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J Cent South Univ (Med Sci)

2013, 38(3) htp://; htp://

Efficacy of oral fludarabine in patients with chronic
lymphocytic leukemia/small lymphocytic lymphoma
, QIN Qun
, XIE Zhaoxia
(1. Department of Hematology; 2. Department of Pharmacy, Xiangya Hospital, Changsha 410008, China)
ABSTRACT Objective: To investigate the efficacy and safety of oral fludarabine in patients with chronic
lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Methods: The patients received oral fludarabine 40 mg/(m
d) for 5 consecutive days, each
treatment lasting 4 weeks. Te efcacy was assessed with National Comprehensive Cancer Network
(NCCN) criteria for response.
Results: Twenty-two patients received the treatment, a median of 4 cycles per patient. The rate
of complete response (CR), partial response (PR), and overall response (OR) was 40.9% (9/22),
45.5% (10/22), and 86.4% (19/22), respectively. Among the 17 previously untreated patients,
7 (41.2%) achieved CR and 8 (47.0%) achieved PR. Two of the 5 pre-treated patients achieved
CR and the other 2 achieved PR. During a median observation of 24 months, the overall survival
rate was 81.8%. The main adverse reactions were myelosuppression and infection. Grade 1 to 3
granulocytopenia was found in 7 (31.8%) patients, and infection in 3 (13.6%) patients. Non-
hematologic toxicity was mild. All the adverse reactions were reversible.
Conclusion: The oral fludarabine is effective, safe, and well-tolerated in the patients with CLL/
KEY WORDS fudarabine; chronic lymphocytic leukemia; small lymphocytic lymphoma

( 1. 2. 410008)
Date of reception2012-07-04
Biography ZHU Yan, M.D., atending physician, mainly engaged in the research of leukemia.
Corresponding authorQIN Qun, Email:
( ), 2013, 38(3) htp://; htp:// 222
Chr oni c l y mphoc y t i c l eukemi a (CLL) i s a
lymphoproliferative disorder that arises predominantly
in elderly in Western countries and is considered rare in
Aisan. However, a 3-year study with 342 leukemia patients
from 2 hospitals in Hong Kong showed that CLL was
diagnosed in 19% of Chinese patients with leukemia
Because of the similarities among cytomorphology,
immunophenotype, and cytogenetics, small lymphocytic
lymphoma (SLL) is considered the same disease as CLL
by the World Health Organization (WHO). Fludarabine,
a purine analogue, has been proven to possess antitumor
activity as evidenced by a direct intereference with DNA
synthesis, DNA repair mechanisms, and induction of
. It has been recommended as the first-
line treatment for CLL/SLL by NCCN. Intravenous
fludarabine has been shown to be effective for Chinese
patients with CLL/SLL
, while oral fludarabine is
available in recent years in China. Te oral fudarabine has
been approved by State Food and Drug Administration
in China. In China, the clinical study on oral fludarabine
treatment in the patients with CLL/SLL is rare. Tis study
was conducted to assess oral fudarabine treatment in the
patient with CLL/SLL in terms of efcacy and safety.
1 Materials and methods
Between January 2006 and October 2010, 22 patients
including 16 with CLL and 6 with SLL were enrolled,
in which 17 patients were untreated and 5 previously
treated with chlorambucil, COP, or CHOP chemotherapy.
The median age was 62 years (range, 5375 years). The
characteristics of the 22 patients were summarized in Table 1.
All the patients received oral fudarabine 40 mg/(m
d) for
5 consecutive days, every 4 weeks. Pretreatment staging
evaluation included physical examination, complete blood
count, biochemistry tests, immunophenotyping, bone
marrow aspirate, chest X-ray, and abdominal ultrasound
scan. The curative effect was judged after 4 cycles.
Response evaluations were carried out according to the
NCCN criteria
. Toxicity was evaluated according to
WHO criteria afer each cycle of treatment. Te duration
of response and overall survival were calculated using the
method of Kaplan and Meier.
Table 1 Characteristics of the patients
Characteristics Number of patients
Number of patients treated 22
Number of men/women 13/9
Median age (range)/year 62 (5375)
Disease stage
CLL Rai Stage II 7
IV 3
SLL Stage III 5
IV 1
2 Results
Ninety-seven cycles of chemotherapy were delivered
to 22 patients, a median of 4 cycles per patient (from
3 to 6 cycles). Sixteen patients received 4 cycles, and 5
received 6 cycles, while 1 patient only 3 cycles because of
liver damage. Te median cycle of onset was 2 cycles. Te
overall response (OR) rate was 86.4% (19 of 22 patients);
40.9% (9 of 22 patients) achieved complete response (CR),
and 45.5% (10 of 22 patients) achieved partial response
(PR), while non-responders represented 13.6% (3/22).
One patient died because of disease progression. Among
the 7 previously untreated patients, 7 patients (41.2%)
achieved CR and 8 (47.0%) achieved PR. Two of the 5
pre-treated patients achieved CR, while PR was obtained
in the other 2 patients (Table 2). Te responding patients
had maintained their response afer a median obversation
[ ] / (chronic lymphocytic leukemia/small
lymphocytic lymphomaCLL/SLL) 40 mg/(m
d)5 d
4 (National Comprehensive Cancer NetworkNCCN) CLL/SLL
22 4 (complete responseCR)
40.9%(9/22)(partial responsePR) 45.5%(10/22)(overall responseOR) 86.4%(19/22)17
CR 7 (41.2%)PR 8 (47.0%)5 2 CR2 PR24
81.8%7 (31.8%) I~III 3 (13.6%)
[ ]
Efcacy of oral fudarabine in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma ZHU Yan, et al. 223
of 13 months (Figure 1). During an observation of
24 months, there was an overall survival of 81.8%, as
showed in Figure 2.
Myel osuppres s i on was t he mai n s i de ef f ect .
Granulocytopenia occurred in 7 (31. 8%) patients
including 2 in Grade 1, 4 in Grade 2, and 1 in Grade 3.
Tree (13.6%) patients had infection, including 1 herpes
zoster and 2 pneumonia. No autoimmune hemolytic
anemia or thrombocytopenia caused by oral fudarabine
was recorded in this study. Non-hematological toxicity
was mild, consisting mainly of Grade 12 nausea (3 of
22 pat i ent s, 13. 6%). Onl y one pat i ent requi red
withdrawal from the treatment because of liver damage
in Grade 3 afer the third cycle. All the adverse reactions
were reversible.
Table 2 Response rate by oral fudarabine
Groups CR PR NR
Pre-untreated patients/No.(%) 7(41.2) 8(47.0) 2(11.8)
Pre-treated patients/No.(%) 2(40) 2(40) 1(20)
Total/ No.(%) 9(40.9) 10(45.5) 3(13.6)
NR=No response.
Figure 1 K-M estimation of response duration. Figure 2 K-M estimation of response duration.
0.00 5.00 10.00 15.00 20.00 25.00
0.00 5.00 10.00 15.00 20.00 25.00 30.00
3 Discussion
Chlorambucil has been the standard treatment for CLL
for several decades. It was very effective in controlling
symptom and tumor burden although the CR rate was
. Since the 1990s, fludarabine, a purine nucleoside
derivative, has been reported to be effective in the
treatment of indolent lymphoid malignancies
. It has yield
higher response rates, and longer durations of remission
and progression-free survival than chlorambucil
Some studies
have showed that CR was achieved in
20% to 40% and OR in 60% to 80% of CLL/SLL patients
accepting intravenous fudarabine.
In 2001, an oral formulation of fudarabine was licensed
for the treatment of CLL. The pharmacokinetic studies
demonstrate that a once-daily dose of 40 mg/m
a systemic exposure similar to that of 25 mg/(m
intravenous fludarabine and the bio-availability of oral
fludarabine is unaffected by food
. The efficacy data
retrieved from observation studies with oral fudarabine
are similar to the historical data concerning treatment
with intravenous fludarabine whether in previously
untreated or treated CLL patients
. Te data from this
study showed that the oral fudarabine is efective to the
patients with CLL/SLL. The rates of CR and OR were
40.9% and 86.4%, respectively. In previously untreated
patients, the rates of CR and OR were 41.2% and 88.2%,
respectively. The oral fludarabine is also effective to
the pre-treated patients. The lymphocyte counts of the
responders decreased not only in peripheral blood but
also in bone marrow. Some patients lymphocyte ratio
in bone marrow fell to normal, which hardly happened
i n the chl orambuci l therapy. The recommended
duration of treatment is 6 to 8 cycles. Some patients
with PR may get beter efect afer an additional 2 cycles.
Myelosuppression and infectious complications were the
most common adverse events. Non-hematologic toxicity
was mild. All the adverse reactions were reversible.
In summary, we believe that oral fudarabine is efective
and well-tolerated for the patients with CLL/SLL. In
addition, the patients can benefit from being treated in
outpatient because of no associated clinic and nursing cost
so as to reduce the overall cost of treatment
. Since the
fewer cases in this study, we should enroll more patients to
investigate the efcacy, safety, and combination treatment
of oral fudarabine further.
( ), 2013, 38(3) htp://; htp:// 224

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(Edited by CHEN Liwen)
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, 2013, 38(3): 221-224. DOI:10.3969/j.issn.1672-7347.2013.03.001
Cite this article as: ZHU Yan, QIN Qun, XIE Zhaoxia. Efficacy of
oral fludarabine in patients with chronic lymphocytic leukemia/small
lymphocytic lymphoma[J]. Journal of Central South University. Medical
Science, 2013, 38(3): 221-224. DOI:10.3969/j.issn.1672-7347.2013.03.001