon-
generation by peripheral blood mononuclear cells and susceptibility to
opportunistic intracellular infections. It has now been shown that
cladribine-induced responses in HCL resulted in improved interferon-
generation by these mononuclear cells, which may lessen the risk of
opportunistic infections.23
Very few studies have evaluated the role of neutrophil
colony-stimulating factors in the treatment of HCL. In a prior report 10 years ago by Glaspy et al,12 it was reported that, of 4 consecutive patients with HCL complicated by severe neutropenia, 3 patients significantly improved their neutrophil count, 2 patients had resolution of their infections, and 1 patient developed acute neutrophilic dermatosis (Sweet's syndrome). No patient developed Sweet's syndrome in the study reported here. A study conducted by
Juliusson et al24 in Sweden identified pretreatment anemia, bone marrow differential with a high percentage of hairy cells, and a
low percentage of myelopoietic cells as predictive factors for the
development of neutropenic fever in 102 patients undergoing infusional
cladribine. In the 12 patients who received GM-CSF at 400 µg/d on
days 1 through 21, GM-CSF did not improve neutropenia or febrile episodes.
We previously performed a double-blind, placebo-controlled study of
pentoxifylline (400 mg orally 4 times daily for 10 days), a modulator
of tumor necrosis factor- and other cytokines, to determine whether
the incidence of neutropenic fever would be reduced.25
Although pentoxifylline treatment resulted in fewer febrile, hospital,
and antibiotic therapy days than placebo, none achieved statistical
significance except for the number of days in hospitalized patients.
Until the pathogenesis of the fever that follows cladribine use is
elucidated, it is unlikely that empiric therapeutic interventions will
be successful.
In conclusion, filgrastim regularly increases the neutrophil count in
patients with HCL and shortens the duration of severe neutropenia after
cladribine, although the number of patients hospitalized and the number
of hospital days were not significantly different in the two groups.
There are multiple other trials both in hematopoietic and
nonhematopoietic malignancies in which colony-stimulating factors
resulted in reductions of the severity and duration of neutropenia but
did not provide practical clinical benefits.26,27 This
phase II study, with comparison to historical controls, failed to
detect any clinical advantage from the use of filgrastim with cladribine in the treatment of HCL. Accordingly, the routine use of
filgrastim as an adjunct to treatment with cladribine cannot be
recommended for HCL patients.
| |
FOOTNOTES |
Submitted August 13, 1998; accepted December 1, 1998.
Supported in part by Ortho Biotech (Raritan, NJ; manufacturer of
cladribine), Amgen (Thousand Oaks, CA; manufacturer of filgrastim), the
Hairy Cell Leukemia Foundation (Newton, MA), and the Hairy Cell
Leukemia Research Foundation (Schaumburg, IL).
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 solely to indicate this fact.
Address reprint requests to Alan Saven, MD, Head, Division of
Hematology/Oncology, Scripps Clinic, 10666 N Torrey Pines Rd, La Jolla,
CA 92037.
| |
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INTRODUCTION