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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 71-75
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Fludarabine and cyclophosphamide with filgrastim support in
patients with previously untreated indolent lymphoid malignancies
Ian W. Flinn,
John C. Byrd,
Candis Morrison,
Janet Jamison,
Louis F. Diehl,
Timothy Murphy,
Steve Piantadosi,
Eric Seifter,
Richard F. Ambinder,
Georgia Vogelsang, and
Michael R. Grever
From Johns Hopkins Oncology Center, Baltimore, MD, and Walter Reed
Army Medical Center, Washington, DC.
 |
Abstract |
To evaluate the response rate and potential toxicities, a phase II
trial was conducted of fludarabine and cyclophosphamide with filgrastim
support in patients with previously untreated low-grade and select
intermediate-grade lymphoid malignancies. Symptomatic patients with
preserved end organ function received cyclophosphamide 600 mg/m2 intravenous (iv) day 1 and fludarabine 20 mg/m2 iv days1 through 5, followed by filgrastim 5 µg/kg
subcutaneous starting approximately day 8. Treatment was repeated every
28 days until maximum response or a maximum of 6 cycles. Sixty
patients, median age 53.5 years, were enrolled. Thirty-seven
patients with non-Hodgkin lymphoma (NHL) were stage IV and
6 were stage III. Eleven of 17 patients with chronic lymphocytic
leukemia (CLL) were Rai intermediate risk and 6 were high risk. The
overall complete response (CR) rate was 51% and the partial response
(PR) rate was 41%. Of patients with CLL, 47% achieved a CR and the
remaining 53% achieved a PR. Of patients with follicular lymphoma,
60% achieved CR and 32% achieved a PR. Although the toxicity of this
regimen was mainly hematologic, significant nonhematologic
toxicities, including infections, were seen. Twenty-four
patients subsequently received an autologous or allogeneic stem
cell transplant. Engraftment was rapid, and there were no
noticeable procedure toxicities in the immediate posttransplant period
attributable to the fludarabine and cyclophosphamide regimen.
Fludarabine, cyclophosphamide, and filgrastim make up a highly
active and well-tolerated regimen in CLL and NHL.
(Blood. 2000;96:71-75)
© 2000 by The American Society of Hematology.
| |
Introduction |
Although most patients with low-grade lymphomas and
chronic lymphocytic leukemia (CLL) are often initially sensitive to
chemotherapy, remissions induced by these agents are usually not
complete and patients always progress.1 In addition, there
has been no demonstrable improvement in survival for these patients in
the last 3 decades.2 The lack of improvement in survival
may be due in part to the fact that the majority of patients have
residual disease detectable after chemotherapy with current regimens. A
first step in improvement in survival for these patients is the
development of chemotherapeutic regimens that have the potential to
produce true complete responses in the majority of patients. The
approval of nucleoside analogs such as fludarabine for the treatment of
low-grade lymphomas in the early 1990s brought with it a significant
increase in complete response rate. Combining a DNA damaging agent,
cyclophosphamide, with fludarabine may enhance the activity of the
nucleoside analog.3 Several investigators have demonstrated
enhancement of the activity of a purine nucleoside analog by combining
it with a DNA damaging agent in vitro.4,5 This hypothesis
has also been examined in vivo. Several trials have been conducted
examining the combination of nucleoside analogs with alkylating
agents.6-8 In one phase I/ II study in low-grade lymphomas,
an 89% complete response (CR) rate and a 100% overall response rate
were seen as demonstrating the significant activity of this combination
in vivo.8 A follow-up report indicates that these responses
remain durable.9 However, another trial using fludarabine
in combination with chlorambucil in patients with CLL has raised
concern about the toxicities of these regimens, especially the
infectious complications.10 In addition, questions have
been raised about the ability of patients who have received
fludarabine-based chemotherapy to undergo subsequent high-dose therapy
and stem cell transplant. To further evaluate the efficacy in relation
to potential toxicities, we conducted a phase II trial of fludarabine
and cyclophosphamide (Flu/Cy) in patients with previously untreated
low-grade and select intermediate-grade lymphoproliferative disorders.
The objectives of this study were to determine the CR and partial
response (PR) rates of this regimen and to determine the associated
toxicity. Secondary objectives included determining the effect of prior
therapy with this regimen on patients' ability to undergo stem cell
transplant. Engraftment, peritransplant infections, and survival were endpoints.
| |
Patients and methods |
Eligibility criteria
Patients enrolled in this multicenter study had previously untreated
indolent lymphoproliferative disorders, including follicular small,
mixed, and large-cell lymphomas, diffuse small lymphocytic lymphoma
(SLL) or CLL, marginal zone lymphoma, and mantle cell lymphoma.
Patients were required to have progressive disease-related symptoms
(including progressive adenopathy, splenomegaly, or cytopenias). CLL
patients were required to meet the criteria established by the National
Cancer Institute's Working Group on CLL recommendations for starting
therapy. Asymptomatic patients could enter the trial if the intention
was to prepare for stem cell transplant. Good end organ function (serum
creatinine level less than 2 mg/dL, bilirubin level less than 2 mg/dL
unless elevated secondary to tumor, left ventricular ejection fraction
greater than 45% in patients with a history of heart failure requiring
medications within last 2 years, and forced vital capacity
[FVC], DLCO, and FEV1 greater than 50% of predicted) was required.
Human immunodeficiency virus (HIV)-positive patients were not eligible.
All participants gave written informed consent before they entered the
study. The study protocol was approved by the institutional review
board of each participating hospital before patients were entered into the study.
Chemotherapy
Patients received cyclophosphamide 600 mg/m2 intravenous
(iv) day 1 and fludarabine (Berlex, Richmond, CA) 20 mg/m2
iv days 1 through 5. Filgrastim (Amgen, Thousand Oaks, CA) 5 µg/kg
subcutaneous was given starting approximately day 8 for 10 to 14 days
or until postnadir absolute neutrophil count was greater than
10 000/mL. The chemotherapy was repeated every 28 days until maximum
response or a maximum of 6 cycles. Patients proceeding to stem cell
transplantation received a maximum of 4 cycles of chemotherapy.
Patients received Pneumocystis carinii prophylaxis (PCP) with
trimethoprim/sulfamethoxasole (TMP/SMX) twice daily on Mondays,
Wednesdays, and Fridays or equivalent, starting with the initiation of
chemotherapy and continuing for at least 6 months after the last dose
of chemotherapy. Allopurinol 300 mg/d orally was administered on the
first 7 days of the first cycle of chemotherapy.
Toxicity assessment and dose modifications
Toxicity in patients with non-Hodgkin lymphoma (NHL) was graded
according to the National Cancer Institute (NCI) Common Toxicity criteria. In patients with CLL, toxicity was graded according to the
NCI Working Group for CLL protocols criteria.11 Fludarabine doses were reduced for patients whose creatinine level was 1.5 to 2.0 mg/dL. Reductions were calculated in proportion to the reduction in
measured creatinine clearance compared with a normal creatinine
clearance. Doses of both fludarabine and cyclophosphamide were reduced
in proportion to hematopoetic toxicity. Patients whose pretreatment
hemoglobin or platelet count dropped by 25% to 49% received a 25%
dose reduction. Doses were reduced by 50% or 75% for patients whose
hemoglobin or platelet count dropped 50% to 74% or greater than 75%.
All reductions were made assuming a maximum pretreatment hemoglobin of
10.0 g/dL and platelet count of 150 000/mL. In addition, only in
patients with NHL, doses of fludarabine and cyclophosphamide were
reduced by 25% if the nadir absolute neutrophil count was less than
500/mL and dropped by 75% of pretreatment value. Doses were increased
if the 2 subsequent doses were well tolerated.
Staging and response criteria
All patients were carefully staged with physical examination,
computed tomographic (CT) scans of the chest, abdomen, and pelvis, and
bone marrow biopsy and aspirate with flow cytometry. Patients with NHL
were staged according to the Ann Arbor Classification system,12 whereas patients with CLL were staged according
to the Rai staging criteria.13 Response was assessed after
every 2 cycles of chemotherapy with careful physical examination and CT
examinations at sites of prior disease. Patients with prior bone marrow
involvement had repeat bone marrow examinations with flow cytometry if
there was no other site of disease to follow for response. Responses
for patients with CLL were judged according to the NCI Working Group
for CLL criteria.14 Patients with "nodular complete
remissions" were considered to have partial remissions. Complete
response (CR) for patients with lymphoma was defined as complete
disappearance of all clinically detectable malignant disease for at
least 4 weeks. Partial response (PR) required greater than or equal to
50% decrease in tumor area for at least 4 weeks without increase in
size of any area of known malignant disease. Stable disease was defined
as no increase in measurable disease for at least 4 weeks. Response
assessment was determined independently by 2 of the investigators
(I.W.F. and J.C.B.). Patients had follow-up examinations, including CT
examinations of the chest, abdomen, and pelvis, every 3 months for the
first year, then every 6 months thereafter.
The Johns Hopkins Oncology Center has a policy to audit all intramural
protocols to assure protocol compliance. The records of 30 (50%)
patients on this trial were reviewed by independent auditors who
reported to the clinical research office.
Stem cell transplantation
Patients seeking autologous or allogeneic transplant received a
maximum of 4 cycles of chemotherapy. These patients received PCP
prophylaxis until the time of transplant. Eligible patients received
either autologous marrow or peripheral blood stem cell or allogeneic
stem cell transplant according to the availability of an HLA-matched
donor and institutional protocols. The preparative regimens and
posttransplant supportive care, including prophylactic antibiotics and
growth factor support, and posttransplant adjuvant therapy also varied
according to individual transplant protocols. Patients were followed
for engraftment, peritransplant infections, and survival.
Statistics
The study was designed assuming a response rate on standard therapy
of 30% to reliably detect a response rate of 50%. Using the optimal
2-stage design, with an alpha of 0.05 and a sample size of 60, the
study would have a power of 90%. The primary analysis was based on the
number of complete and partial response rates and their 95% exact
binomial confidence intervals. Fisher exact test was used to determine
differences in response rate. Paired Student t test was used to
determine differences between immunoglobulin levels and lymphocyte
subsets before and after therapy.
| |
Results |
Sixty patients (45 male:15 female) were enrolled (Table
1). Forty-three had NHL and 17 had CLL. The
median age at time of registration was 53.5 years (range, 30-73 years).
Thirty-five patients with NHL were stage IV and 8 were stage III. The
median time from diagnosis to treatment was 3 months (range, 0-268 months). Eleven of 17 patients with CLL were Rai intermediate risk and 6 were high risk. All patients with CLL had progressive symptoms requiring chemotherapy. None were entered to the study for the sole
purpose of proceeding to stem cell transplantation. Two hundred thirty-two cycles of chemotherapy were delivered to the 60 patients for
a median of 4 cycles per patient (range, 1-6 cycles). Two hundred nine
cycles were delivered on schedule. Twenty-three cycles (10%) were
delayed a median of 1 week (range, 1-3 weeks). Cause of treatment
delays varied, with only 6 patients being delayed secondary to
hematopoetic toxicity.
Response
The overall CR rate was 51% (95% CI 0.37, 0.64) and the PR rate
was 42% (95% CI 0.30, 0.56) (Table 2). Of
patients with CLL, 47% achieved a CR (95% CI 0.23, 0.72) and the
remaining 53% achieved a PR (95% CI 0.28, 0.77). Of patients with
follicular lymphoma, 60% achieved CR (95% CI 0.36, 0.81) and 35%
achieved a PR (95% CI 0.15, 0.59). Of patients with mantle cell
lymphoma, 40% achieved a CR (95% CI 0.12, 0.74) and 40% (95% CI
0.12, 0.74) achieved a PR. Fisher exact tests indicate no statistical
differences in response rates by histology for either complete or
partial response (P > .2). These comparisons were made
between CLL and NHL as well as its subtypes. The median follow-up time
for CLL and NHL were 246 and 259 days, respectively.
Toxicity
Grades III to V nonhematologic toxicity was seen in 10% of patients
within 30 days of last dose of chemotherapy (Table
3). One patient died in the middle of the
second cycle of multisystem organ failure and clinical picture of
sepsis. No organism was cultured from the blood; however, P
carinii was reported in the sputum. The treating physician
confirmed that the patient had faithfully taken TMP/SMX. One patient
developed cryptococcal pneumonia coincident with the second cycle of
chemotherapy. This patient had fevers and a cough before receiving the
first cycle of chemotherapy but no evidence of pneumonia on CT
examination.
Focal seizures developed in 1 patient 1 month after completing
chemotherapy. These seizures never recurred. Extensive neurologic evaluation revealed only a very focal and subtle area of demyelination apparent on magnetic resonance imaging. A deep venous thrombosis developed in 1 patient that required intravenous heparin. Pneumonitis rapidly responsive to corticosteroids developed in 2 patients. However,
1 of these patients had progressive disease and, on open lung biopsy,
was also found to have an infiltrate consistent with his underlying
malignancy. The exact cause of his pulmonary complications is uncertain.
Hematopoetic toxicity was mild with filgrastim support (Table
4). Five patients with NHL experienced
grade IV neutropenia in 1 cycle of treatment. Grade III neutropenia was
seen in 12 patients for a total of 13 cycles. Grade III anemia was seen
in 4 patients in a total of 4 cycles. In patients with CLL, no grade III and IV anemia was seen (Table 5). Two
patients had grade III thrombocytopenia in a total of 2 cycles and 1 patient had 1 cycle of grade IV thrombocytopenia.
Several infections have been seen subsequent to chemotherapy. In 3 patients herpes zoster developed, 1 patient had a reactivation of
chronic hepatitis B develop, 1 patient had a lower extremity cellulitis
develop, and 1 patient had sinusitis develop. Other infectious toxicity
included confirmed PCP in 1 patient who had been taking prednisone for
immune-mediated thrombocytopenia and had stopped his TMP/SMX.
Immunologic effects
CD4 counts dropped significantly with Flu/Cy. The mean pretreatment
absolute CD4 count was 799 cells/µL (range, 18-2450 cell/µL). This
value was significantly reduced (P < .001) to 139 cells/µL (range, 9-376 cells/µL) after treatment. Quantitative
assessment of immunoglobulins before and after chemotherapy revealed a
significant decrease in serum levels of IgG and IgA (P = .015
and P = .001, respectively) and a trend toward lower values
(P = .085) in serum IgM levels. The mean values before and
after chemotherapy were 1109.7 and 906.5 mg/dL for IgG, 129.4 and 99.2 mg/dL for IgA, and 327 and 172.8 mg/dL for IgM, respectively. However,
the postchemotherapy values were still within normal range for adults.
Stem cell transplantation
This study also sought to determine whether Flu/Cy is detrimental to
patients seeking stem cell transplantation, both in terms of
eligibility and transplant outcome. Pulmonary function was assessed
before after completing chemotherapy because of the known pulmonary
toxicity of fludarabine. There was no significant change in pulmonary
function before and after chemotherapy. The median value for each test
is FEV1 97.7% predicted (59.4-144.5) before, 98.7% predicted
(67-123.4) after; FVC 99.1% predicted (50-156.1) before, 100%
predicted (72-130.3) after; DLCO 98% predicted (55-129) before, 98.4%
predicted (52-122) after. In 1 patient grade IV interstitial
pneumonitis did develop, which would have prohibited proceeding with
peripheral blood stem cell transplantation (PBSCT). No cardiac or renal
toxicity from the regimen eliminated the option of stem cell
transplantation for any patient on this study.
Twenty-four patients received high-dose therapy and stem cell
transplant. An autologous graft suitable for transplant was obtained in
all patients seeking autologous transplant. The choice of stem cell
source varied according to institutional protocols and the date of
transplant. The characteristics of the preparative regimen and graft
composition are listed in Table 6.
Harvest of autologous stem cells varied by institution, time, and
protocol, and content was not prospectively assessed. However, engraftment, defined as absolute neutrophil count greater than 500/mL
and unsupported platelets greater than 20 000/mL days for 7 days
occurred at a median of day 17.5 (range, 14-25) after transplant in
patients receiving autologous peripheral blood stem cells (PBSC). Four
of the transplant recipients, 2 allogeneic and 1 autologous marrow, and
1 autologous PBSC, died. Cause of death in the 2 allogeneic recipients
was interstitial pneumonitis. Cause of death in the autologous marrow
recipient was Pseudomonas sepsis and multisystem organ failure
after graft failure occurred in the recipient of autologous PBSC.
| |
Discussion |
Despite the introduction of multiple chemotherapeutic regimens for
the treatment of low-grade lymphoid malignancies over the last 3 decades, there has been no improvement is survival demonstrated for
these patients.2 However, although the majority of patients initially respond to chemotherapy, only a minority achieve a complete remission.2,15 Experience with other hematologic
malignancies suggest that overall survival does not improve until the
majority of patients achieve a complete remission.16
Although this may be readily apparent in more aggressive diseases such
as acute leukemia or aggressive lymphomas, it is also true of hairy
cell leukemia, another low-grade lymphoid malignancy. The introduction of purine nucleoside analogs into the treatment of this disease brought
with it not only a high complete remission rate but also improvement in
overall survival17,18 relative to historical controls.
Our data demonstrate that the combination of fludarabine and
cyclophosphamide is a highly active regimen that was well tolerated by
most patients, requiring dose modifications in only 10% of patients.
The complete response rate in follicular lymphomas is less than that
seen in a phase I/II study reported preliminarily by the Eastern
Cooperative Oncology Group in which a variety of doses of
cyclophosphamide were used. This difference may be real or may be a
function of the relatively small number of patients with follicular
lymphoma in the 2 studies. This regimen compares favorably with the
fludarabine and mitoxantrone regimen in which a 43% CR and 91%
overall response rate has been reported.19 Comparison with
the fludarabine, mitoxantrone, and dexamethasone regimen is difficult
as publications to date have largely been in patients with relapsed
disease.20
The results of this regimen in patients with CLL are quite encouraging.
To our knowledge, complete and overall response rates of this magnitude
are previously unreported in CLL with fludarabine and alkylating agent
combinations. Prior studies of fludarabine and alkylating agents in CLL
have been complicated by excessive toxicity, predominantly hematopoetic
and infectious. The arm containing the combination of fludarabine and
chlorambucil in the intergroup randomized phase III trial comparing
single agents fludarabine, chlorambucil, and the combination
fludarabine and chlorambucil was closed early because of excessive
toxicity.21 Differences in doses may explain this
difference or there may in fact be poorly understood but real
differences between chlorambucil and cyclophosphamide. In addition,
because of information gained from the intergroup study and other
studies using combination regimens with nucleoside analogs, significant
attention was made to supportive care, including hematopoetic support
with growth factors and the use of PCP prophylaxis. However,
significant nonhematopoetic toxicity was seen with this regimen and
these toxicities should be considered when evaluating a patient for
this therapy. The response rates in CLL compare favorably with other
small series of concomitant or sequential fludarabine and
cyclophosphamide in previously untreated patients with CLL. In 14 previously untreated patients, a response was noted in 13 patients.22 The CR rate was not reported. Using a
sequential design of fludarabine followed by cyclophosphamide, 8 of 21 patients achieved a CR and 11 of 21 achieved a PR.23
The use of high-dose therapy and stem cell transplantation is
increasingly common in patients with low-grade lymphoproliferative disorders. Unfortunately, the morbidity and mortality appears to be
higher in this group than that seen in some other patient populations.24 One concern that has been raised is the use
of fludarabine in these patients. Fludarabine is clearly
immunosuppressive, which may increase the risk of infectious
complications with a transplant. Furthermore, there is preliminary data
to suggest that it is more difficult to obtain a viable autologous stem
cell graft from patients who have had prior therapy with
fludarabine.25 Our results indicate that fludarabine and
cyclophosphamide treatment does not prevent patients from receiving
high-dose therapy with stem cell transplantation. We were able to
harvest a graft in all patients seeking an autologous transplant.
However, it is important to note that we limited the number of cycles
of chemotherapy in those patients seeking stem cell transplantation.
The results may be different if more cycles are given. In addition,
there was no significant pulmonary or other toxicity that would render a patient ineligible for transplant. As this regimen achieved a high
complete response rate in patients with CLL, it may have rendered more
patients eligible for transplant than would be expected with single
agent fludarabine or other regimens.
The combination of fludarabine and cyclophosphamide is clearly
immunosuppressive. CD4 counts drop significantly after this therapy.
Prior combination therapy with fludarabine has been limited by
concomitant increases in infectious toxicity. Infections in this study
may have been minimized by the use of prophylactic TMP/SMX and
filgrastim; however, they were not eliminated. Although no infections
with varicella-zoster virus were seen during the chemotherapy,
depression of CD4 counts can be expected for at least 6 months or
longer, during which time patients are at risk for
varicella-zoster virus and other opportunistic infections. An increase
in these infections has been noted in patients with CLL
receiving fludarabine-based regimens.10,26 Patient
teaching, close surveillance, and the early institution of antibiotics
is warranted. An alternative solution is to decrease the
immunosuppression associated with nucleoside analog-based
chemotherapy. Our group is pursuing this strategy using
interleukin-2 during chemotherapy in a randomized, blinded,
placebo-controlled study to prevent CD4 depression.
The long-term toxicities of this regimen are unknown. Myelodysplasia
has been seen in patients treated with purine analogs.27 A
recent report suggests there may be a increase in myelodysplastic syndromes with the combination of chlorambucil and fludarabine in
patients with CLL.28 Although we did not note this in our patients, follow-up remains short, and we will continue to monitor these patients.
It is clear from our experience with other hematologic malignancies
that we are unlikely to change the natural history of a disease until
we can achieve a complete remission in the majority of patients. The
ultimate value of the combination of fludarabine and cyclophosphamide
in CLL and low-grade lymphomas remains to be proven. The Eastern
Cooperative Oncology Group is currently evaluating this regimen in
comparison with single agent fludarabine in a randomized study in
patients with previously untreated CLL. A similar regimen is being
evaluated in Eastern Cooperative Oncology Group in low-grade lymphoma
patients. However, ultimately to improve the outcome for patients with
low-grade lymphoid malignancies, regimens like Flu/Cy that produce
complete responses in the majority of patients will be needed.
| |
Footnotes |
Submitted June 29, 1999; accepted February 22, 2000.
Supported in part by grants from Amgen and Berlex.
Reprints: Ian W. Flinn, Johns Hopkins Oncology Center,
Cancer Research
Building Room 388, 1650 Orleans St, Baltimore, MD 21231.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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1999;18:9a.
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Top
Abstract
Introduction