中南大学学报（医学版）

J Cent South Univ (Med Sci) 2013, 38(3) http://www.csumed.org; http://xbyx.xysm.net221

Efficacy of oral fludarabine in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

ZHU Yan1, QIN Qun2, XIE Zhaoxia1

(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/(m2.d) for 5 consecutive days, each treatment lasting 4 weeks. The efficacy 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/SLL.

KEY WORDS fludarabine; chronic lymphocytic leukemia; small lymphocytic lymphoma

口服氟达拉滨治疗慢性淋巴细胞白血病 / 小淋巴细胞瘤患者的疗效观察

祝焱1，秦群2，谢兆霞1

( 中南大学湘雅医院 1. 血液科；2. 药剂科，长沙 410008)

Date of reception：2012-07-04

Biography： ZHU Yan, M.D., attending physician, mainly engaged in the research of leukemia.

Corresponding author：QIN Qun, Email: qinqun@hotmail.com

DOI:10.3969/j.issn.1672-7347.2013.03.001

http://xbyx.xysm.net/xbwk/fileup/PDF/201303221.pdf

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中南大学学报 ( 医学版 ), 2013, 38(3) http://www.csumed.org; http://xbyx.xysm.net222

C h r o n i c l y m p h o c y t i c l e u k e m i a ( C L L) 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[1]. 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 apoptosis[2-3]. 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 [4-6], while oral fludarabine is available in recent years in China. The oral fludarabine 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. This study was conducted to assess oral fludarabine treatment in the patient with CLL/SLL in terms of efficacy 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, 53–75 years). The characteristics of the 22 patients were summarized in Table 1. All the patients received oral fludarabine 40 mg/(m2.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[7]. Toxicity was evaluated according to WHO criteria after each cycle of treatment. The 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 (53–75)

Disease stage

CLL Rai Stage II 7

III 6

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. The median cycle of onset was 2 cycles. The 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). The responding patients had maintained their response after a median obversation

[ 摘要 ] 目的：观察口服氟达拉滨治疗慢性淋巴细胞白血病 / 小淋巴细胞瘤 (chronic lymphocytic leukemia/small

lymphocytic lymphoma，CLL/SLL) 患者的疗效及耐受性。方法：患者口服氟达拉滨片 40 mg/(m2.d)，连续 5 d，每

4 周一个疗程。根据美国国立癌症综合网络 (National Comprehensive Cancer Network，NCCN) 中 CLL/SLL 治疗指南

标准判断疗效。结果：22 例患者接受了治疗，每例患者中位疗程为 4 疗程。完全缓解 (complete response，CR) 率

40.9%(9/22)，部分缓解 (partial response，PR) 率 45.5%(10/22)，总有效 (overall response，OR) 率 86.4%(19/22)。17 例

初治患者中 CR 7 例 (41.2%)，PR 8 例 (47.0%)。5 例复治患者中 2 例 CR，2 例 PR。中位随访 24 个月，患者生存率为

81.8%。主要的不良反应为骨髓抑制和感染。7 例 (31.8%) 患者发生 I~III 级的中性粒细胞减少，3 例 (13.6%) 患者发生

感染。非血液学毒性轻微。不良反应均可恢复。结论：口服氟达拉滨对于 CLL/SLL 患者安全、有效，并且耐受性较好。

[ 关键词 ] 氟达拉滨；慢性淋巴细胞白血病；小淋巴细胞淋巴瘤

Efficacy of oral fludarabine 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.

My e l o s u p p re s s i o n w a s t h e m a i n s i d e e f f e c t . Granulocy topenia occurred in 7 (31.8%) patients including 2 in Grade 1, 4 in Grade 2, and 1 in Grade 3. Three (13.6%) patients had infection, including 1 herpes zoster and 2 pneumonia. No autoimmune hemolytic anemia or thrombocytopenia caused by oral fludarabine was recorded in this study. Non-hematological toxicity was mild, consisting mainly of Grade 1–2 nausea (3 of

22 pat ients , 13 .6%). Only one pat ient required withdrawal from the treatment because of liver damage in Grade 3 after the third cycle. All the adverse reactions were reversible.

Table 2 Response rate by oral fludarabine

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.

1.0

0.8

0.6

0.4

0.2

0.0

Prob

abili

ty

Time/month0.00 5.00 10.00 15.00 20.00 25.00

1.0

0.8

0.6

0.4

0.2

0.0

Time/month

Prob

abili

ty

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 low[8]. Since the 1990s, fludarabine, a purine nucleoside derivative, has been reported to be effective in the treatment of indolent lymphoid malignancies[9]. It has yield higher response rates, and longer durations of remission and progression-free survival than chlorambucil[10-11]. Some studies[12-14] have showed that CR was achieved in 20% to 40% and OR in 60% to 80% of CLL/SLL patients accepting intravenous fludarabine.

In 2001, an oral formulation of fludarabine was licensed for the treatment of CLL. The pharmacokinetic studies demonstrate that a once-daily dose of 40 mg/m2 provides a systemic exposure similar to that of 25 mg/(m2.d) intravenous fludarabine and the bio-availability of oral fludarabine is unaffected by food[15-16]. The efficacy data retrieved from observation studies with oral fludarabine are similar to the historical data concerning treatment with intravenous fludarabine whether in previously untreated or treated CLL patients[17-19]. The data from this

study showed that the oral fludarabine is effective 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 in the chlorambuci l therapy. The recommended duration of treatment is 6 to 8 cycles. Some patients with PR may get better effect after 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 fludarabine is effective 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[20]. Since the fewer cases in this study, we should enroll more patients to investigate the efficacy, safety, and combination treatment of oral fludarabine further.

中南大学学报 ( 医学版 ), 2013, 38(3) http://www.csumed.org; http://xbyx.xysm.net224

参考文献

1. Kwong YL, Wong KF, Chan LC, et al. The spectrum of chronic

lymphoproliferative disorders in Chinese people. An analysis of 64

cases [ J]. Cancer, 1994, 74(1): 174-181.

2. Podhorecka M, Halicka HD, Klimek P, et al. Thalidomide induces

phosphorylation of histone H2AX and increases rate of apoptosis

caused by f ludarabine in malignant lymphoc y tes of chronic

lymphocytic leukemia in short term cell cultures [ J]. Leuk Res, 2009,

33(7): 997-1000.

3. Podhorecka M, Halicka D, Klimek P, et al. Resveratrol increases rate

of apoptosis caused by purine analogues in malignant lymphocytes of

chronic lymphocytic leukemia [ J]. Ann Hematol, 2011, 90(2): 173-183.

4. 陈霄峰, 陈钰, 沈杨. 以氟达拉滨为主方案治疗慢性淋巴细胞白

血病24例[ J]. 肿瘤研究与临床, 2006, 18(12): 843-844.

CHEN Xiaofeng , CHEN Yu, SHEN Yang. Fludarabine-based

chemotherapy in twenty-four patients with chronic lymphocytic

leukemia [ J]. Cancer Research and Clinic, 2006, 18(12): 843-844.

5. 赵曙, 张小三, 姬颖华, 等. 氟达拉滨联合环磷酰胺治疗小淋巴细

胞淋巴瘤/慢性淋巴细胞白血病临床观察[ J]. 新乡医学院学报,

2008, 25(6): 588-590.

ZHAO Shu, ZHANG Xiaosan, JI Yinghua, et al. Clinical observation of

fludarabine combined with cyclophosphamide on patients with small

lymphocytic lymphoma/chronic lymphocytic leukemia [ J]. Journal of

Xinxiang Medical College, 2008, 25(6): 588-590.

6. 杨怡敏, 潘迎英, 张永华. FC方案治疗小淋巴细胞淋巴瘤/慢性

淋巴细胞白血病临床观察[ J]. 河北医药, 2011, 33(1): 70-71.

YANG Yimin, PAN Yingying, ZHANG Yonghua. Clinical study of

fludarabine combined with cyclophosphamide in patients with small

lymphocytic lymphoma/chronic lymphocytic leukemia [ J]. Hebei

Medical Journal, 2011, 33(1): 70-71.

7. Eichorst B, Hallek M. Revision of the guideline for diagnosis and

therapy of chronic lymphocytic leukemia (CLL) [ J]. Best Pract Res

Clin Haematol, 2007, 20(3): 469-477.

8. CLL trialists’ collaborative group. Chemotherapeutic options in

chronic lymphocytic leukemia: a meta-analysis of the randomized trials

[ J]. J Natl Cancer Inst, 1999, 91(10): 861-868.

9. Chun HG, Leyland-Jones B, Cheson BD. Fludarabine phosphate:a

synthetic purine antimetabolite with significant activity against

lymphoid malignancies [ J]. J Clin Oncol, 1991, 9(1): 175-188.

10. Steurer M, Pall G, Richards S, et al. Single-agent purine analogues for

the treatment of chronic lymphocytic leukemia: a systematic review

and meta-analysis [ J]. Cancer Treat Rev, 2006, 32(5): 377-389.

11. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with

chlorambucil as primary therapy for chronic lymphocytic leukemia [ J].

N Engl J Med, 2000, 343(24): 1750-1757.

12. 吕书晴, 王建民, 宋献民, 等. 含氟达拉滨的联合化疗方案治疗慢

性淋巴细胞白血病/小淋巴细胞性淋巴瘤[ J]. 临床肿瘤学杂志,

2008, 13(2): 119-122.

LÜ Shuqing, WANG Jianmin, SONG Xianmin, et al. Fludarabine-

based combine chemotherapy in patients with chronic lymphocytic

leukemia/small lymphocytic lymphoma [ J]. Chinese Clinical

Oncology, 2008, 13(2): 119-122.

13. Bosch F, Ferrer A, Villamor N, et al. Fludarabine, cyclophosphamide,

and mitoxantrone as initial therapy of chronic lymphocytic leukemia:

high response rate and disease eradication [ J]. Clin Cancer Res, 2008,

14(1): 155-161.

14. Shustik C, Turner AR, Desjardins P, et al. Oral fludarabine in untreated

patients with B-cell chronic lymphocytic leukemia [ J]. Leukemia,

2010, 24(1): 237-239.

15. Foran JM, Oscier D, Orchard J, et al. Pharmacokinetic study of single

doses of oral fludarabine phosphate in patients with low-grade non-

Hodgkin’s lymphoma and B-cell chronic lymphocytic leukemia[ J].

J Clin Oncol, 1999, 17(5):1574-1579.

16. Oscier D, Orchard J, Culligan D, et al. The bioavailability of oral

fludarabine phosphate is unaffected by food [ J]. Hematol J, 2001, 2(5):

316-321.

17. 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]. J Clin Oncol, 2004, 22(7): 1260-1267.

18. Boogaerts MA, Van Hoof A, Catovsky D, et al. Activity of oral

ludarabine phosphate in previously treated chronic lymphocytic

leukemia [ J]. J Clin Oncol, 2001,19(22): 4252-4258.

19. Laurenti L, De Padua L, Tarnani M, et al. Comparison between oral

and intravenous fludarabine plus cyclophosphamide regime as front-

line therapy in patients affected by chronic lymphocytic leukaemia:

influence of biological parameters on the clinical outcome [ J]. Ann

Hematol, 2011, 90(1): 59-65.

20. Delgado J, Febrer L, Nieves D, et al. Cost-reduction analysis for oral

versus intravenous fludarabine (Beneflur) in Spain[ J]. Farm Hosp,

2009, 33(5): 240-246.

(Edited by CHEN Liwen)

本文引用： 祝焱 , 秦群 , 谢兆霞 . 口服氟达拉滨治疗慢性淋巴细

胞白血病 / 小淋巴细胞瘤患者的疗效观察 [ J]. 中南大学学报 : 医

学版 , 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