bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase ii trial of the german chronic lymphocytic leukemia study group Bendamustine in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

Bendamustine in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

  1. Clemens-Martin Wendtner⇓
  1. Kirsten Fischer, Paula Cramer, Jasmin Bahlo, Silke Schott, Valentin Goede, Susanne Isfort, Julia von Tresckow, Anna-Maria Fink, Karl-Anton Kreuzer, Barbara F. Eichhorst, Michael Hallek, and Clemens-Martin Wendtner, University of Cologne, Cologne; Raymonde Busch, Institute of Medical Statistics and Epidemiology of the Technical University; Clemens-Martin Wendtner, Klinikum München-Schwabing, Munich; Sebastian Böttcher, Matthias Ritgen, and Michael Kneba, University Hospital, Kiel; Jörg Schubert, Evangelical Krankenhaus Hamm, Hamm; Karl H. Pflüger, Evangelical Diakonissenanstalt Bremen, Bremen; Andreas Bühler, Dirk Winkler, Hartmut Döhner, and Stephan Stilgenbauer, University Hospital, Ulm; and Peter Staib, St. Antonius Hospital, Eschweiler, Germany.
  1. Corresponding author: Clemens-Martin Wendtner, MD, Department I of Internal Medicine, University of Cologne, Kerpener Str 62, 50937 Köln, Germany; e-mail: clemens.wendtner{at}uni-koeln.de.

  1. Presented in part at the 51st Annual Meeting of the American Society of Hematology, New Orleans, LA, December 5-8, 2009.

  1. S.S. and C.-M.W. contributed equally to this work.

 
Next Section

Abstract

Purpose We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL).

Patients and Methods In all, 117 patients, age 34 to 78 years, 46.2% of patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m2 on days 1 and 2 combined with 375 mg/m2 rituximab on day 0 of the first course and 500 mg/m2 on day 1 during subsequent courses for up to six courses.

Conclusion Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.

Previous SectionNext Section

INTRODUCTION

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, and it has an extremely variable course.1,2 Other than allogeneic stem-cell transplantation, which is considered an appropriate therapy for selected patients with poor prognosis only, there is no curative treatment.1,3 However, over the past five decades, the management of CLL apart from stem-cell transplantation has evolved considerably, resulting in high and durable response rates.4,5 The purine analog fludarabine and its combinations have markedly improved treatment success demonstrating higher response rates and longer progression-free survival (PFS) in younger patients with CLL.6–11 More recent trials evaluated the impact of chemoimmunotherapy in patients with CLL showing that the addition of the anti-CD20 monoclonal antibody rituximab to fludarabine and cyclophosphamide improved PFS and overall survival (OS).10,12–14 However, the findings were associated with an increased toxicity: 76% of the patients experienced at least one grade 3 or 4 event; hematologic toxicity grade 3 or 4 occurred in 56% of the patients.14

Bendamustine has structural similarities to both alkylating agents and purine analogs and has shown considerable activity as a single agent for lymphoid malignancies, including CLL.15–19 Encouraging clinical results have been obtained by using bendamustine in combination with rituximab in relapsed and/or refractory CLL in many elderly and high-risk patients with advanced disease.20 In light of these promising clinical data, we initiated this phase II trial to evaluate the safety and efficacy of bendamustine and rituximab combination treatment in previously untreated patients with symptomatic CLL regardless of age and fitness.

Previous SectionNext Section

PATIENTS AND METHODS

Study Design and Objective

This prospective, multicenter, nonrandomized, phase II study was approved by the competent institutional review board and was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines. All patients provided written informed consent. The primary end point was the overall response rate (ORR). Secondary end points included toxicity, quality and duration of response, event-free survival (EFS), minimal residual disease (MRD) levels, and ORR in biologically defined risk groups.

Patients and Treatment Schedule

Patients included in the trial had to be diagnosed with CLL in need of treatment according to the National Cancer Institute (NCI) guidelines. Eligible patients were at least 18 years of age, had a WHO performance status of 0 to 2, a life expectancy of at least 12 weeks, and adequate renal (creatinine clearance > 30 mL/min) and liver function (total bilirubin, aminotransferases ≤ 2 × the institutional upper limit of normal). All patients were scheduled to receive 90 mg/m2 bendamustine on days 1 and 2 combined with 375 mg/m2 rituximab on day 0 for the first course and 500 mg/m2 on day 1 for all subsequent courses, based on previously published data for fludarabine, cyclophosphamide, and rituximab.10,21 Treatment was administered every 28 days for up to six courses, depending on response and toxicity.

Criteria for Response and Toxicity

Response was determined according to the NCI Working Group 1996 Criteria for CLL, including bone marrow examination and radiographic confirmation of complete response (CR).22 Responses and disease progression were assessed by the study investigators and verified by a central investigator independent medical review. The response achieved after termination of therapy had to be maintained for at least 2 months. Radiographic imaging was performed at the discretion of the treating physician at screening and during interim staging and follow-up. Treatment toxicity was reported by the investigators according to NCI Common Toxicity Criteria (CTC) version 3.0.23

Biologic Prognostic Markers

Analysis of genomic aberrations by interphase fluorescent in situ hybridization, immunoglobulin heavy variable chain (IGHV) mutational status by sequencing, MRD by four-color flow cytometry of peripheral blood and bone marrow, and flow cytometric assessment of CD38 and ZAP-70 expression were performed in the central reference laboratories of the German CLL Study Group.24,25

Statistical Methods

The sample size estimation was performed according to the Simon two-stage optimal design with type I error = 0.05 to determine the efficacy of a regimen that was not of interest (response rate < 70%) and a type II error = 0.10, suggesting the rejection of an active regimen (response rate > 90%).12,26 The primary end point of ORR was calculated on the intent-to-treat (ITT) population defined by all patients who received at least one dose of study medication. Secondary end points were the response rate in biologically defined risk groups, MRD response rate, and the duration of response, defined as the time period between the first documentation of response and the initial documentation of progressive disease or death as a result of any cause. An additional secondary end point was EFS defined as the date of first treatment with bendamustine and rituximab (BR) to the date of progressive disease, the beginning of new treatment for any hematologic malignancy, or death as a result of any cause. Median EFS and duration of response were estimated by the Kaplan-Meier method and were performed for the ITT population.

Previous SectionNext Section

RESULTS

Patient Characteristics

Between March 2007 and September 2008, 117 patients were enrolled onto the trial at 40 centers in Germany. All 117 patients received at least one dose of treatment and constitute the ITT population for basic characteristics, safety, and efficacy analysis. The median age was 64.0 years (range, 34.0 to 78.0 years). Thirty patients (25.6%) were age 70 years or older and 46.2% of patients were at Binet stage C at study entry. Forty-one patients (35.0%) had a creatinine clearance ≤ 70 mL/min (Table 1).

View this table:
Table 1.

Patients' Demographic and Baseline Characteristics

A deletion of chromosome 17p13 (del(17p)) was detected in 7.3% of the patients, del(11q) in 19.1%, and unmutated IGHV in 61.8%. The study cohort was characterized by the following high-risk features: 80% of the patients were characterized by high levels of serum thymidine kinase (s-TK >10 U/L; median, 26.0 U/L; range, 2.0 to 600.0 U/L), 45.9% of patients presented with high levels of serum β2-microglobulin (> 3.5 mg/L; median, 3.4 mg/L; range, 0.2 to 10.0 mg/L), and 15.7% of patients were positive for ZAP-70 expression (Table 1).

Treatment

A total of 599 treatment courses were administered (median number per patient, 6.0): 86 patients (73.5%) received the full six courses of therapy, three patients received five courses, seven patients received four courses, six received three courses, seven received two courses, and eight received one course. Therefore, 102 patients (87.2%) received at least three courses. Eighty-five patients (72.6%) received infectious prophylaxis (Appendix, online only) before treatment. Granulocyte colony-stimulating factor was administered to 25 patients (21.4%) for a median duration of 5 days. In 73 patients (62.4%), treatment was delayed between 1 and 28 days. Regarding the dose-intensity, 58 patients (49.6%) received the full dose-intensity of BR; the median dose-intensity of rituximab was nearly 100%. Dose reductions of either of the two drugs by more than 10% of the planned dose were used for 59 patients (50.4%), mostly because of treatment-related hematologic toxicity. Thirty patients (25.6%) had a dose reduction of rituximab alone, 47 (40.2%) of bendamustine alone, and 16 patients (13.7%) had dose reductions of both rituximab and bendamustine. Treatment was discontinued early (during the first or second course of therapy) in 15 patients (12.8%) because of withdrawal of consent (n = 1), toxicity (n = 8), allergic reaction (n = 1), protocol violation (n = 2), progressive disease (n = 2), or other reason (n = 1).

Safety

After a median follow-up time of 27 months, 11 deaths occurred: cause of death in six patients was unrelated to treatment in disease progression; among the six patients, three were diagnosed with Richter's transformation. Treatment-related mortality was 3.4%: one patient died after the second course of therapy as a result of liver failure following attempted suicide with doxylamine. Two patients died during their second course of therapy and one during the fifth course of therapy from infections that were related to therapy.

Seventy-five patients (64.1%) experienced at least one adverse event of CTC grade 3 or 4 during treatment or up to 2 months thereafter. The most common adverse events were hematologic toxicities occurring in 61 patients (52.1%): severe neutropenia, thrombocytopenia, and anemia were observed in 23 (19.7%), 26 (22.2%), and 23 (19.7%) patients, respectively (Table 2). On the basis of the number of treatment courses, severe neutropenia, thrombocytopenia, and anemia were observed in 6.0%, 5.7%, and 4.5% of all applied treatment courses, respectively (Table 2).

View this table:
Table 2.

Incidence of CTCAE Grade 3 to 4 Adverse Events

Two patients entered the study with an active hemolysis; both cases were stabilized under study treatment. infection was the most common nonhematologic toxicity. infections (12 grade 3; three grade 4), mainly febrile neutropenias and pneumonias, occurred in nine patients (7.7%). The numbers of other nonhematologic toxicities are listed in Table 2. Of note, the incidence of nonhematologic toxicity was higher in patients older than age 70 years compared with patients age ≤ 70 years (65.4% v 33.0%; P = .004).

Also of note, the incidence of severe leukopenia, anemia, and nonhematologic toxicity was higher in patients with a creatinine clearance ≤ 70 mL/min compared with patients with normal renal function (41.5% v 23.7% [P = .057], 37.7% v 14.5% [P = .033], and 51.2% v 34.2% [P = .08], respectively). Patients with an impaired creatinine clearance did not require more dose reductions (P = .56) but did experience more infections than patients with a creatinine clearance greater than 70 mL/min (29.3% v 15.8% [P = .097]).

Treatment Efficacy

On the basis of the ITT population, the ORR was 88.0% (95% CI, 80.7% to 100.0%; n = 103), with a CR rate of 23.1% (n = 27), 1.7% nodular partial responses (n = 2), and a partial response rate of 63.2% (n = 74). Stable disease was observed in 9.4% (n = 11), and none of the patients had progressive disease. In three patients (2.6%), no response assessment was performed as a result of death before interim staging (n = 2) and diagnosis of mantle-cell lymphoma during the first course of therapy (n = 1). Excluding these patients from analysis, ORR and CR rates were 90.4% and 23.7%, respectively.

After a median observation time of 27.0 months, the median EFS was 33.9 months (95% CI, 31.9 to 35.9 months). As for OS, 106 patients (90.5%) were still alive. Median EFS was reached at 35.5 months for patients with Binet stage C and at 32.4 months for patients with Binet stage B. For patients with Binet stage A, median EFS has not been reached. Among the 103 responders, the median duration of response was 31.4 months (95% CI, 29.0 to 33.8 months; Fig 2).

Fig 2.
View larger version:
Fig 2.

(A) Event-free survival and (B) overall survival for all patients in the intent-to-treat group. CLL, chronic lymphocytic leukemia; PD, progressive disease.

At the time-point of final staging, 26 (57.8%) of 45 patients had peripheral blood MRD levels below 10−4. Seven (29.2%) of 24 patients achieved MRD negativity in bone marrow. Patients were stratified by MRD into low- (< 10−4), intermediate- (≥ 10−4 to < 10−2), and high-level (> 10−2) cohorts. Low-level MRD in blood and/or bone marrow was associated with prolonged EFS (P < .001; Table 3). In peripheral blood, median EFS was 32.4 months and 11.8 months for intermediate- and high-level MRD groups, respectively, whereas median EFS has not been reached for patients with low-level MRD (Fig 2). Median OS for patients with high-level MRD was 23.2 months and has not been reached for patients with intermediate- and low-level MRD.

View this table:
Table 3.

Response to Treatment

Treatment Efficacy in Prognostic Subgroups

Pretreatment characteristics and clinical and biologic parameters were evaluated for correlations with ORR. ORR was significantly associated with higher cumulative doses of bendamustine and rituximab (bendamustine, P < .001; rituximab, P < .001), lower age (≤ 65 years; P = .026), higher level of hemoglobin (> 10.0 g/dL; P = .003), and lower level of s-TK at study entry (≤ 10 U/L; P = .023). In terms of the prognostic factors CD38 and ZAP-70, a significant level was not achieved when using the established cutoff levels for CD38 and ZAP-70.

Differences in response to treatment were observed among the genetic subgroups (P = .001): 18 patients (90.0%) with del(11q) achieved a remission, and eight patients (40%) achieved a CR. Accordingly, 18 patients (94.7%) with trisomy 12 responded to treatment with a CR rate of 21.1%. In the high-risk group with del(17p), three patients (37.5%) achieved a partial response. Kaplan-Meier analysis showed significant differences for EFS (P < .001), as listed in Table 3 and shown in Figure 3. Fifty-nine patients (89.4%) with unmutated IGHV status were responsive to treatment with a CR rate of 27.3%. Significant differences in EFS were also found for patients with a high level of s-TK (P = .009; Table 3). Of the patients who had an impaired creatinine clearance of ≤ 70 mL/min, 89.7% achieved a response (Table 3).

Fig 3.
View larger version:
Fig 3.

Event-free survival in (A) minimal residual disease (MRD) subgroups (peripheral blood) and in (B) cytogenetic subgroups. CLL, chronic lymphocytic leukemia; PD, progressive disease.

Previous SectionNext Section

DISCUSSION

The addition of rituximab to chemotherapeutic regimens has significantly improved the impact of treatment for both treatment-naive patients and those with relapsed CLL.10–12,14 To the best of our knowledge, this phase II trial is the first trial prospectively assessing safety and efficacy of bendamustine in combination with rituximab in patients with previously untreated CLL.

Compared with a recently published trial14 evaluating efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in a fairly young and physically fit patient population (median age, 61 years), the study population in our trial included a significant proportion of patients (accounting for more than a quarter of the entire study population) who were age 70 years or older. Moreover, 46.2% of the patients presented with Binet stage C at study entry. In addition, 35% of patients had impaired renal function and were therefore not eligible for treatment with FCR.

In light of the patient population in our trial, the ORR of 88.0% (95% CI, 80.7% to 100.0%), including a 23.7% CR rate with a median EFS of 33.9 months, is similar to the results achieved by a study that used chemoimmunotherapy with FCR14 and reported an ORR of 90% with a CR rate of 44% and a median PFS of 51.8 months. Compared with the German CLL Study Group (GCLLSG) CLL8 trial exploring the FCR regimen in first-line treatment of CLL, this trial included older patients (median age, 64 v 61 years) with more advanced disease (46.2% v 31% of patients at Binet stage C). The inferior CR rate might be partially explained by the incidence of a high proportion of patients with a clinical CR (n = 28) that did not fulfill the strict CR criteria according to NCI criteria because of missing bone marrow biopsy and missing radiographic examination (n = 14), missing bone marrow biopsy (n = 11), or incomplete clinical response because of toxicity (n = 3). Despite the fact that results of bone marrow biopsies are missing for many patients, it would be inappropriate to add the clinical complete responses to the CR rate. However, the MRD results described earlier also reported a higher number of patients who were MRD free by flow cytometry in peripheral blood.14,27 Interestingly, the MRD levels achieved in this trial predicted an EFS and PFS similar to that recently reported for treatment with FCR or FC: 11.8 (BR) v 15.4 months (FCR) for high-level MRD groups; 32.4 (BR) v 40.5 months (FCR) for intermediate-level MRD groups; and not reached (BR) v 68.7 months (FCR) for low-level MRD groups. Thus, these results support the concept of using MRD as a predictive marker and an end point for treatment efficacy in future clinical trials.27

Compared with trials that used FCR in first-line CLL, the observed adverse effects of the BR regimen compare favorably, although the study population in our trial displayed more poor-risk factors. Although severe neutropenia of grade 3 and higher was noticed in only 19.7% of patients and 6.0% of courses treated with BR, this rate was reported to be between 34% per patient and 24% per course in the trials evaluating FCR and 13% per course in a trial using FCR-Lite.10,14,28 The incidence of both thrombocytopenia (grade 3 to 4, 22.2%) and anemia (grade 3 to 4, 19.7%) appears to be higher compared with the reported numbers in the FCR trial because different versions of the NCI-CTC were used for grading hematologic toxicities (version 3.0 for this trial, version 2.0 for CLL8). When applying CTC version 2.0, grade 3 to 4 thrombocytopenia occurred in 11.5% of the patients, and grade 3 anemia occurred in 4.3% of the patients. The reported low rate of severe infections in 7.7% of patients receiving BR treatment also compares favorably to the rate in patients receiving FCR, with a reported infection rate of 25%.14 Importantly, other nonhematologic adverse effects were rare. In particular, no neurologic adverse effects or skin reactions were observed in our trial, although they have occasionally been reported in other trials that use bendamustine.29,30

In conclusion, we describe a representative population of patients with CLL (including patients with advanced disease and renal function impairment) who received BR treatment for their previously untreated disease. Except for patients with del(17p) who did not respond to the treatment regimen as the other genetic subgroups, the combination of bendamustine and rituximab offers an effective and safe treatment for patients with treatment-naive CLL. To evaluate the use of BR in elderly patients with CLL or in those with CLL who do not qualify for treatment, further studies with well-defined patient populations with an assessment of a comorbidity score need to be performed. On the basis of the promising results obtained in this phase II trial, we initiated a phase III trial comparing the BR regimen with standard first-line therapy (FCR) for physically fit patients with previously untreated CLL to study the question of whether therapy with BR is not inferior to therapy with FCR.

Previous SectionNext Section

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Karl-Anton Kreuzer, Mundipharma (C), Roche (C); Michael Kneba, Roche (C); Barbara F. Eichhorst, Gilead Sciences (C), Pharmacyclics (C); Michael Hallek, Mundipharma (C), Roche (C); Stephan Stilgenbauer, Cephalon (C), Mundipharma (C), Roche (C); Clemens-Martin Wendtner, Mundipharma/Cephalon (C), Roche (C) Stock Ownership: None Honoraria: Sebastian Böttcher, Roche; Valentin Goede, Roche; Karl-Anton Kreuzer, Mundipharma, Roche; Peter Staib, Roche; Barbara F. Eichhorst, Mundipharma, Roche; Michael Hallek, Mundipharma, Roche; Stephan Stilgenbauer, Cephalon, Mundipharma, Roche; Clemens-Martin Wendtner, Mundipharma/Cephalon, Roche Research Funding: Sebastian Böttcher, Roche; Valentin Goede, Roche; Karl-Anton Kreuzer, Roche; Peter Staib, Roche; Matthias Ritgen, Roche; Michael Kneba, Mundipharma, Roche; Barbara F. Eichhorst, Mundipharma, Roche; Michael Hallek, Mundipharma, Roche; Stephan Stilgenbauer, Cephalon, Mundipharma, Roche; Clemens-Martin Wendtner, Mundipharma, Roche Expert Testimony: Karl-Anton Kreuzer, Roche (C) Other Remuneration: Kirsten Fischer, Roche (travel grants); Sebastian Böttcher, Roche (travel grants); Anna-Maria Fink, Roche (travel grants); Matthias Ritgen, Roche (travel grants)

Previous SectionNext Section

AUTHOR CONTRIBUTIONS

Conception and design: Kirsten Fischer, Raymonde Busch, Michael Hallek, Clemens-Martin Wendtner

Financial support: Michael Hallek, Clemens-Martin Wendtner

Administrative support: Kirsten Fischer, Jasmin Bahlo, Silke Schott, Michael Hallek, Clemens-Martin Wendtner

Provision of study materials or patients: Kirsten Fischer, Sebastian Böttcher, Jasmin Bahlo, Jöerg Schubert, Susanne Isfort, Julia von Tresckow, Michael Kneba, Michael Hallek, Stephan Stilgenbauer, Clemens-Martin Wendtner

Collection and assembly of data: Kirsten Fischer, Paula Cramer, Raymonde Busch, Sebastian Böttcher, Jasmin Bahlo, Jöerg Schubert, Karl H. Pflüger, Silke Schott, Valentin Goede, Susanne Isfort, Julia von Tresckow, Anna-Maria Fink, Andreas Bühler, Dirk Winkler, Karl-Anton Kreuzer, Peter Staib, Matthias Ritgen, Michael Kneba, Hartmut Döhner, Barbara F. Eichhorst, Stephan Stilgenbauer, Clemens-Martin Wendtner

Data analysis and interpretation: Kirsten Fischer, Paula Cramer, Raymonde Busch, Sebastian Böttcher, Jasmin Bahlo, Susanne Isfort, Julia von Tresckow, Anna-Maria Fink, Karl-Anton Kreuzer, Peter Staib, Michael Kneba, Barbara F. Eichhorst, Michael Hallek, Stephan Stilgenbauer, Clemens-Martin Wendtner

Manuscript writing: All authors

Final approval of manuscript: All authors

Previous SectionNext Section

Acknowledgment

We thank all patients and physicians for their participation in the study.

Previous SectionNext Section

Appendix

The following centers and investigators participated in this study: Ludwig-Maximilians-Universität München: Wolfgang Hiddemann, Martin Dreyling; Universitätsklinikum Schleswig-Holstein Campus Kiel: Michael Kneba, Matthias Ritgen; Universitätsklinikum Essen: Jan Düring; Charite Campus Benjamin Franklin, Berlin: Lutz Uharek, Birte Friedrichs; Universitätskliniken des Saarlandes, Homburg/Saar: Michael Pfreundschuh, Gerhard Held; Uniklinik Köln: Peter Borchmann, Marcel Reiser, Karin Töpelt, Clemens-Martin Wendtner; Universitätsklinik Tübingen: Martin Sökler; Klinikum der Humboldt-Universität zu Berlin, Charité Mitte, Christian Scholz, Lorenz Kleeberg; Klinikum der Universität Regensburg: Jochen Pfirstinger; Ernst-Moritz-Arndt-Universität Greifswald: Gottfried Dölken, Christoph Busemann, Frank Schüler; Universitätsklinik Ulm: Andreas Bühler, Stephan Stilgenbauer, Andreas Viardot; Klinikum Frankfurt/Oder: Michael Kiehl, Wolfgang Stein; Evangelical Krankenhaus Hamm: Jörg Schubert, Elisabeth Lange, Andrea Stoltefuß; Klinik für Knochenmarktransplantation und Hämatologie/Onkologie, Idar-Oberstein: Axel Fauser, Harald Reiner Biersack, Nasar Gulzad, Eva Roemer; Klinikum Lüdenscheid: Gerhard Heil; Städt. Klinikum Magdeburg: Christoph Kahl, Carsten Roll; Klinikum Ernst von Bergmann, Potsdam: Georg Maschmeyer, Frank Rothmann; Krankenhaus der Barmherzigen Brüder, Regensburg: Heribert Stauder; Caritas-Klinik St. Theresia, Saarbrücken: Axel Matzdorf; Krankenanstalt Mutterhaus der Borromäerinnen, Trier: Michael Clemens; Heinrich-Braun-Krankenhaus Zwickau: Uwe Gabb, Waltraud Zschille; Evangelical Diakonissenanstalt Bremen: Karl-Heinz Pflüger, Christoph Diekmann; Klinikum Garmisch-Partenkirchen: Lothar Schulz; Sana-Krankenhaus Düsseldorf-Benrath: Barbara Günther; Onkologische Gemeinschaftspraxis Dres. Wolf/Freidt, Dresden: Heiner Wolf, Anke Freidt; Internistische Gemeinschaftspraxis Dres. Rohrberg/Hurtz/Schmidt, Halle: Hans-Jürgen Hurtz, Robert Rohrberg; Gemeinschaftspraxis Schick/Schick/Schmidt/Wiesmeier, München: Burkhardt Schmidt; Internistische Praxis Dr. Stauch, Kronach: Martina Stauch; Schwerpunktpraxis für Hämatologie und Onkologie Siegburg: Stefan Fronhoff; Internistische Gemeinschaftspraxis Dres. Otremba/Hinrichs/Zirpel/Reschke, Oldenburg: Burkhard Otremba, Daniel Reschke; Onkologische Schwerpunktpraxis Dres. Springer/Fiechtner, Stuttgart: Gregor Springer, Heinrich Fiechtner; Internistische Praxis Dr. Schlag, Würzburg: Rudolf Schlag; Internistische Gemeinschaftspraxis Dres. Balló/Böck, Offenbach: Harald Balló, Hans-Peter Böck; Onkologisch-Hämatologische Schwerpunktpraxis Hamburg: Sigrun Müller-Hagen; Internist. Schwerpunktpraxis Dr. Würmell, Rüsselsheim: Michael Baldus; Hämatologische/Onkologische Praxis Dr. Schmidt, Neunkirchen: Peter Schmidt; Hämatologische/Onkologische Praxis Dr. Kleeberg, Hamburg: Erik Engel, Michael von Staden; Gemeinschaftspraxis Dr. Gröpler/Trieglaff, Wismar: Katrin Göpler.

Previous SectionNext Section

Baseline Assessment

After obtaining a signed informed consent form, a screening evaluation to determine patient eligibility was conducted within 2 weeks of registration except for the chest x-ray that could be performed up to 4 weeks before registration. The following were included: medical history (including stage and date of original B-cell chronic lymphocytic leukemia diagnosis, prior therapy, and response to prior therapy) and concomitant medication notation; physical examination (including measurement of lymph nodes [longest diameter of the node as measured by palpation], liver [measured as longest length palpable below the right costal margin in the midclavicular line], and spleen [measured as the longest length palpable below the left costal margin]); WHO performance status; vital signs (blood pressure, pulse, temperature); height, weight, and calculation of body-surface area; assessment of disease-related “B” symptoms; laboratory and diagnostic assessments (including CBC with differential and platelet count, CD4+ count, serum chemistry [sodium, potassium, calcium, creatinine, total bilirubin, AST, ALT, and lactate dehydrogenase]); direct and indirect Coombs; immunoglobulins (IgG and IgM); serum or urine pregnancy test as appropriate; thymidine kinase; β2-microglobulin; immunophenotyping for confirmation of diagnosis (co-expression of CD5 and at least one of the B-cell markers CD19, CD20, CD23, or CD38); molecular cytogenetics; minimal residual disease testing; CD38/ZAP-70; chest x-ray (posterior-anterior view); ultrasound or computed tomography scan of the abdomen if clinically indicated (other questionable clinical involvements should also be checked by using adequate methods); bone marrow aspirate/trephine biopsy if clinically indicated. Bone marrow aspirate, if aspirate is obtained, will be sent for minimal residual disease testing.

Previous SectionNext Section

Footnotes

  • See accompanying editorial on page 3162

  • Written on behalf of the German Chronic Lymphocytic Leukemia Study Group.

  • Supported by research grants from F. Hoffman La Roche and Mundipharma. The German Chronic Lymphocytic Leukemia Study Group receives financial support by the German Cancer Aid.

  • Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Clinical trial information can be found for the following: NCT00274989.

  • Received September 7, 2011.
  • Accepted May 30, 2012.
Previous Section
 

REFERENCES

  1. ↵
    1. Hallek M,
    2. Cheson BD,
    3. Catovsky D,
    4. et al.
    (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: A report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111:5446–5456.
    Abstract/FREE Full Text
  2. ↵
    1. Zenz T,
    2. Mertens D,
    3. Küppers R,
    4. et al.
    (2010) From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 10:37–50.
    Medline
  3. ↵
    1. Dreger P,
    2. Döhne H,
    3. Ritgen M,
    4. et al.
    (2010) Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: Long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood 116:2438–2447.
    Abstract/FREE Full Text
  4. ↵
    1. Gribben JG
    (2010) How I treat CLL up front. Blood 115:187–197.
    Abstract/FREE Full Text
  5. ↵
    1. Hallek M,
    2. Pflug N
    (2011) State of the art treatment of chronic lymphocytic leukaemia. Blood Rev 25:1–9.
    CrossRefMedline
  6. ↵
    1. Catovsky D,
    2. Richards S,
    3. Matutes E,
    4. et al.
    (2007) Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): A randomised controlled trial. Lancet 370:230–239.
    CrossRefMedline
    1. Eichhorst BF,
    2. Busch R,
    3. Hopfinger G,
    4. et al.
    (2006) Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 107:885–891.
    Abstract/FREE Full Text
    1. Flinn IW,
    2. Neuberg DS,
    3. Grever MR,
    4. et al.
    (2007) Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 25:793–798.
    Abstract/FREE Full Text
    1. Keating MJ,
    2. Kantarjian H,
    3. Talpaz M,
    4. et al.
    (1989) Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 74:19–25.
    Abstract/FREE Full Text
  10. ↵
    1. Keating MJ,
    2. O'Brien S,
    3. Albitar M,
    4. et al.
    (2005) Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 23:4079–4088.
    Abstract/FREE Full Text
  11. ↵
    1. Rai KR,
    2. Peterson BL,
    3. Appelbaum FR,
    4. et al.
    (2000) Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750–1757.
    CrossRefMedline
  12. ↵
    1. Wierda W,
    2. O'Brien S,
    3. Wen S,
    4. et al.
    (2005) Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 23:4070–4078.
    Abstract/FREE Full Text
    1. Robak T,
    2. Dmoszynska A,
    3. Solal-Céligny P,
    4. et al.
    (2010) Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 28:1756–1765.
    Abstract/FREE Full Text
  14. ↵
    1. Hallek M,
    2. Fischer K,
    3. Fingerle-Rowson G,
    4. et al.
    (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: A randomised, open-label, phase 3 trial. Lancet 376:1164–1174.
    CrossRefMedline
  15. ↵
    1. Ozegowski W,
    2. Krebs D
    (1963) W-[bis-(chlorethyl)-amino-benzimidazolyl-(2)]-propionic or butyric acids as potential cytostatic agents. J Prakt Chem 20:178–186.
    CrossRef
    1. Ozegowski W,
    2. Krebs D
    (1971) IMET 3393, gamma-(1-methyl-5-bis-(ß-chloräthyl)-amino-benzimidazolyl(2)-buttersäure-hydrochlorid, ein neues Zytostatikum aus der Reihe der Benzimidazol-Loste [in German] Zbl Pharm 110:1013–1019.
    Search Google Scholar
    1. Hartmann M,
    2. Zimmer C
    (1972) Investigation of cross-link formation in DNA by the alkylating cytostatic IMET 3106, 3393 and 3943. Biochim Biophys Acta 287:386–389.
    Medline
    1. Cheson BD,
    2. Wendtner CM,
    3. Pieper A,
    4. et al.
    (2010) Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: Treatment recommendations from an international consensus panel. Clin Lymphoma Myeloma Leuk 10:21–27.
    CrossRefMedline
  19. ↵
    1. Knauf WU,
    2. Lissichkov T,
    3. Aldaoud A,
    4. et al.
    (2009) Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27:4378–4384.
    Abstract/FREE Full Text
  20. ↵
    1. Fischer K,
    2. Cramer P,
    3. Busch R,
    4. et al.
    (2011) Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: A multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 29:3559–3566.
    Abstract/FREE Full Text
  21. ↵
    1. Bergmann MA,
    2. Goebeler ME,
    3. Herold M,
    4. et al.
    (2005) Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: Results of a phase I/II study of the German CLL Study Group. Haematologica 90:1357–1364.
    Abstract/FREE Full Text
  22. ↵
    1. Cheson BD,
    2. Bennett JM,
    3. Grever M,
    4. et al.
    (1996) National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990–4997.
    FREE Full Text
  23. ↵
    1. National Cancer Institute, Cancer Therapy Evaluation Program:
    Common Terminology Criteria for Adverse Events (CTCAE) and Common Toxicity Criteria (CTC) http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
  24. ↵
    1. Kröber A,
    2. Seiler T,
    3. Benner A,
    4. et al.
    (2002) V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:1410–1416.
    Abstract/FREE Full Text
  25. ↵
    1. Döhner H,
    2. Stilgenbauer S,
    3. Benner A,
    4. et al.
    (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916.
    CrossRefMedline
  26. ↵
    1. Simon R
    (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10.
    Medline
  27. ↵
    1. Böttcher S,
    2. Ritgen M,
    3. Fischer K,
    4. et al.
    (2012) Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: A multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol 30:980–988.
    Abstract/FREE Full Text
  28. ↵
    1. Foon KA,
    2. Boyiadzis M,
    3. Land SR,
    4. et al.
    (2009) Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27:498–503.
    Abstract/FREE Full Text
  29. ↵
    1. Reck M,
    2. Haering B,
    3. Koschel G,
    4. et al.
    (1998) [Chemotherapy of advanced non-small-cell and small-cell bronchial carcinoma with bendamustine: A phase II study] [in German] Pneumologie 52:570–573.
    Medline
  30. ↵
    1. Cheson BD,
    2. Kroll ML
    (2009) Bendamustine induced neurotoxicity. Clin Adv Hematol Oncol 7:743–746.
    Medline

Related Article

  • EDITORIALS: Making Advances in First-Line Chronic Lymphocytic Leukemia Treatment
    • William G. Wierda
    JCO Sep 10, 2012:3162-3164; published online on August 6, 2012;
| Table of Contents

This Article

  1. Published online before print August 6, 2012, doi: 10.1200/JCO.2011.39.2688 JCO vol. 30 no. 26 3209-3216
  1. Abstract
  2. » Full Text
  3. PDF
  4. Publisher's Note

Classifications

Related Content

  1. Related Article

Navigate This Article

Current Issue

  1. July 20, 2013, 31 (21)
  1. Alert me to new issues of JCO
    • Advertisement
    • Advertisement
    • Advertisement