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Efficacy and Safety of Oral Fludarabine Phosphate in Previously Untreated Patients With Chronic Lymphocytic Leukemia

From the CHU, Montpellier; Service des Maladies du Sang-Medecine Interne, Angers; CHU, Brest; CHU, Besançon, France; Schering SA, Lys-les-Lannoy, France; AZ St Jan, Brugge; AZ Middelheim, Antwerpen; Institute Jules Bordet, Brussels, Belgium; Taunton and Somerset Hospital, Taunton; St Bartholomew's Hospital, London; John Radcliffe Hospital, Oxford; Addenbrooke's Hospital, Cambridge; Schering Health Care Ltd, Burgess Hill, United Kingdom; Meander Medisch Centrum, Amersfoort, the Netherlands; Ospedale Niguarda Cà Grande, Milano, Italy.

Address reprint requests to Jean-Francois Rossi, MD, Hematology Oncology Department, University Hospital, 375 Avenue Doyen Giraud —CHU Lapeyronie, Montpellier 34295, France; e-mail: jf-rossi{at}chu-montpellier.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: A prospective, multicenter, open-label, phase II clinical trial to assess oral fludarabine phosphate treatment in terms of safety, efficacy, and quality of life. Reference to a historical group of patients treated with the intravenous (IV) formulation allowed the two formulations to be compared.

PATIENTS AND METHODS: Patients with previously untreated B-cell chronic lymphocytic leukemia received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m²/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. Efficacy was assessed using International Workshop on Chronic Lymphocytic Leukemia and National Cancer Institute criteria for response. Safety monitoring included WHO toxicity grading for adverse events. Quality of life was also assessed.

RESULTS: Eighty-one patients received treatment. According to International Workshop on Chronic Lymphocytic Leukemia criteria, the overall response rate was 71.6% (complete remission, 37.0%; partial remission, 34.6%). The response rate using National Cancer Institute criteria was 80.2% (complete remission, 12.3%; partial remission, 67.9%). Median time to progression was 841 days (range, 28 to 1,146 days). The most frequently reported grade 3/4 toxicity was myelosuppression. WHO grade 3/4 hematological toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). Gastrointestinal toxicity was more common with the oral formulation than with IV fludarabine phosphate, but was generally mild to moderate and did not require treatment. Statistically significant improvements in mean emotional and insomnia quality-of-life scores were seen after treatment.

CONCLUSION: This study demonstrates that oral fludarabine phosphate is clinically effective and generally well tolerated by patients with previously untreated B-cell chronic lymphocytic leukemia. Oral fludarabine phosphate has a similar clinical efficacy and safety profile to the IV formulation. Oral fludarabine phosphate does not adversely affect quality of life and may improve emotional and insomnia scores.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
B-cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder that arises predominantly in older age groups, and is the most common leukemia occurring in Western countries.¹ The disease has a variable clinical presentation and course; it may not impact affect the expected life span of a patient with low-risk disease but can reduce life expectancy to less than 2 years.²

The intravenous (IV) form of the fluorinated nucleotide analog fludarabine phosphate (Fludara; Schering AG, Berlin, Germany) is the most effective single agent for the treatment of patients with relapsed or refractory B-CLL.^3-5 Overall response rates of up to 55% following second-line IV fludarabine phosphate have been achieved in studies carried out in the United States and Europe.^4,6,7 In a study comparing IV fludarabine phosphate with cyclophosphamide + doxorubicin + prednisone in 100 previously untreated and 96 previously treated patients with chronic lymphocytic leukemia (CLL), more patients responded to fludarabine phosphate treatment (71% v 60%, P = .26, for previously untreated patients; 48% v 27%, P = .036, for previously treated patients).⁴ In another large study of previously untreated patients with CLL, the overall response rate was significantly higher among 170 patients receiving IV fludarabine phosphate, compared with 181 patients treated with low-dose, oral chlorambucil (63% v 37%, P < .001).⁸ Furthermore, the median duration of remission and median time to progression were significantly longer in the IV fludarabine phosphate group (25 months and 20 months, respectively), compared with chlorambucil-treated patients (both 14 months, P < .001). The investigators concluded that although IV fludarabine phosphate may be less convenient to use than oral chlorambucil, it offers the possibility of a prolonged progression-free interval, during which no further therapy is required.⁸ In addition, it has been reported that there is an increase in response rate and a trend toward better tolerability with IV fludarabine phosphate in comparison with standard polychemotherapy regimens.⁹

A more convenient oral formulation of fludarabine phosphate, an immediate-release 10-mg tablet, has been developed and compared with the IV formulation in pharmacokinetic studies in patients with non-Hodgkin's lymphoma or B-CLL.^10,11 These studies demonstrated that a once-daily oral dose of 40 mg/m² provides a systemic exposure similar to that of 25 mg/m²/d IV fludarabine phosphate,¹⁰ and that the bioavailability of oral fludarabine phosphate is unaffected by food.¹¹ In a European multicenter phase II study, retrospective analysis with historical controls has confirmed that, in previously treated patients, the oral formulation had efficacy and safety similar to the IV formulation.¹²

The present study was conducted to assess oral fludarabine phosphate treatment in previously untreated patients with B-CLL, in terms of safety, efficacy, and quality of life (QOL). To compare the two formulations of fludarabine phosphate, a retrospective comparison was made with a group of previously untreated B-CLL patients who had received treatment with the IV formulation.⁴

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
This prospective, multicenter, open-label phase II clinical trial was carried out at 24 centers in Belgium, France, Italy, the Netherlands, and the United Kingdom. The objective was to assess the response rate (complete remission [CR] and partial remission [PR]), safety profile, and QOL after orally administered fludarabine phosphate in patients with previously untreated B-CLL.

The study was conducted in accordance with the International Conference on Harmonization Note for Guidance on Good Clinical Practice (January 1997), and complied with the recommendations of the Declaration of Helsinki. The protocol met all the requirements of the appropriate regulatory authorities and received formal approval from the appropriate central and local ethics committees. All eligible patients gave their written, informed consent to participate in the study.

Male and female patients aged 18 to 75 years were included if they had symptomatic B-CLL as defined by the National Cancer Institute (NCI)–sponsored working group¹³; had not received any previous treatment for their disease; and had either Binet stage A progressive, stage B, or stage C disease. Progressive stage A disease was defined by at least one of the following: a lymphocyte count more than 30 x 10⁹/L, and a persistent rise in the lymphocyte count with a doubling time of less than 12 months; a downward trend in hemoglobin and/or platelet counts; a 50% increase in the size of the liver and/or spleen and/or lymph nodes, or appearance of lymphadenopathy, hepatomegaly, or splenomegaly if not previously present; and constitutional symptoms attributable to the disease (eg, pyrexia, night sweats, weight loss), once other causes had been excluded. Eligible patients also had a WHO performance status of 0, 1, or 2, and a life expectancy of more than 6 months.

Patients were excluded if they had previously received any treatment for B-CLL; if they required regular systemic corticosteroid therapy; if they had active infections requiring systemic antibiotics, or had severe or life-threatening concomitant disease or autoimmune thrombocytopenia or autoimmune hemolytic anemia (AIHA); or if they had had prior malignancies.

Patients were scheduled to receive six cycles of treatment, each consisting of oral fludarabine phosphate at a dose of 40 mg/m²/d for 5 days every 4 weeks. Provision was made in the protocol for up to two further cycles (to a maximum of eight), to be given to patients who were responding to treatment but had not achieved a CR after the sixth cycle. Appropriate supportive therapy, including irradiated blood transfusions, antiemetics, anti-infection prophylaxis, and hematopoietic growth factors, could be provided at the discretion of the investigator, but other cytotoxic drugs, regular systemic corticosteroids, and experimental drugs were prohibited.

Patients who did not respond or who, in the opinion of the investigator, demonstrated disease progression after two cycles of treatment, were withdrawn from the study. In addition, patients who achieved CR were also permitted to discontinue the study. Other reasons for premature withdrawal included unacceptable toxicity; loss of patient to follow-up; refusal to continue treatment; or death.

Although WHO grade 4 nonhematologic toxicity resulted in automatic withdrawal from the study, the protocol included provision for postponement and modification of doses in the event of WHO grade 2 or 3 hematologic or nonhematologic toxicities. Treatment cycles were delayed for a maximum of 2 weeks if the granulocyte count was less than 1 x 10⁹/L and/or the platelet count was less than 100 x 10⁹/L (unless disease-related). The dose was reduced to 30 mg/m²/d if, after 2 weeks, the granulocyte count remained at 0.5 x 10⁹/L to 1.0 x 10⁹/L and/or the platelet count was 50 x 10⁹/L to 100 x 10⁹/L. The dose was lowered to 20 mg/m²/d if, after postponement, the granulocyte and/or platelet counts were less than 0.5 x 10⁹/L and/or less than 50 x 10⁹/L, respectively. In the event of WHO grade 2 or 3 nonhematological toxicity (except for nausea/vomiting, hair loss, constipation, and hemorrhage), treatment was delayed until the patient had recovered, up to a maximum of 2 weeks. After resolution of the toxicity, subsequent treatment could be given at a reduced dose of 30 or 20 mg/m²/d after grade 2 or 3 toxicity, respectively.

Baseline Assessments
Baseline assessments included demographic information, stage of disease, WHO performance status, physical examination, and laboratory tests, including immunophenotyping, bone marrow aspirate and biopsy, chest x-ray, and additional radiological assessments if clinically indicated. Medical history and surgical history were also recorded, as were details of previous and concomitant medications. Baseline toxicity and QOL assessments were also performed.

Efficacy Criteria
The primary efficacy measure was response to treatment (CR, PR, stable disease, or progressive disease [PD]), evaluated 3 to 5 weeks after the last treatment cycle. This end-of-treatment assessment of efficacy included a physical examination and laboratory values. All patients were examined for enlargement of lymph nodes, liver, and spleen.

A bone marrow aspirate and biopsy was carried out for all patients who achieved a response. CR was defined as the absence of disease in accordance with NCI¹³ and International Workshop on Chronic Lymphocytic Leukemia (IWCLL)¹⁴ criteria; PR, stable disease, and PD were also defined by these criteria. A global assessment of response was made by comparing the extent of disease at the final examination with the patient's baseline status (using the staging criteria of both Binet et al² and Rai et al¹⁵). The efficacy analysis included all patients for whom response could be evaluated by the investigator, regardless of whether a patient discontinued treatment prematurely.

Safety Criteria
Physical examination and laboratory tests were performed at baseline, at each visit during the study (< 48 hours before each treatment cycle), and 3 to 5 weeks after the last treatment cycle. Grading of all acute and subacute toxicity, using WHO criteria (grade 0 [absence of toxicity] through to grade 4), was also carried out at these time points. Laboratory abnormalities and adverse events not covered by the WHO toxicity criteria were documented separately.

QOL Evaluation
In order to assess QOL, patients were asked to complete the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-30¹⁶ and Spitzer's Quality of Life Index (QLI)¹⁷ questionnaires at baseline, after three cycles of treatment, and 3 to 5 weeks after the last treatment cycle. WHO performance status was also assessed at baseline and after treatment.

Statistical Evaluation
The target sample size for this study was 80 patients, calculated as sufficient to allow the detection of a 20% change in overall response rate following oral fludarabine phosphate, with a probability of 96%, compared with historical data from 53 previously untreated CLL patients who had received IV fludarabine phosphate in a comparative trial with cyclophosphamide + doxorubicin + prednisone.⁴

The efficacy, safety, and QOL analyses were based on the intent-to-treat (ITT) population, which included all 81 patients who received study treatment.

The primary end point was overall response (CR + PR). Exact two-sided one-sample tests were used to compare the overall response rate from the present study with the overall response rate of 70% reported for the historic control population of previously untreated patients receiving IV fludarabine phosphate. Exact 95% CIs for overall response rates were determined. Changes from baseline in QOL parameters were analyzed using the Wilcoxon signed-rank test. Time to progression was determined in the ITT population according to the methodology of Kaplan and Meier,¹⁸ and calculated from the time of first treatment to the date of progressive disease. Duration of response was determined in all responders, calculated from the date of first observation of response until the date of progressive disease.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
A total of 82 patients with previously untreated B-CLL were recruited; one patient was found to be ineligible and was withdrawn before starting treatment. The remaining 81 patients (the ITT population, including four patients strictly ineligible due to previous malignancies) were treated and assessed for efficacy, safety, and QOL. Table 1 lists the demographic characteristics of the ITT and historical control populations. The arms were well balanced, except for the larger number of Binet stage A patients in this study compared with the historical control.

Efficacy Evaluation
The overall response rate according to NCI criteria was 80.2% (65 of 81 patients; 95% CI, 69.9% to 88.3%); 12.3% (10 of 81 patients) achieved CR; and 67.9% (55 of 81 patients) achieved PR (including 14 PR nodular, four PR marrow failure, and one PR nodular or marrow failure; Table 2). When the 20 patients who prematurely discontinued treatment were excluded from the analysis, the overall response [OR] rate was determined as 69.1%, according to NCI criteria.

The majority of patients achieved maximal response after six cycles. However, 18 patients (22.2%, IWCLL criteria) or 21 patients (25.9%, NCI criteria) achieved their maximum responses after cycles 7 or 8. Overall, the mean number of treatment cycles received was 5.9. Response rates by cycle are presented in Table 4.

View larger version (12K): [in this window] [in a new window]   Fig 1. Duration of response—International Workshop on Chronic Lymphocytic Leukemia criteria—Kaplan-Meier survival curve for intent-to-treat population.

The most frequently reported toxicity during treatment with oral fludarabine phosphate was myelosuppression; WHO grade 3 or 4 toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%; Table 5). Only four patients received growth factor support for neutropenia. Thirty-five patients received antibacterial or antiviral prophylaxis; seven patients received prophylaxis against both Pneumocystis carinii pneumonia and herpes infection; 27 patients received Pneumocystis carinii pneumonia prophylaxis only; and one patient received herpes prophylaxis only. A total of 41 patients (50.6%) had infections, but there were only four (4.9%) severe infections. Three of the severe infections were grade 3 (one case of appendicitis, one case of Aspergillus pneumonia, and one case of subacute bacterial endocarditis), and one was grade 4 (pneumonia and septicemia).

One patient had severe (grade 4) impairment of consciousness, but this occurred during the first treatment cycle when the patient developed a bowel infarction and had severe respiratory infections (Aspergillus and cytomegalovirus pneumonia), and therefore cannot be viewed as drug-related neurotoxicity. One patient had grade 4 peripheral neurotoxicity, reported in the fifth cycle; this was associated with foot drop, which was part of this patient's previous medical history, and should therefore be interpreted with caution. One patient had grade 4 pulmonary toxicity in conjunction with pneumonia and septicemia, and subsequently died. The investigator assessed the relationship of the infection to study drug as possible.

Other adverse events of note were one case of erythroblastopenia and three cases of AIHA. All three patients with AIHA were withdrawn from the study and subsequently recovered completely—in one instance, in response to steroids.

Grade 3/4 toxicity was uncommon in relation to liver function (AST was elevated in two patients [2.5%]) and was not recorded for renal function. No patient experienced grade 3/4 alopecia or skin rash.

In total, 14 patients required dose reductions during the study: seven due to hematologic toxicity, three due to nonhematologic toxicity, and four for other reasons. Treatment with the study drug was postponed 20 times in 12 patients due to hematologic toxicity; nine times in eight patients due to nonhematologic toxicity; once in one patient due to both hematologic and nonhematologic toxicity; and 31 times in 21 patients for other reasons. The majority of these postponements did not involve dose reduction; only six patients experienced nine cycles in which both treatment postponement and dose reduction was required. The median dose for all patients during the study was consistently 7 tablets per day. Premature discontinuation of study medication was necessary in 20 patients, 13 of whom discontinued because of adverse events (mainly myelosuppression and infections).

One patient died from septicemia after one cycle of study medication. Three further deaths (from myocardial infarction, Richter's transformation, and medical deterioration in the context of PD) were reported at 7, 12, and 14 months, respectively, after the patients had received their last dose of study medication. All three patients completed the study and did not withdraw prematurely.

In general, treatment was well tolerated and consistent with previous experience with IV fludarabine phosphate.

QOL Evaluations
Using the EORTC QLQ-30 questionnaire, patients at baseline had a high QOL profile that was very similar to that of the general population, as indicated by EORTC QLQ-30 reference values. The greatest impact of B-CLL was observed on the role and emotional-functioning scales, where lower mean scores were evident (moderate differences of 10 to 20 points). Following administration of oral fludarabine phosphate, the only notable change in the multi-item scales was a statistically significant improvement in mean emotional scores from baseline to cycle 3 (8.6-point mean increase, P = .0001) and from baseline to after the end of treatment (7.5-point mean increase, P = .0001); after treatment, this score almost reached the reference value for the general population. In the single-item scales, statistically significant improvements in insomnia scores were seen from baseline to cycle 3 (P = .027) and from baseline to after the end of treatment (P = .0022).

Using Spitzer's QLI questionnaire, a statistically significant decrease in the health score was observed from baseline to cycle 3 (P = .030), corresponding to an improvement in QOL, but the overall change in health score after the end of treatment was not statistically significant.

WHO performance status improved throughout the course of the study in 11 patients (13.6%), remained unchanged in 63 patients (77.8%), and deteriorated in seven patients (8.6%).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
For many years, alkylating agents such as chlorambucil have been the gold standard treatment for previously untreated B-CLL patients.²⁰ However, large randomized trials have confirmed that, as an initial treatment for B-CLL, IV fludarabine phosphate yields higher response rates, improved numbers of complete responses, and longer durations of remission and progression-free survival than these regimens.^8,9 A more convenient oral formulation of fludarabine phosphate provides similar systemic exposure to IV administration¹⁰ after dose adjustment. In the clinical setting of a large multicenter study, the efficacy and safety of oral fludarabine phosphate at 40 mg/m²/d in previously treated patients with B-CLL were similar to expectations from the IV formulation at 25 mg/m²/d.¹²

The data from this study demonstrate that the oral formulation of fludarabine phosphate is also equivalent to the IV formulation, in terms of clinical efficacy, in previously untreated B-CLL. The overall response rate of 71.6% by IWCLL criteria was consistent with the response rate of 70% with IV fludarabine phosphate in the historical control study of similar design,⁴ with no significant difference detected in the statistical comparison. The response determined by NCI criteria was slightly higher (80.2%) than that determined by IWCLL criteria, which was mainly due to a higher PR rate. This is because the NCI criteria require only a 50% improvement in relevant parameters to be categorized as PR, whereas the IWCLL criteria require a downshift of a whole stage. Conversely, the NCI CR rate (12.3%) was lower than the IWCLL CR rate (37.0%) because the most recent NCI CR criteria do not permit the inclusion of nodular infiltration or delayed hematological recovery, even if the total lymphocyte count in the bone marrow is less than 30%; instead, they recommend categorization of these patients as PR nodular and PR marrow failure, respectively. Binet stage A patients were not represented in the historical control patient population; however, when these patients were excluded from the analysis, the OR rates according to IWCLL and NCI criteria were consistent with the 70% OR rate reported for the historical patient cohort.

Following IV fludarabine phosphate, there is a trend toward higher response rates in patients with earlier-stage disease at baseline.⁸ We observed a similar trend following oral fludarabine phosphate, though the most marked difference was between Binet stage B and stage C disease at baseline (IWCLL response rates of 74.5% and 53.3%, respectively). The response rate of 80.0% in the patients with Binet A progressive disease (all with confirmed evidence of PD, such as lymphocyte doubling time, "B" symptoms, and so on) at baseline was, as might be expected, not dissimilar to that in the Binet B group; no historical experience is available in a comparable group treated with IV fludarabine phosphate.

The optimum duration of treatment for most patients was six cycles. However, 22% of patients achieved their maximum responses after an additional one or two cycles of treatment.

Treatment with the oral formulation of fludarabine phosphate was generally well tolerated and there were no unexpected or previously unreported signs of toxicity. Overall, the safety profile of oral fludarabine phosphate during this trial was acceptable and manageable, and was comparable with that of the IV formulation, with the exception of more frequent (though predominantly mild) gastrointestinal toxicity. However, the extremely low incidence of severe nausea/vomiting (1.2% grade 3, no grade 4) and diarrhea (6.2% grade 3, no grade 4) requiring treatment, and the fact that this type of toxicity did not cause compliance problems or withdrawal from the study, suggests that oral fludarabine phosphate is well tolerated.

Three cases of AIHA were reported during the study. In two of these cases (one moderate, one severe), a positive Coombs test was associated with the clinical symptoms, and the third case (mild) was reported as "possible" AIHA (this patient was Coombs test–negative). In the severe case, the patient subsequently had a bone marrow trephine showing heavy leukemic infiltration, leading to the suggestion that this, rather than hemolysis, might have caused the profound anemia. One case of severe thrombocytopenia (in a Coombs-positive patient) and one case of erythroblastopenia were also reported. All these patients were withdrawn from treatment, and made a full recovery. AIHA is a well-known risk in CLL patients, and autoimmune phenomena have also been reported after treatment with IV fludarabine phosphate.

WHO performance status was improved in 14% of patients and maintained in 78% of patients throughout the study, indicating the additional advantages of treatment in terms of patients' improved QOL. This finding is supported by the EORTC QLQ-30 and Spitzer's QLI data, which showed that oral fludarabine phosphate administration did not have a negative impact on QOL overall, and demonstrated improvements in emotional and insomnia scores. However, these improvements in patients' assessments of QOL should be interpreted with caution, as they may not be simply due to treatment, but to the phenomenon of "response shift," whereby patients adjust to their disease over time. Insomnia may be a surrogate for anxiety and may thus be improved by the feeling that treatment is having some benefit. Interestingly, the findings of WHO gastrointestinal toxicity were not reflected in the patients' assessments of their QOL with regard to nausea/vomiting and diarrhea, suggesting that any such effects were generally transient.

In summary, this study demonstrates that oral fludarabine phosphate has similar efficacy and safety to the IV formulation, and is well tolerated by patients with previously untreated B-CLL. This confirms other published data showing that oral fludarabine phosphate, alone or in combination, is simple, well tolerated, and effective,^10,12,21 and provides a more convenient treatment option than others currently available for patients with CLL.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
Investigators who made valuable contributions to this study are as follows: G. Verhoef, W. Schroyens, A. Ferrant, and A. Bosly (Belgium); J.G. Fuzibet and J.-J. Sotto (France); A.T. Maiolo (Italy); J.T.P. Janssen, P.W. Wijermans, and R. Willemze (the Netherlands); C. Poynton (United Kingdom); and O. Benitez (France). The assistance of Parthenon Medical Communications in the preparation of this article is gratefully acknowledged.

	NOTES

 
Supported by Schering AG, Berlin, Germany.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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4. Johnson S, Smith AG, Loffler H, et al: Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia: The French Cooperative Group on CLL. Lancet 347:1432-1438, 1996[Medline]

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7. Sorensen JM, Vena DA, Fallavollita A, et al: Treatment of refractory chronic lymphocytic leukemia with fludarabine phosphate via the group C protocol mechanism of the National Cancer Institute: Five-year follow-up report. J Clin Oncol 15:458-465, 1997[Abstract/Free Full Text]

8. Rai KR, Peterson BS, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750-1757, 2000[Abstract/Free Full Text]

9. Leporrier M, Chevret S, Cazin B, et al: Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 98:2319-2325, 2001[Abstract/Free Full Text]

10. 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 Clin Oncol 17:1574-1579, 1999[Abstract/Free Full Text]

11. Oscier D, Orchard J, Culligan D, et al: The bioavailability of oral fludarabine phosphate is unaffected by food. Hematol J 2:316-321, 2001[CrossRef][Medline]

12. Boogaerts M, Van Hoof A, Catovsky D, et al: Activity of oral fludarabine phosphate in previously treated chronic lymphocytic leukemia. J Clin Oncol 19:4252-4258, 2001[Abstract/Free Full Text]

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Submitted May 1, 2003; accepted August 12, 2003.

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