A Comparison of the Efficacy and Safety

of Oral and Intravenous Fludarabine in

Chronic Lymphocytic Leukemia in the
LRF CLL4 Trial
Claire E. Dearden, MD
1
; Sue Richards, DPhil
2
; Monica Else, MSc
1
; Daniel Catovsky, DSc(Med)
1
; and Peter Hillmen, MD
3
BACKGROUND: An oral formulation of fludarabine was introduced for use in chronic lymphocytic leukemia in 2001
following studies demonstrating the bioequivalence of a 40 mg/m
2
oral dose with a 25 mg/m
2
intravenous dose. We
assessed retrospectively the efficacy of these two routes of administration in the LRF CLL4 trial. METHODS: A total
of 777 patients were randomized from 1999-2004 to receive fludarabine, alone or with cyclophosphamide, or chlor-
ambucil. In 2001, a protocol amendment allowed the oral formulation. There were 117 assessable patients who
received fludarabine intravenously and 252 who received it orally. A total of 387 patients given chlorambucil acted as
a control group. RESULTS: Patients given oral fludarabine were less likely to receive the full dose (P .0004) and
experienced more, predominantly gastrointestinal, toxicity. Progression-free survival (PFS) and overall survival were
not affected by the route of administration (PFS hazard ratio, 1.10; 95% confidence interval, 0.87-1.40), but the overall
rate of response to treatment appeared to be lower with the oral formulation (P .003). However, patients recruited
since 2001 were older (P .03) and were more likely to have TP53 deletion, and response rates after 2001 were also
lower in the chlorambucil group. After excluding patients with TP53 deletion, no significant difference in outcome
was attributable to the route of administration. CONCLUSIONS: Although the LRF CLL4 data suggest no important
difference in the effectiveness of oral compared with intravenous fludarabine, randomized trials are needed to reliably
evaluate this comparison, particularly in combination with rituximab. Meanwhile, it is important to monitor compli-
ance and gastrointestinal side effects with the oral route and to switch to intravenous therapy if a reduced dose is
being received. Cancer 2011;117:245260. VC
2010 American Cancer Society.
KEYWORDS: chronic lymphocyctic leukemia, fludarabine, oral, intravenous, toxicity.
In 2001, an oral formulation of fludarabine was licensed for the treatment of chronic lymphocytic leukemia (CLL). The
oral formulation is now available in over 40 countries, and it was approved by the US Food and Drug Administration in
December 2008. A phase 2 study suggested there was no difference in clinical efficacy between the oral and intravenous
(iv) drug,
1
and subsequent studies have confirmed this impression, whether used alone
2,3
or in combination with oral cy-
clophosphamide.
4-6
Furthermore, the cost-effectiveness and convenience of oral over iv administration has provided a
driver for the introduction of oral fludarabine in many countries. Not only is it 5% cheaper than the iv formulation, but
there are no associated clinic and nursing costs, reducing the overall cost per cycle of treatment to an estimated half of that
of the iv route. Elderly patients, in particular, can benefit from being treated at home and thereby participate more readily
in clinical trials. However, there has never been a comparison between oral versus iv fludarabine in a phase 3 trial, and
questions remain as to whether the efficacy and toxicity are the same.
A multicenter randomized clinical trial was undertaken in the United Kingdom (LRF CLL4) to compare the safety
and efficacy of chlorambucil to fludarabine, used either alone or with cyclophosphamide (FC), in previously untreated
DOI: 10.1002/cncr.25776, Received: July 19, 2010; Revised: October 6, 2010; Accepted: October 11, 2010, Published online December 14, 2010 in Wiley Online
Library (wileyonlinelibrary.com)
Corresponding author: Claire E. Dearden, MD, Department of Haematology, The Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT, UK; Fax:
(011) 020-8642-6782; claire.dearden@rmh.nhs.uk
1
Section of Haemato-Oncology, The Royal Marsden Hospital and The Institute of Cancer Research, Sutton, UK;
2
Clinical Trial Service Unit, Oxford, UK;
3
Leeds
Teaching Hospitals NHS Trust, Leeds, UK
We thank the National Cancer Research Institute Chronic Lymphocytic Leukaemia Working Group, and all doctors and patients involved, for their participation in
this study.
2452 Cancer June 1, 2011
Original Article
patients with CLL requiring therapy. During the course
of the trial, oral fludarabine became available, and a proto-
col amendment allowed its use at a bioequivalent dose.
7
Although the comparison of oral versus iv fludarabine was
not planned as a prospective analysis, the availability of
the oral form provided an opportunity to compare the ef-
ficacy and safety of the 2 routes of administration. The
protocol for patients randomized to receive chlorambucil
remained unchanged, and these patients therefore formed
a control group against which to test whether any changes
in clinical outcomes after the introduction of oral fludara-
bine were attributable to the oral formulation or were the
result of other changes that took place over time. We pres-
ent here the results of this retrospective analysis.
MATERIALS AND METHODS
Over a 66-month period from February 1999 to October
2004, 387 patients in the LRF CLL4 trial were random-
ized to receive chlorambucil, 194 received fludarabine
alone, and 196 received fludarabine with cyclophospha-
mide. The diagnosis of CLL was confirmed via central
review of morphology and immunophenotype with 5
markers: CD5, CD23, CD79b, FMC7, and surface
immunoglobulins with antibodies against light chains.
Other variables recorded at trial entry (either in all
or in the majority of patients) and included in analyses
were: stage of disease, age, gender, b2 microglobulin level,
lactate dehydrogenase level, and absolute lymphocyte
count. A range of other prognostic markers was analyzed
centrally for the majority of trial patients: immunoglobu-
lin heavy chain variable gene (IGHV) mutation status,
CD38, ZAP-70 expression, and cytogenetics via fluores-
cence in situ hybridization (FISH). Five FISH probes
were used: for trisomy 12 and deletions at 6q21, 11q23,
13q14, and 17p13 (the TP53 locus).
Case report forms were kept simple to maximize
recruitment and answer the primary study question.
Questions concerning the treatment given were: date
started, number of courses, administration route, whether
the full dose was given and date completed. Information
was not collected concerning the details of any dose reduc-
tions, nor whether these were protocol-mandated (ie, due
to persistent neutropenia or thrombocytopenia or reduced
kidney function) or the result of individual physician or
patient decisions. The definition of full dose was as per
protocol. No guidance was given on howmuch of a reduc-
tion from this should be classified as not full dose, but was
according to the individual physicians judgement.
Chlorambucil was administered orally, 10 mg/m
2
/d
for 7 days, every 28 days, for up to 12 cycles. Fludarabine
was administered initially iv, 25 mg/m
2
/d for 5 days, or
for 3 days together with cyclophosphamide 250 mg/m
2
/d
for 3 days. When the protocol amendment allowed oral
fludarabine, after February 2001, patients receiving oral
fludarabine monotherapy were given fludarabine at a dos-
age of 40 mg/m
2
/d for 5 days, and those receiving oral FC
were prescribed fludarabine at a dosage of 24 mg/m
2
/d to-
gether with cyclophosphamide at a dosage of 150 mg/m
2
/
d for 5 days. The change from 3 to 5 days for the oral
combination was undertaken to improve gastrointestinal
tolerance and patient compliance. Whether administered
iv or orally, fludarabine and FC were given every 28 days
for up to 6 cycles.
All patients provided written informed consent. The
trial was approved by a United Kingdom multicenter
research ethics committee and followed UK Medical
Research Council guidelines for good clinical practice.
The study was registered as an International Standard
Randomized Controlled Trial (ISRCTN58585610). Pri-
mary results were published in 2007.
8
Table 1. Number of Patients Receiving Intravenous and Oral Fludarabine
Fludarabine
(n5194)
Fludarabine 1
Cyclophosphamide
(n5196)
Total
(N5390)
Intravenous
1999-2000 33 33 66
2001-2004 25 26 51
Oral 123 129 252
Unknown whether
intravenous/oral
7 5 12
Allocated but
not given
6* 3y 9
* Among these patients, 3 received chlorambucil, 1 received fludarabine cyclophosphamide, 1 died before
treatment, and 1 failed to return to the clinic.
y Among these patients, 2 received chlorambucil and 1 died before treatment.
Oral vs Intravenous Fludarabine in LRF CLL4/Dearden et al
Cancer June 1, 2011 2453
Statistical Methods
The response recorded was the best achieved at any time
due to first-line treatment. Overall survival was calculated
from randomization to death from any cause. Progres-
sion-free survival (PFS) was time from randomization to
relapse needing further treatment, or to other progression
date if reported, or death from any cause. (Relapse need-
ing further treatment was defined as any of the following:
lymphocyte doubling time <12 months; downward trend
in hemoglobin level and/or platelet count; 50% increase
in size of liver, spleen, or lymph nodes; appearance of
lymphadenopathy, hepatomegaly, or spenomegaly if not
already present; or B-symptoms not attributable to other
causes.) For nonresponders and those with progressive
disease, the date of progression was when nonresponse or
progressive disease was recorded.
All main analyses were intention to treat; all patients
were analyzed according to the initial treatment given and
the initial route of administration. Comparisons between
categorical variables were made using the chi-squared test;
comparisons between quantitative variables were made
using the Wilcoxon rank sum test. Cochran-Mantel-
Haenszel statistics were used to examine associations
between toxicities and route of administration or treat-
ment, allowing for the other variable. Logistic regression
models were used to determine whether response was
associated with iv versus oral fludarabine independently
of other factors. Multivariate Cox regression analysis was
used to determine which factors were independently asso-
ciated with PFS and survival. All P values were 2-sided.
RESULTS
Patients
The route of administration of fludarabine was known in
369 cases. Of these, 32% received it intravenously (half of
whom were treated before the oral option became avail-
able in 2001, the other half of whom were treated subse-
quently) and 68% received it orally (Table 1). In 2001,
70% of patients given fludarabine received the oral for-
mulation, increasing to 84% in 2002, 88% in 2003, and
89%in 2004 (P for trend .001).
In the trial as a whole, the 641 patients randomized
in 2001-2004 were older (median age, 65 years; range,
35-86 years) than the 136 patients randomized in 1999-
2000 (median age, 63 years; range, 42-84 years) and, in
those tested, more likely to be in the poor risk category
(>10% TP53-deleted cells),
9
but there were no differen-
ces in the men:women ratio or disease stage at entry
(Table 2). Patients who received fludarabine orally were
no different in gender or disease stage from those who
received it intravenously, but they were older, and all 18
patients with TP53 deletion who were allocated to fludar-
abine or FC received it orally (Table 2). The proportion
Table 2. Demographic Characteristics of LRF CLL4 Patients by Trial Entry Date, Drug, and Intravenous Versus Oral Fludarabine
All Trial Patients Fludarabine (Alone or
with Cyclophosphamide)*
Chlorambucil
1999-2000
(n5136)
2001-2004
(n5641)
P Intravenous
(n5117)
Oral
(n5252)
P 1999-2000
(n566)
2001-2004
(n5321)
P
Age, y
.04y .01y NS
<60 56 (41) 199 (31) 48 (41) 74 (29) 27 (41) 100 (31)
60-69 45 (33) 243 (38) 40 (34) 96 (38) 22 (33) 122 (38)
70 35 (26) 199 (31) 29 (25) 82 (33) 17 (26) 99 (31)
Gender NS NS NS
Men 105 (77) 468 (73) 87 (74) 185 (73) 15 (23) 86 (27)
Women 31 (23) 173 (27) 30 (26) 67 (27) 51 (77) 235 (73)
Binet stage NS NS NS
A progressive 30 (22) 161 (25) 28 (24) 61 (24) 12 (18) 84 (26)
B 64 (47) 288 (45) 59 (50) 113 (45) 32 (48) 140 (44)
C 42 (31) 192 (30) 30 (26) 78 (31) 22 (33) 97 (30)
Tested for TP53 deletion 108 463 77 198 52 228
TP53-deleted 2 (2) 31 (7) .05 0 (0) 18 (9) .006 2 (4) 13 (6) NS
All data are presented as n (%).
NS indicates not significant.
* Excludes 21 patients whose route of administration was unknown or who did not receive the treatment allocated.
y Wilcoxon rank sum test.
Original Article
2454 Cancer June 1, 2011
of patients who received the full dose was similar over
time in the chlorambucil group, but for those on fludara-
bine or FC, it was greater overall among those randomized
in 1999-2000 (Table 3). However, it was similar over
time in the iv group, and this difference was due to it
being less likely that the full dose was received if the drug
was given orally. The older the patient, the more likely
they were to receive a reduced dose, whether given iv or
orally (Table 4). Reasons for the reduced dose were not
recorded. There was no significant difference in the num-
ber of cycles of treatment given by route of administration
(data not shown).
Toxicity
Toxicity by treatment group has been reported previ-
ously.
8
Briefly, neutropenia, nausea and vomiting, alope-
cia, and any World Health Organization grade 3 or 4
toxicity were significantly more frequent with FC than
with either chlorambucil or fludarabine alone (all P <
.0001), as were diarrhea (P .01) and other toxicity (P
.004). Hemolytic anemia was less frequent with FC (P
.01).
10
These differences remained significant after
adjustment for the oral or iv route for fludarabine, apart
from grade 3 or 4 diarrhea, which was no longer signifi-
cantly different between fludarabine and FC. Hemolytic
anemia was more common with the oral than the iv flu-
darabine formulation, as were diarrhea and other toxic-
ity, but no other differences in toxicity between the
routes of administration were seen (Table 5). It is not
known how many patients experiencing toxicity with the
oral form were switched to the iv route, but the number
was estimated to be low and was unlikely to have influ-
enced these results.
Allowing for age, treatment, and treatment route,
doses were significantly more likely to be reduced in
patients experiencing febrile episodes (P .01), thrombo-
cytopenia (P .007) and other toxicity (P .02), and
may have been reduced in some cases of neutropenia or
anemia. Doses were not apparently reduced as a result of
any of the other categories of recorded toxicities. In an
analysis of dose by route, with age, treatment, and anemia
or other toxicity included in the model, the route still
affected the dose significantly (P .006).
Response to Treatment
As previously reported, the overall response rate and
good response rate (complete response plus nodular
partial response) were significantly better with FC than
with either chlorambucil or fludarabine alone (P <
.0001).
8
Responses appeared less good with the oral
Table 3. Number of Patients Receiving Full Dose Chemotherapy by Treatment, Route of Administration, and Trial Entry Date
Treatment Route of
Administration
Trial Entry
Date
No. of Patients
Assessable
No. of Patients
Receiving Full Dose (%)
P
Chlorambucil 1999-2000 64 54 (84)
NS
2001-2004 315 261 (83)
F All 1999-2000 32 30 (94)
.06
2001-2004 153 122 (80)
IV 1999-2000 32 30 (94)
NS
2001-2004 25 25 (100)
IV All years 57 55 (96)
.0004
Oral 2001-2004 122 91 (75)
FC All 1999-2000 33 29 (88)
NS
2001-2004 158 127 (80)
IV 1999-2000 33 29 (88)
NS
2001-2004 26 23 (88)
IV All years 59 52 (88)
NS
Oral 2001-2004 127 99 (78)
F and FC All 1999-2000 65 59 (91)
.03
2001-2004 311 249 (80)
IV All years 116 107 (92)
.0003
Oral 2001-2004 249 190 (76)
Patients who were not given their allocated treatment (chlorambucil, n 3; fludarabine, n 6; fludarabine with cyclophosphamide, n 3) or for whom dose
information was missing (chlorambucil, n 5; fludarabine, n 3; fludarabine with cyclophosphamide, n 2) were excluded.
NS indicates not significant; F, fludarabine; FC, fludarabine with cyclophosphamide; IV, intravenous.
Oral vs Intravenous Fludarabine in LRF CLL4/Dearden et al
Cancer June 1, 2011 2455
formulation of fludarabine than with iv, including in those
who received the full dose; however, the differences were
less marked when the TP53-deleted cases were excluded
(Table 6). Response rates were lower in patients receiving a
reduced dose compared with patients receiving the full
dose, irrespective of the route of administration (Table 6).
In addition, a (nonsignificant) decline in response rates was
seen during the course of the trial in all age groups, includ-
ing in the chlorambucil group (Table 7).
Because the comparison of oral and iv administration
was not randomized, an adjustment for possible confound-
ing factors is necessary. A multivariate analysis of response
was therefore conducted for several variables, including age,
randomized treatment, disease stage, gender, and route of
administration. Because no patients in the iv-treated group
had TP53 deletion, and this group is known to respond
extremely poorly ,
9,11
they were excluded fromthe analysis.
In the remaining 331 patients receiving fludarabine or FC
as allocated and whose administration route was known,
treatment was the only significant variable (P < .0001),
with better response rates for FC (odds ratio [OR], 2.43;
95% confidence interval [CI] , 1.58-3.73). The OR for iv
treatment was 1.48 (95% CI, 0.94-2.33; P .09). Restric-
tion to the group that received the full dose did not
Table 4. Number of Patients Receiving Full Dose by Drug, Route of Administration, and Age
Drug and Route of
Administration
Age, y No. of
Patients
Assessable
No. of Patients
Receiving Full
Dose (%)
P for
Trend
Intravenous fludarabine <60 48 47 (98)
.05
60-69 40 36 (90)
70 28 24 (86)
Oral fludarabine <60 73 62 (85)
.009
60-69 94 73 (78)
70 82 55 (67)
Chlorambucil <60 123 103 (84)
.3
60-69 142 123 (87)
70 114 89 (78)
Patients who were not given their allocated treatment or for whom dose information was missing were excluded.
The interaction between age and route of administration was not significant.
Table 5. Percentage of Fludarabine-Treated Patients Experiencing Toxicity by Intravenous
Versus Oral Treatment Route
Toxicity* No. of Patients
Assessable
% with Toxicity P (Adjusted)
Intravenous Oral
Neutropenia 366 47 50 NS
Thrombocytopenia 365 13 15 NS
Hemolytic anemia 364 3 10 .03 (.06)
Febrile episodes 356 28 35 NS
Nausea and vomiting 358 11 9 NS
Nausea and vomiting (all grades) 358 42 43 NS
Alopecia 327 2 0.5 NS
Mucositis 353 1 0.4 NS
Diarrhea 347 3 3 NS
Diarrhea (all grades) 347 15 28 .01 (.01)
Other toxicity
||
298 3 10 .05 (.07)
Other toxicity (all grades) 298 23 41 .002 (.005)
NS indicates not significant.
* World Health Organization grades 3 and 4 only, unless specified otherwise.
y Includes only patients randomized to fludarabine or fludarabine plus cyclophosphamide who received the allo-
cated treatment by known route (n369) and where individual toxicity question was completed.
z Allowing for age and treatment.
One or more episodes.
||
Where the grade was not specified, grade 1 or 2 toxicity was assumed. Cases of other toxicity (n106)
included skin rash (25 cases), infection (22 cases), cardiovascular event (10 cases), fatigue (6 cases), and consti-
pation (5 cases).
Original Article
2456 Cancer June 1, 2011
materially alter this finding (OR, 1.42; 95% CI, 0.86-
2.35). Other risk factors (11q deletion, elevated b2 micro-
globulin level, and unmutated IGHV genes and/or
IGHV3-21 usage) were available for only 152 of the
patients in this group, and in this subset the ORfor iv treat-
ment was 1.20 (95%CI, 0.61-2.36).
PFS and Overall Survival
At a median follow-up of 8 years for the iv group and 6
years for the oral group, there was no significant difference
between groups in either PFS or overall survival, either
overall (P 1.00, 0.25, respectively), or within the fludara-
bine and FCtreatments (Figure 1). In multivariate analyses
in the trial as a whole, prognostic factors found to be signifi-
cant were unmutated IGHV genes and/or IGHV3-21
usage, 11q deletion, elevated b2 microglobulin level and
treatment allocation, for predicting shorter PFS, and older
age, elevated b2 microglobulin level, unmutated IGHV
genes and/or IGHV3-21 usage and treatment allocation,
for predicting shorter overall survival.
9
In Cox regression
analyses, excluding TP53-deleted cases, the hazard ratios
(HR) for oral versus iv administration were 1.02 (95% CI,
0.80-1.31) for PFS and 1.07 (95%CI, 0.78-1.48) for over-
all survival, in a model including only treatment and route.
In subsets with complete data, the HRs were modified
from 0.85 (95% CI, 0.59-1.21) to 0.91 (95% CI, 0.63-
1.31) for PFS and from 0.81 (95% CI, 0.52-1.27) to 0.82
Table 6. Response Rates by Oral Versus Intravenous Fludarabine
IV Oral Oral Excluding
TP53 Deletion
P
IV vs
Oral
IV vs Oral Excluding
TP53 Deletion
Fludarabine alone
Total patients 56 116 108
Overall response 51 (91%) 87 (75%) 84 (78%) .01 .03
CR and NodPR 27 (48%) 48 (42%) 47 (44%) NS NS
Fludarabine plus cyclophosphamide
Total patients 57 118 110
Overall response 56 (98%) 108 (92%) 106 (96%) NS NS
CR and NodPR 39 (68%) 67 (57%) 66 (60%) NS NS
Full dose received*
Total patients 104 180 167
Overall response 99 (95%) 153 (85%) 148 (89%) .009 NS
CR and NodPR 64 (62%) 96 (53%) 94 (56%) NS NS
Full dose not received*
Total patients 8 52 49
Overall response 7 (87.5%) 41 (79%) 41 (84%) NS NS
CR and NodPR 2 (25%) 18 (35%) 18 (37%) NS NS
All
Total patients 113 234 218
Overall response 107 (95%) 195 (83%) 190 (87%) .003 .03
CR and NodPR 66 (58%) 115 (49%) 113 (52%) NS NS
Only patients who received their allocated treatment and for whom response was assessable were included.
IV indicates intravenous; CR, complete response; NodPR, nodular partial response; NS, not significant.
* P values for all patients receiving versus not receiving the full dose were: overall response, P .07 (not significant); CR and NodPR, P .001.
Table 7. Response Rates by Treatment and Trial Entry Date
a
Trial Entry Date P
1999-2000 2001-2004
Fludarabine alone
Total patients 32 145
Overall response 29 (91%) 113 (78%) NS
CR and NodPR 15 (47%) 61 (42%) NS
Fludarabine plus cyclophosphamide
Total patients 33 147
Overall response 32 (97%) 137 (93%) NS
CR and NodPR 23 (70%) 86 (58.5%) NS
Chlorambucil
Total patients 63 303
Overall response 52 (83%) 214 (71%) NS
CR and NodPR 21 (33%) 77 (25%) NS
a
Only patients who received their allocated treatment and for whom
response was assessable were included.
NS indicates not significant; CR, complete response; NodPR, nodular par-
tial response.
Oral vs Intravenous Fludarabine in LRF CLL4/Dearden et al
Cancer June 1, 2011 2457
(95% CI, 0.52-1.29) for overall survival via inclusion of all
relevant prognostic factors into the model.
DISCUSSION
On first examination of the results, it seems clear that the
overall response rate is higher in the group of patients
receiving iv versus oral fludarabine, alone or in combina-
tion with cyclophosphamide. However, iv versus oral flu-
darabine (with or without oral cyclophosphamide) was
not a randomized comparison in the LRF CLL4 trial. It is
therefore necessary to make adjustments for confounding
factors when interpreting the results. Of note, a decline in
response rates over the course of the trial affected the
chlorambucil arm, for which no treatment change was
introduced, as well as the fludarabine and FC arms.
Therefore, other variables acting over time must have
affected outcome for patients regardless of the treatment
they received. Two main factors are implicated: 1) the
recruitment of older age patients, possibly as a result of
the more readily administered oral treatment becoming
available; 2) the increased numbers of patients with TP53
deletion. The latter information was only available retro-
spectively, and genetic risk was not controlled for in the
trial randomization. Unexpectedly, all the patients with
TP53 deletion, which was associated with low response
rates across all treatment arms,
9
received oral rather than
iv fludarabine.
The trial results showed that, although older as well
as younger patients responded better to FC than to fludar-
abine alone or chlorambucil, older age was associated with
slightly poorer responses overall.
8
The changes in age
demographics over the course of the trial therefore will
have had an impact on the results. It is more difficult to
judge any specific impact of older age on the efficacy of
oral versus iv administration. Older patients were less
likely than younger ones to receive the full dose, particu-
larly if they received the oral formulation. Age-related
physiological changes may affect the pharmacology
(absorption, distribution, metabolism, renal clearance),
but there are no reliable data to confirm this. Further-
more, the fact that older patients may be receiving more
concomitant medications, and also may be less reliable in
administering the oral drugs, could have an impact.
Patients of all ages were more likely to receive a
reduced dose if they were given oral rather than iv fludara-
bine (24%vs 8%). Responses were poorer with the oral for-
mulation even among patients receiving the full dose, but
were also poorer in patients who received a reduced dose
compared with patients receiving the full dose, irrespective
of the route of administration. Clearly, some patients
received a reduced dose due to toxicity, but it is not known
which patients changed from oral to iv, and it is therefore
not possible to assess whether this change-over explains why
some patients with gastrointestinal toxicity were still able to
receive the full dose. The dosing schedule for oral adminis-
tration is complex, involving a different number of tablets
on different days to make up the full dose and usually
involving other medications, such as anti-emetics, co-tri-
moxazole, and fluconazole, each with an individual dosing
schedule. For patients likely to find compliance difficult, it
may be helpful if they are either offered treatment by the iv
route or given aids to increase compliance, such as a chart
showing the schedule for all medications on a daily basis.
In multivariate analysis, route of administration was
not significantly associated with response, either when the
model included randomized treatment, disease stage, age,
Figure 1. A comparison of intravenous and oral fludarabine is
shown for (A) progression-free survival and (B) overall sur-
vival. There were no significant differences between the oral
and intravenous routes. Cases with TP53 deletion occurred
only in patients given the oral formulation and are not
included.
Original Article
2458 Cancer June 1, 2011
and gender or, in the subset with genetic risk factors meas-
ured, when it included randomized treatment and other
risk factors. Nor was the result any different when only
patients who received the full dose were included. This
suggests that the route of administration did not influence
the response rate after adjustment for known confounding
factors.
Importantly, there was no significant difference in
either PFS or overall survival between the oral and iv flu-
darabine treatment groups. There was some increased tox-
icity with the oral formulation, including more reported
cases of diarrhea, which could have resulted in some
patients failing to receive optimal doses of treatment, and
other toxicity, including skin rashes, infections and car-
diovascular events, which may also have resulted in dose
reductions. This observation raises awareness of the need
to switch patients from oral to iv therapy if they experi-
ence gastrointestinal toxicity and, where possible, in cases
of other toxicity.
The changes in results over time in the LRF CLL4
trial raise a number of issues in relation to the conduct of
trials in general, especially those recruiting patients over a
protracted time period. There is a need to be aware that
the generalizability of results is related both to the patient
population recruited and to management issues. Even in
the chlorambucil arm, there would have been different
response rates seen at an interim recruitment point com-
pared with the end of the trial. This highlights the diffi-
culty of extrapolating data from small nonrandomized
phase 2 trials and comparing results with historical stud-
ies. In addition, it has raised our awareness of the inherent
difficulties in interpretation of the data after a trial
amendment is made part-way through a study, even if no
effect on outcome is anticipated.
Although the treatments given in the LRF CLL4
trial have now been superseded by the introduction of
chemo-immunotherapy combinations, the question of
the efficacy of oral fludarabine compared with iv
remains highly relevant. Fludarabine is still a major
component of most regimens for the treatment of CLL
(notably FC plus rituximab, which has been adminis-
tered iv thus far
12,13
) and the ability to deliver the drug
as an oral therapy offers practical and cost advantages.
Overall, there was no evidence of any clinically relevant
difference in trial endpoints for patients treated on LRF
CLL4 which could be attributed to the route of admin-
istration of fludarabine. However, this was a retrospec-
tive comparison, and large randomized trials are needed
to reliably evaluate the efficacy of oral versus iv fludara-
bine, particularly in combination with rituximab and
other chemo-immunotherapy agents. Meanwhile, it is
important to recognize issues both of compliance and
tolerability with the oral form, particularly gastrointesti-
nal toxicity, which can lead to a reduced dose being
received, and to switch to iv therapy in such cases to
ensure that the optimal dose is given.
CONFLICT OF INTEREST DISCLOSURES
The LRF CLL4 trial was funded by a core grant from Leukae-
mia Research UK. Laboratory studies were funded by an educa-
tional grant from Schering Health Care (United Kingdom) and
Schering AG (Germany). The Clinical Trial Service Unit
received research support from the Medical Research Council
and Cancer Research UK. M.E. was supported by the Arbib
Foundation. C.E.D. has acted as a consultant for Roche,
BSPharma, and Genzyme Inc. D.C. has acted as a consultant
for and has received research funding from Roche, Glaxo-
SmithKline, Parexel, and Schering AG. P.H. has acted as a con-
sultant and received research support from Genzyme Inc, Roche,
and GlaxoSmithKline.
REFERENCES
1. Boogaerts MA, Van Hoof A, Catovsky D, et al. Activity
of oral fludarabine phosphate in previously treated
chronic lymphocytic leukemia. J Clin Oncol. 2001;19:
4252-4258.
2. Rossi JF, van Hoof A, de Boeck K, et al. Efficacy and safety
of oral fludarabine phosphate in previously untreated
patients with chronic lymphocytic leukemia. J Clin Oncol.
2004;22:1260-1267.
3. Shustik C, Turner AR, Desjardins P, et al. Oral fludarabine
in untreated patients with B-cell chronic lymphocytic leuke-
mia. Leukemia. 2010;24:237-239.
4. Cazin B, Divine M, Lepretre S, et al. High efficacy with
five days schedule of oral fludarabine phosphate and cyclo-
phosphamide in patients with previously untreated chronic
lymphocytic leukaemia. Br J Haematol. 2008;143:54-59.
5. Forconi F, Fabbri A, Lenoci M, et al. Low-dose oral fludar-
abine plus cyclophosphamide in elderly patients with
untreated and relapsed or refractory chronic lymphocytic
leukaemia. Hematol Oncol. 2008;26:247-251.
6. Laurenti L, Tarnani M, De Padua L, et al. Oral fludarabine
and cyclophosphamide as front-line chemotherapy in
patients with chronic lymphocytic leukemia. The impact of
biological parameters in the response duration. Ann Hema-
tol. 2008;87:891-898.
7. Foran JM, Oscier D, Orchard J, et al. Pharmacokinetic
study of single doses of oral fludarabine phosphate in
patients with low-grade non-Hodgkins lymphoma and B-
cell chronic lymphocytic leukemia. J Clin Oncol. 1999;17:
1574-1579.
8. Catovsky D, Richards S, Matutes E, et al. Assessment of flu-
darabine plus cyclophosphamide for patients with chronic
lymphocytic leukaemia (the LRF CLL4 Trial): a randomised
controlled trial. Lancet. 2007;370:230-239.
Oral vs Intravenous Fludarabine in LRF CLL4/Dearden et al
Cancer June 1, 2011 2459
9. Oscier D, Wade R, Davis Z, et al. Prognostic factors identi-
fied three risk groups in the LRF CLL4 trial, independent
of treatment allocation. Haematologica. 2010;95:1705-1712.
10. Dearden C, Wade R, Else M, et al. The prognostic signifi-
cance of a positive direct antiglobulin test in chronic lym-
phocytic leukemia: a beneficial effect of the combination of
fludarabine and cyclophosphamide on the incidence of he-
molytic anemia. Blood. 2008;111:1820-1826.
11. Dohner H, Fischer K, Bentz M, et al. p53 gene deletion
predicts for poor survival and non-response to therapy with
purine analogs in chronic B-cell leukemias. Blood. 1995;
85:1580-1589.
12. Hallek M, Fingerle-Rowson G, Fink A-M, et al. First-line
treatment with fludarabine (F), cyclophosphamide (C), and
rituximab (R) (FCR) improves overall survival (OS) in pre-
viously untreated patients (pts) with advanced chronic lym-
phocytic leukemia (CLL): results of a randomized phase III
trial on behalf of an international group of investigators and
the German CLL study group. Blood (ASH Annual Meeting
Abstracts). 2009;114:535.
13. Keating MJ, OBrien S, Albitar M, et al. Early results of a
chemoimmunotherapy regimen of fludarabine, cyclophos-
phamide, and rituximab as initial therapy for chronic lym-
phocytic leukemia. J Clin Oncol. 2005;23:4079-4088.
Original Article
2460 Cancer June 1, 2011