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V O L U M E 2 7 ⅐ N U M B E R 2 6 ⅐ S E P T E M B E R 1 0 2 0 0 9 Phase III Randomized Study of Bendamustine Compared With Chlorambucil in Previously Untreated Patients With University Hospital, Jena; DSH Statistical Wolfgang U. Knauf, Toshko Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul Herbrecht, Gunnar Juliusson, Gerhard Postner, Liana Gercheva, Stefan Goranov, Martin Becker, Hans-Joerg Fricke, Francoise Huguet, Ilaria Del Giudice, Peter Klein, Lothar Tremmel, Karlheinz Merkle, and Marco Montillo Hospital, Plovdiv, Bulgaria; Department of Oncology, Universita degli Studi, Perugia; This randomized, open-label, parallel-group, multicenter study was designed to compare the efficacy and safety of bendamustine and chlorambucil in previously untreated patients with advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL).
Universita “La Sapienza,” Roma, Italy; Patients and Methods
Patients (Յ 75 years of age) were randomly assigned to receive bendamustine 100 mg/m2/d Princesa, Madrid, Spain; Hematology & intravenously on days 1 to 2, or chlorambucil 0.8 mg/kg (Broca’s normal weight) orally on days 1 and 15; treatment cycles were repeated every 4 weeks for a maximum of six cycles. The response tology, Hopital Purpan, Toulouse, France; to treatment was assessed according to National Cancer Institute Working Group criteria, and the final determination of response was made by a blinded independent review committee.
A total of 319 patients were randomly assigned (162 bendamustine, 157 chlorambucil). Complete or partial responses were achieved in 110 (68%) of 162 bendamustine-treated and 48 (31%) of 157 chlorambucil-treated patients (P Ͻ .0001). More patients showed complete responses with bendamustine than with chlorambucil (31% v 2%). Median progression-free survival was 21.6 months with bendamustine and 8.3 months with chlorambucil (P Ͻ .0001). Bendamustine was also associated with an improvement in duration of remission, compared with chlorambucil (median, 21.8 v 8.0 months). Hematologic National Cancer Institute Common Toxicity Criteria grade 3 to 4 adverse events were more common with bendamustine than with chlorambucil (occurring in 40% v 19% of patients). Severe infections (grade 3 to 4) occurred in 8% of bendamustine-treated patients and 3% of chlorambucil-treated patients.
Bendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity
profile, when used as first-line therapy in patients with advanced CLL.
J Clin Oncol 27:4378-4384. 2009 by American Society of Clinical Oncology without affecting overall survival.4,5 However, there INTRODUCTION
remains a need for new treatment options in pa- Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western Bendamustine is a novel agent, synthesized world.1 Although patients with early-stage disease with the intent of combining the alkylating proper- ties of mechlorethamine and the purine antimetab- have a life expectancy of longer than 10 years, those who progress or have advanced disease (Binet stage olite properties of benzimidazole.6,7 This agent, B or C or Rai stage II to IV) have a median survival of alone or in combination with other chemotherapeu- approximately 2 to 7 years.2,3 First-line treatment is tic agents, has been shown to produce good clinical frequently conducted with chlorambucil, fludara- efficacy and acceptable tolerability in patients with bine, or fludarabine plus cyclophosphamide, either non-Hodgkin’s lymphoma8,9 and multiple myelo- alone or in combination with rituximab. Fludara- ma.10 In phase I/II trials in patients with advanced bine has been reported to produce higher response relapsed or refractory CLL, bendamustine has rates, a longer duration of remission, and longer been shown to produce overall response rates progression-free survival than chlorambucil in pre- (ORR) similar to or higher than those achieved with viously untreated younger patients with CLL, but chlorambucil.11-14 Therefore, a phase III trial was 2009 by American Society of Clinical Oncology Downloaded from on July 17, 2011. For personal use only. No other uses without permission.
Copyright 2009 American Society of Clinical Oncology. All rights reserved.
Bendamustine v Chlorambucil in CLL
undertaken to compare the efficacy and tolerability of bendamustine investigator to the same maximum of six cycles. Patients with progressive with that of chlorambucil in previously untreated patients with CLL.
disease were withdrawn. After the last treatment cycle, patients were moni-tored for response and survival at 3-month intervals. Final assessment of bestresponse was performed in a blinded fashion by an Independent Committee PATIENTS AND METHODS
for Response Assessment (ICRA) and classified as CR, PR, PR with nodularinvolvement, stable disease, or progressive disease based on the NationalCancer Institute Working Group criteria.15 The study was a randomized, open-label, parallel-group, phase III trial con- Primary end points were the overall response rate and progression-free ducted at 45 centers in Austria, Bulgaria, France, Germany, Italy, Spain, Swe- survival. Secondary end points included time to progression, duration of den, and the United Kingdom. The protocol was approved by local ethics remission, and overall survival. Safety end points were infection rates and committees at all participating centers, and the study was conducted in accor- dance with the International Conference on Harmonization Good ClinicalPractice guidelines and the Declaration of Helsinki.
Statistical Methods and Sample Size Calculation
The statistical analysis was performed on the intention-to-treat (ITT) Patients
patient population. The safety population consisted of all patients who re- Previously untreated patients up to 75 years of age with Binet stage B (ie, ceived at least one dose of study medication.
3 lymph node regions involved including hepatomegaly and splenomegaly) Statistical analysis of the primary end points was performed by means of or Binet stage C (ie, anemia and/or thrombocytopenia regardless of the num- an a priori–sequenced hypothesis testing and an adaptive group sequential test ber of lymph node regions) CLL confirmed by demonstration of coexpression procedure. Overall remission rate was analyzed by means of Fisher’s exact test, of CD5, CD23, and either CD19, CD20, or both, and in need for treatment15,16 stratified by Binet stage; progression-free survival was analyzed by log-rank were included. All patients were required to have a WHO performance status test, stratified by Binet stage. All tests were two tailed with a multiple signifi- of 0 to 2 and a life expectancy of at least 3 months. Women of childbearing potential were required to use adequate contraception for at least 6 months A five-stage adaptive group sequential procedure with Pocock cut-offs of after treatment. Patients with a second malignancy other than cured basal cell ␣ ϭ .016 was used, with a maximum of four planned interim analyses, of carcinoma or cured cervical cancer were excluded, as were patients with which three were performed (first analysis after treated 85 patients with a manifest immune hemolysis or thrombocytopenia that could be treated with follow-up of at least 5 months; second analysis after 158 patients; third analysis corticosteroids alone, and patients with Richter’s syndrome or transformation after 264 patients). In each interim analysis, ORR was tested first, while to prolymphocytic leukemia. Other exclusion criteria were hepatic dysfunc- progression-free survival was tested only if the first was significant, thus con- tion (bilirubin Ͼ 2.0 mg/dL, transaminases Ͼ 3ϫ upper limit of normal, or trolling for multiple testing.17 The P values of the individual sequences were both), renal dysfunction (calculated creatinine clearance Ͻ 30 mL/min), sig- combined using the ␸Ϫ1 method17; since patients included in each interim nificant medical or mental disorders, known HIV infection, pregnancy orlactation, hypersensitivity to study drugs, major surgery within 30 days beforethe start of the trial, and participation in another clinical trial within 4 weeksbefore the study. Written informed consent was obtained from all patientsbefore inclusion in the study.
Table 1. Demographic Characteristics of the Intention-to Treat Population
Recruitment started in November 2002 and was stopped in Novem- Study Design and Treatment
Patients were randomly assigned in a 1:1 ratio to receive bendamustine or chlorambucil, and stratified by center and Binet stage. Bendamustine (Ri- bosepharm, Munich, Germany) was administered by intravenous infusion over 30 minutes at a dose of 100 mg/m2/d on days 1 to 2 every 4 weeks.
Chlorambucil (GlaxoSmithKline, Uxbridge, United Kingdom) was given orally at a dose of 0.8 mg/kg (Broca’s normal weight in kg: the body weight for the dose being the height of the patient in cm minus 100) on days 1 and 15 (or as divided doses on days 1 to 2 and 15 to 16 for patient comfort in some individual cases) every 4 weeks. Treatment was to be suspended if platelet counts decreased to below 20 ϫ 109/L, hemoglobin decreased to below 7 g/dL, or the absolute neutrophil count decreased to lower than 0.5 ϫ 109/L. Doses were to be modified according to the National Cancer Institute Working Group guidelines15 if hematologic toxicities developed. For Common Toxicity Criteria grade 3 nonhematologic toxicities other than nausea and vomiting or alopecia, the dose was to be reduced by 50% or the patient withdrawn from the study, depending on the investigator’s judgment; if any grade 4 toxicity devel- oped, the patient was to be withdrawn. Patients for whom dose reduction was necessary could have the dose restored to the original level if they had tolerated the reduced dose. Prophylactic hyperuricemic treatment was recommended to prevent uric acid-induced nephropathy. Nonprotocol antineoplastic drugs were not allowed. The study protocol did not provide recommendations for the prophylactic use of antibiotics or antiemetics. The use of hematopoietic Patients were assessed for response after three cycles of treatment. Two additional cycles were recommended for patients with complete response (CR) or partial response (PR), up to a maximum limit of six cycles in total. The response criteria according to the National Cancer Institute Sponsored Work- Abbreviations: BEN, bendamustine; CLB, chlorambucil; SD, standard devia- ing Group guidelines for CLL15 had to be met for at least 8 weeks. Patients with no change were allowed to receive additional cycles at the discretion of the 2009 by American Society of Clinical Oncology Downloaded from on July 17, 2011. For personal use only. No other uses without permission.
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Knauf et al
Table 2. Quality of Response According to Independent Committee for Response Assessment: Intention-to-Treat Population
Abbreviations: BEN, bendamustine; CLB, chlorambucil.
analysis were still under observation, these values were not definitive, and in the chlorambucil group required at least one dose reduction. The were used only to determine whether to continue the study with the new principal reasons for dose reduction in both groups were neutropenia sample size or to terminate the study. After each interim analysis the safety and efficacy data were reviewed by an independent data monitoring com- Overall, 110 bendamustine-treated patients (68%), and 48 mittee who decided about study continuation. After the third interimanalysis, the independent data monitoring committee recommended (31%) chlorambucil-treated patients achieved a CR or PR as deter- the termination of the recruitment and the final analysis to be per- mined by the ICRA (P Ͻ .0001). The proportion of patients with CR formed with the available data. Thus, the enrollment of patients or PR is summarized in Table 2. The proportion of patients with a CR was higher with bendamustine than with chlorambucil (31% v 2%), as Sample size calculations were based on data from a study comparing was the proportion with nodular PR (11% v 3%). Patients with stage C fludarabine and chlorambucil in previously untreated CLL patients,4 which disease showed a higher likelihood of CR with bendamustine: nine suggesting a 30% difference in overall remission rate between treatments, and patients (20%) with bendamustine showed a CR, whereas no a 6-month difference in median progression-free survival. From this, it wascalculated that approximately 42 patients per group would be required to chlorambucil-treated patient did so.
achieve 80% power to show a significant difference in overall response rate, The median observation time was 35 months (range, 1 to 68) at assuming a two-sided level of statistical significance of ␣ ϭ .05. For the second the time of the analysis presented here. The median progression-free primary end point— progression-free survival—it was calculated that a total survival was 21.6 months in the bendamustine group and 8.3 months of 326 patients would be required if no interim analyses were to be performed.
in the chlorambucil group (P Ͻ .0001; Fig 1). This difference was Since it was uncertain whether the assumptions based on the data from the evident in patients with Binet stage B disease (bendamustine: median previous study4 would apply to this study, the adaptive group sequential 21.4 months; chlorambucil: median 9.0 months) as well as in stage C procedure described above was used. Using this approach, the final sample sizewas estimated to be approximately 350 patients.
disease (bendamustine: median 25.4 months; chlorambucil: median6.3 months).
The median duration of response in the bendamustine and chlorambucil groups was 21.8 months and 8.0 months, respectively.
Between November 2002 and November 2006, 319 patients wererandomly assigned,162 to bendamustine and 157 to chlorambucil. Sixpatients randomly assigned to chlorambucil and one to bendamustine were not treated. The ITT population includes all 319 randomly as- signed patients and the safety population includes 312 treated patients.
Demographic characteristics of the ITT population are sum- marized in Table 1. Overall, patient characteristics were well bal- anced between the groups. One hundred sixteen (72%) in the bendamustine group and 111 (71%) in the chlorambucil group had Binet stage B disease, while 46 (28%) and 46 (29%), respec- tively, had stage C disease. The mean time from initial diagnosis to registration in the trial was 18.8 months (standard deviation [SD], 32.3) in the bendamustine group and 24.6 months (SD, 33.9) in the chlorambucil group (P ϭ .12).
The median number of treatment cycles per patient was six in both arms. The mean number of treatment cycles per patient was 4.9 Fig 1. Progression-free survival based on the assessment of Independent
(SD, 1.7) with bendamustine and 4.9 (SD, 1.7) with chlorambucil.
Committee for Response Assessment: intention-to-treat population. BEN, ben- Overall, 54 patients (34%) in the bendamustine group and 46 (31%) 2009 by American Society of Clinical Oncology Downloaded from on July 17, 2011. For personal use only. No other uses without permission.
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Bendamustine v Chlorambucil in CLL
The adherence to the dosing schedule was high in both treatment arms. In total, 90% of the planned bendamustine dose and 95% of the planned chlorambucil dose were administered.
PR-BEN (N = 60; median, 17.4)PR-CLB (N = 45; median, 8) Severe infections of grade 3 or 4 occurred in 8% and 3% of treated patients in the bendamustine and chlorambucil arm, respectively, with one singular grade 4 infection in the chlorambucil arm.
Fifty-eight patients (36%) in the bendamustine group and six patients (4%) in the chlorambucil group received antiemetic therapy.
Antiemetics were given as preventive therapy in 46 of the 58 patients in the bendamustine group and in two of six patients in the chloram-bucil group.
There was a single report of a new malignancy during follow-up; a bronchial carcinoma in a patient who had received bendamustine was detected 12 months after the patient has finished treatment There were two reports on tumor lysis syndrome, both in pa- tients who had received their first cycle of bendamustine. However, Fig 2. Duration of responses according to Independent Committee for Re-
these events were not fatal and the two patients continued treatment.
sponse Assessment: intention-to-treat population. BEN, bendamustine; CLB,chlorambucil; CR, complete response; PR, partial response.
The median duration of CR (Fig 2) in bendamustine-treated patients This study has shown that bendamustine induces significantly higher was 29.3 months. The median duration of PR was 17.4 months with response rates and longer progression-free survival than chlorambucil bendamustine and 8.0 months with chlorambucil.
in first-line therapy in patients with CLL. Chlorambucil was chosen as Further follow-up is required to comment on survival. Overall, the comparator because it was approved for first-line use in CLL in all 72 patients (31 in the bendamustine group, 41 in the chlorambucil participating countries when the trial was planned in 2001. Further- group) died during follow-up. Death due to CLL was reported for 13 more, chlorambucil exhibits a favorable toxicity profile that makes this patients in the bendamustine group and 21 patients in the chloram- agent suitable in the elderly CLL patients.4,18 bucil group. So far, no significant differences in overall survival have The cumulative dose of chlorambucil was carefully considered and was at the higher end compared to doses used in other random-ized trials (Table 4). The cumulative dose of chlorambucil in this study Safety
was similar to that used in a recently completed trial.19 A total of 23 patients—18 from the bendamustine and five from The response rate achieved with chlorambucil is comparable the chlorambucil group—were withdrawn from the study due to with that achieved in another trial4 with this agent, in which the total unacceptable toxicity or the risk/benefit assessment was no longer dose per cycle was below 100 mg/cycle. A higher response rate of 59% acceptable. The most frequent adverse events (AEs) leading to termi- was reported by Eichhorst et al18 in an elderly study population, nation of the study were hypersensitivity reactions including skin and however, without external monitoring and without independent re- subcutaneous tissue (nine patients treated with bendamustine, two sponse assessment. In our trial, ORR achieved with chlorambucil treated with chlorambucil). Two patients in the bendamustine arm assessed by the treating physician was 40%, while with the rigorous but none in the chlorambucil arm experienced grade 3 hypersensitiv- ity reactions. Grade 4 hypersensitivity was not observed at all (Table 3).
The overall response rate achieved with bendamustine was com- AE s were reported in 143 (89%) of 161 patients in the bendamustine parable with that obtained with fludarabine4,20-22 or cladribine.23 The group and 122 (81%) of 151 in the chlorambucil group. Most fre- 31% CR rate achieved with bendamustine is higher than those recently quently occurring AEs were hematologic with the number of events reported for fludarabine alone.18,24,25 However, other studies with being higher in the bendamustine arm (neutropenia in 27%, throm- fludarabine monotherapy have reported CR rates up to 40%.4,20 Sim- bocytopenia in 25%, and anemia in 22% of patients) than in the ilar or higher CR rates have been reported with combinations of chlorambucil arm (neutropenia in 14%, thrombocytopenia in 21%, fludarabine with cyclophosphamide22,24,25 or rituximab26 or with and anemia in 14% of patients). GI events (nausea, vomiting, and both.27-29 Nevertheless, the high CR rate with bendamustine is an diarrhea) were also more frequent under bendamustine than under important finding because there is evidence that the CR is associated chlorambucil (Table 3). Neutropenia of National Cancer Institute with longer progression-free survival.28-31 Working Group grade 3 or 4 occurred in 37 bendamustine-treated Progression-free survival was significantly longer with benda- patients (23%) and 16 chlorambucil-treated patients (11%), granulo- mustine than with chlorambucil, and similar to that reported with cyte colony-stimulating factors were used on the discretion of the fludarabine,22,25 and alemtuzumab.19 This represents a valuable investigators in 23 (3%) of 783 cycles in the bendamustine and in two clinical benefit since prolonged progression-free survival is as- (0.3%) of 733 cycles in the chlorambucil arm. Erythropoetin was used sumed to be associated with improved quality of life. The median in 0.5% and 0.3% of all cycles in the bendamustine and chlorambucil progression-free survival in chlorambucil-treated patients was lower than in other trials.4,18,19,24 In addition to methodologic 2009 by American Society of Clinical Oncology Downloaded from on July 17, 2011. For personal use only. No other uses without permission.
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Knauf et al
Table 3. Summary of Adverse Events Occurring in At Least 5% of Patients by System Organ Class and Preferred Terms
System Organ Class Preferred Term by Disorder General disorders and administration site conditions Abbreviations: BEN, bendamustine; CLB, chlorambucil.
differences (ie, external monitoring, blinded assessment) this may grade 3 to 4 infection rates of 11% and 15% have been recently be due to differences in the patient population. These other studies reported for fludarabine22 and fludarabine with cyclophospha- have included patients with Binet stage A (ie, Ͻ 3 lymph node mide28 in similar populations. The difference may be explained by regions involved, corresponding in part to Rai stages 0 to 1) disease different etiologies. Infections occurring during bendamustine treatment may be related to transient neutropenia, whereas flu- Toxicity of bendamustine was manageable and of short dura- darabine is associated with prolonged T-cell depletion.33 tion. Severe infections are of particular interest since they are a There are anecdotal reports on transient hemolysis in two pa- major cause of morbidity and mortality in CLL patients.32 Com- tients treated with bendamustine and one treated with chlorambucil.
mon Toxicity Criteria grade 3 to 4 infections occurred in 8% of All of these patients had positive DAT at study entry. At the end of patients with bendamustine and 3% with chlorambucil. Notably, therapy active hemolysis was apparent in none of these patients.
Table 4. Comparison of Total Doses Chlorambucil in Different Trials Based on an Average Patient (70 kg/1.75 m/1.85 m2)
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Bendamustine v Chlorambucil in CLL
The two reports on tumor lysis syndrome during the first cycle of Employment or Leadership Position: None Consultant or Advisory
treatment with bendamustine merit particular attention. Tumor lysis Role: Wolfgang U. Knauf, Ribosepharm, Germany and Mundipharma,
syndrome is reported as a rare but potentially fatal event in fludarabine Germany (C); Hans-Joerg Fricke, Ribosepharm, Germany (C); Karlheinz
Merkle, Ribosepharm and Mundipharma (C) Stock Ownership: None
treatment of CLL and to occur predominantly in high-risk patients Honoraria: Wolfgang U. Knauf, Ribosepharm, Germany and
presenting with high lymphocyte counts and hepatosplenomegaly.34 Mundipharma, Germany Hans-Joerg Fricke, Ribosepharm, Germany; Both affected patients in our trial presented with a high tumor burden.
Marco Montillo, Mundipharma Italy Research Funding: Peter Klein,
At least in such cases it is urgently recommended to administer pro- Ribosepharm, Germany; Marco Montillo, Mundipharma International phylactic therapy against hyperuricemia and to provide the patients Expert Testimony: Gunnar Juliusson, Swedish National CLL Group (U)
with adequate fluid intake during the initial phase of treatment.
Other Remuneration: Gunnar Juliusson, Bayer Schering, Roche
Meanwhile, the combination of bendamustine with rituximab was reported to be feasible.35 This combination may offer an addi- AUTHOR CONTRIBUTIONS
tional option for treatment of patients with CLL.
In conclusion, this study has shown that bendamustine offers Conception and design: Wolfgang U. Knauf, Karlheinz Merkle
Administrative support: Karlheinz Merkle
significantly greater efficacy than chlorambucil, and a manageable toxicity Provision of study materials or patients: Wolfgang U. Knauf, Toshko
profile, when used as first-line therapy in patients with advanced CLL. In Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul March 2008, the US Food and Drug Administration approved benda- Herbrecht, Gunnar Juliusson, Gerhard Postner, Liana Gercheva, Stefan mustine for the treatment of CLL with regard to data of this trial.
Goranov, Martin Becker, Hans-Joerg Fricke, Francoise Huguet, Ilaria Del
Guidice, Marco Montillo
Collection and assembly of data: Wolfgang U. Knauf, Toshko
Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul
Herbrecht, Gunnar Juliusson, Gerhard Postner, Liana Gercheva, StefanGoranov, Martin Becker, Hans-Joerg Fricke, Francoise Huguet, Ilaria DelGuidice, Karlheinz Merkle, Marco Montillo Although all authors completed the disclosure declaration, the following Data analysis and interpretation: Wolfgang U. Knauf, Peter Klein,
author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked Manuscript writing: Wolfgang U. Knauf, Gunnar Juliusson, Peter Klein,
with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed Final approval of manuscript: Wolfgang U. Knauf, Toshko Lissichkov,
description of the disclosure categories, or for more information about Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul Herbrecht, Gunnar ASCO’s conflict of interest policy, please refer to the Author Disclosure Juliusson, Gerhard Postner, Liana Gercheva, Stefan Goranov, Martin Declaration and the Disclosures of Potential Conflicts of Interest section in Becker, Hans-Joerg Fricke, Francoise Huguet, Ilaria Del Guidice, Peter Klein, Lothar Tremmel, Karlheinz Merkle, Marco Montillo nisone (COP) in advanced indolent non-Hodgkin’s mustine HCl in pretreated patients with B– chronic REFERENCES
lymphoma and mantle lymphoma: Results of a ran- lymphocytic leukaemia (Binet stages B and C) re- domized phase III trial (OSHO #19). J Cancer Res quiring therapy. J Cancer Res Clin Oncol 132:99- 1. Rai KR, Keating MJ: Chronic lymphocytic leu-
kemia, in Holland J, Frei E (eds): Cancer Medicine 9. Rummel MJ, Al-Batran SE, Kim SZ, et al:
15. Cheson BD, Bennett JM, Grever M, et al:
(ed 5). Hamilton, Ontario, B.C. Decker Inc, 2000, pp Bendamustine plus rituximab is effective and has a National Cancer Institute – Sponsored Working favorable toxicity profile in the treatment of mantle Group guidelines for chronic lymphocytic leukemia: 2. French Cooperative Group on CLL: Long-term
cell and low-grade non-Hodgkin’s lymphoma. J Clin Revised guidelines for diagnosis and treatment.
results of the CHOP regimen in stage C chronic lymphocytic leukemia: French Cooperative Group on 10. Po¨nisch W, Mitrou PS, Merkle K, et al: Treat-
16. Hallek M, Cheson B, Catovsky D, et al: Guide-
Chronic Lymphocytic Leukemia. Br J Haematol 73: ment of bendamustine and prednisone in patients lines for the diagnosis and treatment of chronic with newly diagnosed multiple myeloma results in lymphocytic leukemia: A report from the Interna- 3. Keating M: Chronic lymphocytic leukemia.
superior complete response rate, prolonged time to tional Workshop on Chronic Lymphocytic Leukemia treatment failure and improved quality of life com- updating the National Cancer Institute Working 4. Rai KR, Peterson BL, Appelbaum FR, et al:
pared to treatment with melphalan and prednisone: Group 1996 guidelines. Blood 111:5446-5456, 2008 Fludarabine compared with chlorambucil as primary A randomized phase III study of the East German 17. Lehmacher W, Wassmer G: Adaptive sample
therapy for chronic lymphocytic leukemia. N Engl Study Group of Hematology and Oncology (OSHO).
size calculations in group sequential trials. Biomet- J Cancer Res Clin Oncol 132:205-212, 2006 5. Steurer M, Pall G, Richards S, et al: Single-
11. Kath R, Blumenstengel K, Fricke HJ, et al:
18. Eichhorst BF, Busch R, Stauch M, et al: No
agent purine analogues for the treatment of chronic Bendamustine monotherapy in advanced and refrac- significant clinical benefit of first line therapy with lymphocytic leukaemia: A systematic review and tory chronic lymphocytic leukemia. J Cancer Res fludarabine in comparison to chlorambucil in elderly meta-analysis. Cancer Treat Rev 32:377-389, 2006 patients with advanced chronic lymphocytic leukae- 6. Leoni LM, Bailey B, Reifert J, et al: Benda-
12. Aivado M, Schulte K, Henze L, et al: Benda-
mia (CLL): Results of a phase III study of the mustine (Treanda) displays a distinct pattern of mustine in the treatment of chronic lymphocytic German CLL Study Group. Blood 110:194a, 2007 cytotoxicity and unique mechanistic features com- leukemia: Results and future perspectives. Semin pared with other alkylating agents. Clin Cancer Res 19. Hillmen P, Skomicki AB, Robak T, et al: Ale-
13. Bergmann MA, Goebeler ME, Herold M, et al:
mtuzumab compared with chlorambucil as first-line 7. Niemeyer C, Bailey B, Reifert J, et al: SDX-
Efficacy of bendamustine in patients with relapsed therapy for chronic lymphocytic leukemia. J Clin 105 (bendamustine) is a clinically active chemother- or refractory chronic lymphocytic leukemia: Results apeutic agent with a distinct mechanism of action.
of a phase I/II study of the German CLL Study 20. Leporrier M, Chevret S, Cazin B, et al: Ran-
domized comparison of fludarabine, CAP, and ChOP 8. Herold M, Schulze A, Niederweiser D, et al:
14. Lissitchkov T, Arnaudov G, Peytchev D, et al:
in 938 previously untreated stage B and C chronic Bendamustine, vincristine and prednisone (BOP) Phase I/II study to evaluate dose limiting toxicity, lymphocytic leukemia patients. Blood 98:2319- versus cyclophosphamide, vincristine and pred- maximum tolerated dose, and tolerability of benda- 2009 by American Society of Clinical Oncology Downloaded from on July 17, 2011. For personal use only. No other uses without permission.
Copyright 2009 American Society of Clinical Oncology. All rights reserved.
Knauf et al
21. Johnson S, Smith AG, Lo¨ffler H, et al: Multi-
26. Byrd JC, Peterson BL, Morrison VA, et al:
leukemia (CLL) receiving fludarabine regimens as centre prospective randomised trial of fludarabine Randomized phase 2 study of fludarabine with con- initial therapy. Blood 92:1165-1171, 1998 versus cyclophosphamide, doxorubicin, and pred- current versus sequential treatment with rituximab 31. Bosch F, Ferrer A, Villamor N, et al: Fludara-
nisone (CAP) for treatment of advanced-stage in symptomatic, untreated patients with B-cell bine, cyclophosphamide, and mitoxantrone as initial chronic lymphocytic leukaemia. Lancet 347:1432- chronic lymphocytic leukemia: Results from cancer therapy of chronic lymphocytic leukemia: High re- and leukemia group B9712 (CALGB 9712). Blood sponse rate and disease eradication. Clin Cancer 22. Flinn IW, Neuberg DS, Grever MR, et al:
Phase III trial of fludarabine plus cyclophosphamide 27. Keating MJ, O’Brien S, Albitar M, et al: Early
32. Morrison VA, Rai KR, Peterson BL, et al:
compared with fludarabine for patients with previ- results of a chemoimmunotherapy regimen of flu- Impact of therapy with chlorambucil, fludarabine, or ously untreated chronic lymphocytic leukemia: US darabine, cyclophosphamide, and rituximab as initial fludarabine plus chlorambucil in infections in pa- Intergroup Trial E2997. J Clin Oncol 25:793-798, therapy for chronic lymphocytic leukemia. J Clin tients with chronic lymphocytic leukemia: Inter- group Study Cancer and Leukemia Group B9011.
23. Robak T, Blon´ski JZ, Kasznicki M, et al:
28. Hallek M, Fingerle-Rowson G, Fink AM, et al:
Cladribine with prednisone versus chlorambucil with Immunochemotherapy with fludarabin (F), cyclo- 33. Cheson BD: Infectious and immunosuppres-
prednisone as first-line therapy in chronic lympho- phosphamide (C), and rituximab (R) (FCR) versus sive complications of purine analog therapy. J Clin cytic leukemia: Report of a prospective, randomized, fludarabine and cyclophosphamide (FC) improves multicenter trial. Blood 96:2723-2729, 2000 24. Catovsky D, Richards S, Matutes E, et al:
response rates and progression – free survival (PFS) 34. Cheson BD, Frame JN, Vena D, et al: Tumor
Assessment of fludarabine plus cyclophosphamide of previously untreated patients (pts) with advanced lysis syndrome: Uncommon complication of fludara- for patients with chronic lymphocytic leukaemia (the chronic lymphocytic leukemia (CLL). Blood 112:125, bine therapiy on chronic lymphocytic leukemia.
LRF CLL4 trial): A randomised controlled trial. Lan- 29. Tam CS, OЈBrien S, Wierda W, et al: Long
35. Fischer K, Stilgenbauer S, Schweighofer C, et
25. Eichhorst BF, Busch R, Hopfinger G, et al:
term results of the fludarabine, cyclophosphamide al: Bendamustine in combination with rituximab (BR) Fludarabine plus cyclophosphamide versus fludara- and rituximab regimen as initial therapy of chronic for patients with relapsed chronic lymphocytic leu- bine alone in first-line therapy of younger patients lymphocytic leukaemia. Blood 112:975-980, 2008 kemia (CLL): A multicentre phase II trial of the with chronic lymphocytic leukemia. Blood 107:885- 30. Keating MJ, O’Brien S, Lerner S, et al: Long-
German CLL Study Group (GCLLSG). Blood 112, term follow-up of patients with chronic lymphocytic 2009 by American Society of Clinical Oncology Downloaded from on July 17, 2011. For personal use only. No other uses without permission.
Copyright 2009 American Society of Clinical Oncology. All rights reserved.


Microsoft word - cv_nih training_proposal_patricia.doc

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