This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boogaerts, M. A. Articles by Klein, M. Search for Related Content PubMed PubMed Citation Articles by Boogaerts, M. A. Articles by Klein, M. Social Bookmarking                            What's this?

Activity of Oral Fludarabine Phosphate in Previously Treated Chronic Lymphocytic Leukemia

From the University Hospital, Leuven; St Jan Hospital, Brugge; and Hôpital Erasme, Brussels, Belgium; Royal Marsden Hospital, London; and Addenbrookes Hospital, Cambridge, United Kingdom; London Regional Cancer Center, London, Ontario, Canada; Ospedale Niguarda Ca’Granda, Milan; and Institute of Hematology "Seràgnoli," Bologna, Italy; Hôpital Pitié-Salpêtrière, Paris, France; Hospital Clinic i Provincial, Barcelona, Spain; and Schering AG, Berlin, Germany.

Address reprint requests to Marc Boogaerts, MD, PhD, Department of Hematology, University Hospital, U.Z. Gasthuisberg, Herestraat 49, B-2000 Leuven, Belgium; email: marc.boogaerts{at}uz.kuleuven.ac.be

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: A prospective, multicenter, open-label phase II clinical trial was conducted to assess the efficacy and safety of oral fludarabine phosphate. Reference to an historical group of patients treated with the intravenous (IV) formulation allowed the investigators to compare the two formulations.

PATIENTS AND METHODS: Efficacy was assessed using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and National Cancer Institute (NCI) criteria for complete remission (CR), partial remission (PR), stable disease, or disease progression. Safety monitoring included World Health Organization (WHO) toxicity grading for all adverse events.

RESULTS: Seventy-eight (96.3%) of 81 recruited patients with previously treated B-cell chronic lymphocytic leukemia (CLL) 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. According to IWCLL criteria, the overall remission rate was 46.2% (CR, 20.5%; PR, 25.6%). The comparative figures using NCI criteria were 51.3% (CR, 17.9%; PR, 33.3%). Overall, 30 incidents of severe adverse events were reported for 22 patients. WHO grade 3 or grade 4 hematologic toxicities included granulocytopenia (53.8%), leukocytopenia (28.2%), thrombocytopenia (25.6%), and anemia (24.4%). Gastrointestinal adverse events were more common with the oral formulation than previously reported with IV fludarabine phosphate. However, these events were generally mild to moderate.

CONCLUSION: This study demonstrates that oral fludarabine phosphate has similar clinical efficacy to the IV formulation and a safety profile that is both predictable and essentially similar to that of the IV formulation.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
FLUDARABINE PHOSPHATE, 2-fluoro-9-(5-O-phosphono-ß-D-arabinofuranosyl)-9H-purin-6-amine, is a nucleotide analog of adenine arabinoside. The intravenous (IV) formulation is indicated for the treatment of patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to, or whose disease has progressed during or after, treatment with at least one standard alkylating agent–containing regimen.

Fludarabine phosphate has proved to be a highly effective second-line agent in numerous clinical trials in CLL. Treatment with fludarabine phosphate (20 to 30 mg/m²/d for 5 days repeated every 3 to 5 weeks), has pro-duced objective response rates of 40% to 60% using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) or National Cancer Institute (NCI) response criteria for CLL.^1-4

Response and survival after treatment with fludarabine phosphate in advanced CLL are strongly correlated with disease stage and the degree of previous chemotherapeutic treatment.^4-8 Resistance of disease to alkylating agents is also significantly correlated to outcome.⁵ Perhaps not surprisingly, overall response rates have been greatest in patients with the lowest risk status or disease stage.⁶

Patients with nonrefractory CLL survive longer than patients with refractory disease (29 v 9 months).⁵ In addition, more patients respond if they have received only one previous chemotherapy regimen (82% v 44%) compared with those who have received more than three prior treatment regimens.⁵

Higher response rates after treatment with fludarabine phosphate are achieved by patients with relapsed CLL compared with patients with previously resistant disease (62% v 20%).⁸ Furthermore, responses are dose-dependent: 30 mg/m² IV once weekly achieved a 23% response rate,⁹ but when fludarabine phosphate was administered three times per week, overall response increased to 46%.¹⁰ Following a five times per week schedule, at this dose, patients achieved a 52% response rate.⁷ Similar response rates (53% and 59%, respectively) are obtained with 25 mg/m²/d IV and 30 mg/m²/d IV, given for 5 consecutive days every 4 weeks.¹¹

Fludarabine phosphate has also been evaluated against cyclophosphamide, doxorubicin, and prednisone (CAP) in 105 treatment-naive and 103 previously treated patients with CLL.¹² Compared with CAP, significantly more patients respond to fludarabine treatment (60% v 44%; P = .023), and significantly more previously treated patients respond to fludarabine phosphate (48% v 27%; P = .036).¹² When compared with chlorambucil in treatment-naive CLL patients,¹³ treatment with fludarabine phosphate also resulted in a higher response rate (63% v 37%) and longer progression-free survival (20 v 14 months).

Patients with CLL are typically 60 to 70 years of age, and in this age group, age-related concomitant diseases are quite common, which in turn may increase the risk of complications with fludarabine therapy. This is an important factor in determining the most appropriate mode of treatment. Another factor to be considered in this age group is the difficulty of obtaining venous access, particularly in heavily pretreated individuals.

Furthermore, IV chemotherapy with fludarabine phosphate entails regular visits to the hospital as an outpatient or admission for inpatient treatment, as a typical treatment cycle consists of 25 mg/m² given over 30 minutes every day for 5 days and repeated every 4 weeks. For this reason, an oral formulation would be more convenient for both patients and health care workers and may also be more cost-effective than IV therapy.

An oral formulation of fludarabine phosphate, comprising an immediate-release tablet containing 10 mg of fludarabine phosphate, has now been developed. Pharmacokinetics confirm that single doses of the oral formulation, given to patients with low-grade non-Hodgkin’s lymphoma and CLL, result in dose-dependent increases in the maximum plasma concentration (C_max) and 24-hour area under the concentration-time curve (AUC_{(0 to 24 hours)}), similar to those recorded after dose adjustment of IV fludarabine phosphate.¹⁴ Linear increases in AUC_{(0 to 24 hours)} corresponded well with increases in oral dosage and, furthermore, bioavailability was approximately 55%, with low intraindividual variation, and the time to reach C_max was dose-independent. The conclusion from this pharmacokinetic study was that oral doses of fludarabine phosphate could achieve an AUC_{(0 to 24 hours)} similar to that of the IV formulation with dose adjustment and dose-independent bioavailability.

This, and other pharmacokinetic studies,^15,16 have demonstrated that a once-daily oral dose of 40 mg/m² would provide a similar systemic exposure to 25 mg/m²/d IV. The present study was designed to investigate the efficacy and safety of oral fludarabine phosphate treatment. In addition, a retrospective comparison with the IV regimen in a similar patient population was made.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
A prospective, multicenter, open-label, phase II clinical trial was carried out at 29 centers in Belgium, Canada, France, Germany, Great Britain, Italy, the Netherlands, Spain, and Sweden. The objective of the study was to assess the response rate (complete remission [CR] and partial remission [PR]) and the safety profile of orally administered fludarabine phosphate in patients with previously treated CLL.

The study was conducted in accordance with European Good Clinical Practice guidelines (July 1990) and complied with the recommendations of the Declaration of Helsinki (Hong Kong Amendment, 1989). The protocol met all the requirements of the appropriate regulatory authorities and received formal approval from the Ethics Committee of the Berlin Chamber of Physicians. All eligible patients gave written consent to participate in the study.

Male or female patients aged 18 to 75 years were included if they had evolutive CLL as defined by the NCI-sponsored Working Group.¹⁷ Patients were included only if they had failed to respond to or had relapsed during or after previous treatment with at least one therapeutic regimen containing an alkylating agent. Eligible patients also had World Health Organization (WHO) performance status of 0 to 2 and a life expectancy of more than 6 months. Patients were excluded from the study if they had received prior treatment with purine analogs, mitoxantrone, or anthracyclines or had severe or life-threatening concomitant disease, autoimmune thrombocytopenia, or autoimmune hemolytic anemia (AIHA). Other exclusion criteria included impaired renal or hepatic function and progression to more aggressive B-cell cancers. Patients who were pregnant or lactating or who had not fully recovered from previous treatments were also excluded.

Patients received 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 cycles) to be given to patients in remission after the sixth cycle. Appropriate supportive therapy, including transfusions, antiemetics, anti-infection prophylaxis, and hematopoietic growth factors, could be provided at the discretion of the investigator, but other cytotoxic drugs and corticosteroids were prohibited.

Patients who did not respond or who, in the opinion of the responsible investigator, showed 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 from the study 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 0.5 x 10⁹/L or the platelet count was less than 50 x 10⁹/L. The dose was reduced to 30 mg/m²/d if, after 2 weeks, the granulocyte count remained 0.5 to 1.0 x 10⁹/L or the platelet count was 50 to 100 x 10⁹/L. The dose was lowered to 20 mg/m²/d if, after postponement, the granulocyte and platelet counts were less than 0.5 x 10⁹/L and less than 50 x 10⁹/L, respectively.

Efficacy Criteria
The primary efficacy measure was response to treatment, evaluated 3 to 5 weeks after the last treatment cycle. End-of-treatment assessment included a physical examination, laboratory values, and documentation of adverse events and WHO toxicity. All patients were examined for unilateral or bilateral enlargement of lymph nodes, hepatomegaly, and splenomegaly.

A bone marrow aspirate or biopsy was carried out for all patients who achieved CR. CR was defined as the absence of disease in accordance with the NCI¹⁷ and IWCLL¹⁸ criteria. PR, stable disease (SD), and progression of disease 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 both Binet and Rai staging criteria) and WHO performance status.

Safety Criteria
Baseline assessment included age, sex, ethnicity, height, weight, and body-surface area. Previous treatment for CLL and medical and surgical history were also recorded, as were details of previous and concomitant medications. Physical examinations were carried out at baseline, before the start of each treatment cycle, and at the final assessment.

Grading of all acute and subacute toxicity was carried out using WHO criteria (grade 0, absence of toxicity, to grade 4, severe toxicity). Assessments were made at baseline and again before each cycle of therapy. Adverse events not covered by the WHO toxicity criteria were documented separately. Records of adverse events also included the investigator’s opinion regarding the relationship of the event to the study drug (ie, unrelated, unlikely, possible, probable, or definite).

Statistical Evaluation
Response was defined as a binary variable; a patient was defined as a responder if he or she achieved CR or PR according to IWCLL criteria. SD and progressive disease were defined as no response. These definitions also applied to evaluations using NCI criteria. All clinical assessments were evaluated for intent-to-treat patients (ITT population; all patients who received treatment).

Where feasible, as soon as a patient withdrew from the study, an assessment of response to treatment was carried out. All patients were included for whom response could be evaluated by the investigator, regardless of whether a patient prematurely discontinued treatment.

The null hypothesis for this study established that response rates under fludarabine phosphate equal to 45%, with a 95% confidence interval (CI) of 24.2% to 52.8%, could not be rejected. The historical control group comprised 53 patients with previously treated CLL who were treated with fludarabine phosphate as part of a comparative study with CAP.¹²

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
A total of 81 patients were recruited; two patients withdrew their consent before receiving the first dose of fludarabine phosphate and one patient was found not to have B-CLL and was therefore excluded before the first cycle of therapy. The remaining 78 patients (the ITT population) were treated and assessed for efficacy and safety. Table 1 lists the demographic characteristics of the ITT population and of the historical control population. All patients were previously treated for the underlying hematologic illness with cytotoxic drugs. Almost all of the patients had previous treatment with chlorambucil alone or in combination with prednisolone. Most of the patients who then experienced treatment failure with this regimen received cyclophosphamide alone or in combination with vincristine and prednisone. Some patients also received hydroxyurea, methotrexate, or interferon.

Safety Evaluation
The most frequently reported toxicity during treatment with oral fludarabine phosphate was myelosuppression; WHO grade 3 or 4 toxicities included granulocytopenia (53.8%), leukocytopenia (28.2%), thrombocytopenia (25.6%), and anemia (24.4%). There were 35 cases of infection (44.8%) reported during the study. Six (7.7%) of these were of WHO grade 3 severity infection (Table 6). Cases of atypical infections were seen, including cytomegalovirus (n = 1), adenovirus (n = 1), Legionella (n = 1), and aspergillosis (n = 1).

One patient was reported to have had a severe consciousness-related adverse event. The severe impairment of consciousness in this patient occurred during the last treatment cycle, while the patient had severe hemolytic anemia. In all, 15.4% patients experienced mild consciousness-related adverse events and 6.4% reported mild to moderate peripheral nervous system disorders during the study.

In general, treatment was well tolerated and in line with previous experience with IV fludarabine phosphate; most dose reductions were due to hematologic toxicity. A total of 20 patients (25.6%) required dose reductions because of hematologic toxicity, three patients because of nonhematologic toxicity, and two because of both hematologic and nonhematologic toxicity.

Four deaths were documented during the study in patients who had been prematurely withdrawn; two because of disease progression and two because of pulmonary infections. In total, 30 incidents of severe adverse events were reported for 22 patients, including AIHA (n = 4), pneumonia (n = 3), anemia (n = 2), leukopenia (n = 2), thrombocytopenia (n = 2), anorexia (n = 2), fever (n = 2), headache (n = 1), infection (n = 2), carcinoma (n = 1), and pancytopenia (n = 1). Three of the patients in whom AIHA occurred required hospitalization. In two of these cases, the patients recovered within a month of fludarabine phosphate discontinuation and treatment with corticosteroids or blood transfusions. In the third case the anemia was prolonged even after treatment with corticosteroids, immunoglobulins, cyclophosphamide, and blood transfusions.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Although alkylating agents such as chlorambucil have been the mainstay of treatment in newly diagnosed patients with CLL for many years,¹⁹ fludarabine phosphate is now regarded as the treatment of choice for patients with relapsed or refractory disease.¹ Even in high-risk patients, response rates of more than 35% have been achieved by second-line treatment with fludarabine phosphate.

The data from this study demonstrate that the oral formulation of fludarabine phosphate is essentially similar to the IV formulation in terms of clinical efficacy. In the present study, the overall response rates were consistent with the efficacy profile of IV fludarabine phosphate in the historical control group, for which a response rate of 45.3% was observed. The historical control group consisted of patients recruited using similar eligibility criteria. However, the mean number of previous treatments was slightly higher in the study population than in the historical group (mean, 2 v 1.2) and there were more Binet stage A patients. According to the IWCLL response criteria, 36 patients (46.2%) responded to treatment, with 20.5% achieving CR and 25.6% achieving PR. By NCI criteria, the overall response rate was 51.3%. These analyses showed that the null hypothesis established for the study, that the response rates were equal to 45%, could not be rejected.

Because the NCI bone marrow response criteria do not permit nodular infiltration, even when the total lymphocyte count is less than 30%, analysis by NCI criteria assessed one patient less as achieving CR (17.9%) compared with IWCLL criteria (20.5%). However, more patients were considered to have achieved PR according to NCI as compared with IWCLL criteria (33.3% v 25.6%), because assessments of parameters such as enlarged lymph nodes, liver, or spleen are less stringent with NCI criteria.

The stage of the patient’s disease at baseline had a predictable impact on response rates during the study. Of the patients at Binet stage A at baseline, 56.5% responded to treatment, compared with 29% patients at Binet stage C. This observation fits closely with that previously reported for the IV formulation.^5-7

The optimum duration of the treatment for most patients was six cycles. A proportion of patients (29.5%) required seven or eight cycles of treatment to achieve the optimum response.

In this population of elderly relapsed and refractory (after previous treatment) patients, 55% maintained WHO performance status throughout the study, indicating that the advantages of treatment extended beyond blood cell responses and exerted a positive effect in maintaining the quality of life of the patients. Furthermore, 15.4% of patients improved their performance status. This is a clear benefit of treatment with oral fludarabine phosphate, which, considering the added benefit of treating CLL patients on an outpatient (or ambulatory) basis, highlights the potential value of fludarabine oral in a palliative setting, where quality of life is an important factor.

The safety profile of fludarabine oral formulation was predictable and entirely comparable to that of the IV formulation, with the exception of more frequent—but predominantly mild—gastrointestinal adverse events. Gastrointestinal effects are of particular relevance in the evaluation of any oral agent, because vomiting or diarrhea may prevent accurate dosing and thus compromise serum levels. Furthermore, patients are naturally averse to nauseating medications. The very low incidence of grade 3 nausea and vomiting (1.3%) or diarrhea (3.8%) suggests that oral fludarabine phosphate was well tolerated.

Among the hematologic toxicities observed during the present study were four cases (5.1%) of AIHA. AIHA has previously been observed after single or repeated cycles of treatment with the IV formulation of fludarabine phosphate, and attention is drawn to the need to monitor patients for this uncommon adverse event when using purine analogs such as fludarabine phosphate. The mechanism by which fludarabine phosphate and the other purine analogs precipitate autoimmune responses of this sort remains uncertain, but in our experience, corticosteroids (eg, prednisone 40 to 60 mg/m²/d) usually prove effective in the management of this adverse event.

There was only one instance of grade 3 or 4 (WHO) alopecia, which is a commonly reported and distressing adverse effect of treatment with many cytotoxic agents including chlorambucil and, to a lesser extent, cyclophosphamide. Similarly, oral fludarabine phosphate showed an advantage over chlorambucil with respect to effects on the skin. There were only four instances of rashes (5.1%) and three instances of pruritus (3.8%) reported during the present study.

Given the ever-widening role of fludarabine phosphate in the therapy of hematologic malignancies and its use in combinations with agents such as mitoxantrone or cytarabine, an oral treatment modality has potential benefit. This is particularly true when other drugs within the potential combinations can be administered orally, for example, oral idarubicin. With clinical equivalence and an essentially similar safety profile, the oral formulation of fludarabine phosphate offers the hematologist a potentially important new treatment option.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Investigators who made valuable contributions to this study are as follows: A. Bosly, MD, D. Bron, MD, and R. Schots, MD (Belgium); J. Johnston, MD, and R.M. Meyer, MD (Canada); M. Leporrier, MD, and A. Travade, MD (France), K.P. Hellriegel, MD, D. Huhn, MD, E. Thiel, MD, W. Knauf, MD, and F. Schriever, MD (Germany); T.A. Lister, MD, J.A. Child, MD, S. Johnson, MD, and A. Lennard, MD (United Kingdom); E. Morra, MD, B. Rotoli, MD, and S. Tura, MD (Italy); R. Willemze, MD, and L.F. Verdonck, MD (the Netherlands); and E. Montserrat Costa, MD (Spain), G. Juliusson, MD, and U. Tidefeldt, MD (Sweden).

	ACKNOWLEDGMENTS

 
Supported financially by Schering AG, Berlin, Germany.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Montserrat E, Bosch F, Rozman C: Treatment of B-cell chronic lymphocytic leukaemia: Current status and future perspectives. J Intern Med 242: 63-67, 1997 (suppl)

2. O’Brien S, Kantarjian H, Beran M, et al: Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 82: 1695-1700, 1993[Abstract/Free Full Text]

3. 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]

4. Adkins JC, Peters DH, Markham A: Fludarabine: An update of its pharmacology and use in the treatment of haematological malignancies. Drugs 53: 1005-1037, 1997[Medline]

5. Keating MJ, O’Brien S, Kantarjian H, et al: Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. Blood 81: 2878-2884, 1993[Abstract/Free Full Text]

6. Keating MJ, O’Brien S, McLaughlin P, et al: Clinical experience with fludarabine in hemato-oncology. Hematol Cell Ther 38: S83-S91, 1996 (suppl 2)

7. Spriano M, Clavio M, Carrara P, et al: Fludarabine in untreated and previously treated B-CLL patients: A report on efficacy and toxicity. Haematologica 79: 218-224, 1994[Abstract/Free Full Text]

8. Montserrat E, Lopez-Lorenzo JL, Manso F, et al: Fludarabine in resistant or relapsing B-cell chronic lymphocytic leukemia: The Spanish Group experience. Leuk Lymphoma 21: 467-472, 1996[Medline]

9. Kemena A, O’Brien S, Kantarjian H, et al: Phase II clinical trial of fludarabine in chronic lymphocytic leukemia on a weekly low-dose schedule. Leuk Lymphoma 10: 187-193, 1993[Medline]

10. Robertson LE, O’Brien S, Kantarjian H, et al: A 3-day schedule of fludarabine in previously treated chronic lymphocytic leukemia. Leukemia 9: 1444-1449, 1995[Medline]

11. Keating MJ, Kantarjian H, Talpaz M, et al: Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 74: 19-25, 1989[Abstract/Free Full Text]

12. 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]

13. Rai KR, Peterson BL, 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]

14. 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]

15. Kemena A, Keating MJ, Plunkett W: Plasma and cellular bioavailability of oral fludarabine. Blood 78: 52a, 1991 (abstr 199)

16. Klein M, Ludwig W-D, Fulle HH, et al: 2f-ara-A pharmacokinetics including systemic availability during treatment with fludarabine phosphate given either perorally as an immediate release tablet formulation, or intravenously as a solution. Onkologie 20: 137a, 1997 (abstr, suppl 1)

17. Cheson BD, Bennett JR, Grever M, et al: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87: 4990-4997, 1996[Free Full Text]

18. International Workshop on Chronic Lymphocytic Leukemia: Chronic lymphocytic leukemia: Recommendations for diagnosis, staging and response criteria. Ann Intern Med 110: 236-238, 1989

19. Montserrat E, Rozman C: Chronic lymphocytic leukemia treatment. Blood Rev 7: 164-175, 1993[Medline]

Submitted December 21, 2000; accepted June 27, 2001.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				K. Tobinai, T. Watanabe, M. Ogura, Y. Morishima, Y. Ogawa, K.-i. Ishizawa, H. Minami, A. Utsunomiya, M. Taniwaki, T. Terauchi, et al. Phase II Study of Oral Fludarabine Phosphate in Relapsed Indolent B-Cell Non-Hodgkin's Lymphoma J. Clin. Oncol., January 1, 2006; 24(1): 174 - 180. [Abstract] [Full Text] [PDF]

				K. Balakrishnan, C. M. Stellrecht, D. Genini, M. Ayres, W. G. Wierda, M. J. Keating, L. M. Leoni, and V. Gandhi Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP Blood, June 1, 2005; 105(11): 4455 - 4462. [Abstract] [Full Text] [PDF]

				J.-F. Rossi, A. Van Hoof, K. De Boeck, S.A. Johnson, D. Bron, C. Foussard, T.A. Lister, C. Berthou, M.H.H. Kramer, T.J. Littlewood, et al. Efficacy and Safety of Oral Fludarabine Phosphate in Previously Untreated Patients With Chronic Lymphocytic Leukemia J. Clin. Oncol., April 1, 2004; 22(7): 1260 - 1267. [Abstract] [Full Text] [PDF]

				W. J. Hogan, M. Maris, B. Storer, B. M. Sandmaier, D. G. Maloney, H. G. Schoch, A. E. Woolfrey, H. M. Shulman, R. Storb, and G. B. McDonald Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients Blood, January 1, 2004; 103(1): 78 - 84. [Abstract] [Full Text] [PDF]

				O. Tournilhac, B. Cazin, S. Lepretre, M. Divine, K. Maloum, A. Delmer, B. Grosbois, P. Feugier, F. Maloisel, F. Villard, et al. Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia Blood, January 1, 2004; 103(1): 363 - 365. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boogaerts, M. A. Articles by Klein, M. Search for Related Content PubMed PubMed Citation Articles by Boogaerts, M. A. Articles by Klein, M. Social Bookmarking                            What's this?