EXHIBIT 2019
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`EXHIBIT 2019
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`Ann liematol (2013) 92:653-660 Ann liematol (2013) 92:653-660
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`Ann liematol (2013) 92:653-660 Ann liematol (2013) 92:653-660
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`DOl 10.10071s00277-012-1660-6 DOl 10.10071s00277-012-1660-6
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`DOl 10.10071s00277-012-1660-6 DOl 10.10071s00277-012-1660-6
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`ORIGINAL ARTICLE ORIGINAL ARTICLE
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`ORIGINAL ARTICLE ORIGINAL ARTICLE
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`Bendamustine compared to fludarabine as second-line Bendamustine compared to fludarabine as second-line
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`Bendamustine compared to fludarabine as second-line Bendamustine compared to fludarabine as second-line
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`treatment in chronic lymphocytic leukemia treatment in chronic lymphocytic leukemia
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`treatment in chronic lymphocytic leukemia treatment in chronic lymphocytic leukemia
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`Norbert Niederle • Dirk Megdenberg • Leopold Balleisen • Norbert Niederle • Dirk Megdenberg • Leopold Balleisen •
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`Norbert Niederle • Dirk Megdenberg • Leopold Balleisen • Norbert Niederle • Dirk Megdenberg • Leopold Balleisen •
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`Wolfgang Heil • Wolfgang Knauf • Johann WeiB • Werner Freier • Wolfgang Heil • Wolfgang Knauf • Johann WeiB • Werner Freier •
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`Wolfgang Heil • Wolfgang Knauf • Johann WeiB • Werner Freier • Wolfgang Heil • Wolfgang Knauf • Johann WeiB • Werner Freier •
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`Axel Hinke • Stefan Ibach • Hartmut Eimermacher Axel Hinke • Stefan Ibach • Hartmut Eimermacher
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`Axel Hinke • Stefan Ibach • Hartmut Eimermacher Axel Hinke • Stefan Ibach • Hartmut Eimermacher
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`Received: 3 April 2012 /Accepted: 17 December 2012 /Publishecl online: 23 January 2013 Received: 3 April 2012 /Accepted: 17 December 2012 /Publishecl online: 23 January 2013 Received: 3 April 2012 /Accepted: 17 December 2012 /Publishecl online: 23 January 2013 Received: 3 April 2012 /Accepted: 17 December 2012 /Publishecl online: 23 January 2013
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`t...7) Springer-Verlag Berlin Heidelberg 2013 t...7) Springer-Verlag Berlin Heidelberg 2013
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`t...7) Springer-Verlag Berlin Heidelberg 2013 t...7) Springer-Verlag Berlin Heidelberg 2013
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`of 25 mg/m2 on days 1 to 5 every 4 weeks. The primary of 25 mg/m2 on days 1 to 5 every 4 weeks. The primary
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`of 25 mg/m2 on days 1 to 5 every 4 weeks. The primary of 25 mg/m2 on days 1 to 5 every 4 weeks. The primary
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`objective was to achieve non-inferior progression-free sur-objective was to achieve non-inferior progression-free sur-
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`objective was to achieve non-inferior progression-free sur-objective was to achieve non-inferior progression-free sur-
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`vival (PFS) with bendamustine. Out of a total of 96 vival (PFS) with bendamustine. Out of a total of 96
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`vival (PFS) with bendamustine. Out of a total of 96 vival (PFS) with bendamustine. Out of a total of 96
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`patients randomized, 92 were eligible, 49 allocated to bend-patients randomized, 92 were eligible, 49 allocated to bend-
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`patients randomized, 92 were eligible, 49 allocated to bend-patients randomized, 92 were eligible, 49 allocated to bend-
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`amustine and 43 to fludarabine. About half of the patients amustine and 43 to fludarabine. About half of the patients
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`amustine and 43 to fludarabine. About half of the patients amustine and 43 to fludarabine. About half of the patients
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`received six or more cycles. Overall response rates were received six or more cycles. Overall response rates were
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`received six or more cycles. Overall response rates were received six or more cycles. Overall response rates were
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`76 % on bendamustine and 62 % on fludarabine, with 76 % on bendamustine and 62 % on fludarabine, with
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`76 % on bendamustine and 62 % on fludarabine, with 76 % on bendamustine and 62 % on fludarabine, with
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`clinical complete response rates of 27 and 9 %, respectively. clinical complete response rates of 27 and 9 %, respectively.
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`clinical complete response rates of 27 and 9 %, respectively. clinical complete response rates of 27 and 9 %, respectively.
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`Median PFS was 20.1 and 14.8 months (hazard ratio, 0.87; Median PFS was 20.1 and 14.8 months (hazard ratio, 0.87;
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`Median PFS was 20.1 and 14.8 months (hazard ratio, 0.87; Median PFS was 20.1 and 14.8 months (hazard ratio, 0.87;
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`90 % confidence interval, 0.60-1.27), median overall survival 90 % confidence interval, 0.60-1.27), median overall survival
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`90 % confidence interval, 0.60-1.27), median overall survival 90 % confidence interval, 0.60-1.27), median overall survival
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`43.8 and 41.0 months (hazard ratio, 0.82). Thrornbocytopenia 43.8 and 41.0 months (hazard ratio, 0.82). Thrornbocytopenia
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`43.8 and 41.0 months (hazard ratio, 0.82). Thrornbocytopenia 43.8 and 41.0 months (hazard ratio, 0.82). Thrornbocytopenia
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`and gastrointestinal toxicities were marginally more frequent and gastrointestinal toxicities were marginally more frequent
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`and gastrointestinal toxicities were marginally more frequent and gastrointestinal toxicities were marginally more frequent
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`on bendamustine, albeit CTC grade 3/4 event incidence was on bendamustine, albeit CTC grade 3/4 event incidence was
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`on bendamustine, albeit CTC grade 3/4 event incidence was on bendamustine, albeit CTC grade 3/4 event incidence was
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`similar. These data suggest at least comparable efficacy of similar. These data suggest at least comparable efficacy of similar. These data suggest at least comparable efficacy of similar. These data suggest at least comparable efficacy of
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`bendamustine vs. fludarabine, pointing to an alternative treat-bendamustine vs. fludarabine, pointing to an alternative treat-bendamustine vs. fludarabine, pointing to an alternative treat-bendamustine vs. fludarabine, pointing to an alternative treat-
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`ment option in relapsing CLL patients after chlorambucil ment option in relapsing CLL patients after chlorambucil ment option in relapsing CLL patients after chlorambucil ment option in relapsing CLL patients after chlorambucil
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`containing initial chemotherapy. containing initial chemotherapy. containing initial chemotherapy. containing initial chemotherapy.
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`Keywords Chronic lymphocytic leukemia • Second-line Keywords Chronic lymphocytic leukemia • Second-line Keywords Chronic lymphocytic leukemia • Second-line Keywords Chronic lymphocytic leukemia • Second-line
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`treatment • Bendamustine • Fludarabine treatment • Bendamustine • Fludarabine treatment • Bendamustine • Fludarabine treatment • Bendamustine • Fludarabine
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`Introduction Introduction Introduction Introduction
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`Chronic lymphocytic leukemia (CLL) is the most common Chronic lymphocytic leukemia (CLL) is the most common Chronic lymphocytic leukemia (CLL) is the most common Chronic lymphocytic leukemia (CLL) is the most common
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`type of leukemia in developed countries of the western world type of leukemia in developed countries of the western world type of leukemia in developed countries of the western world type of leukemia in developed countries of the western world
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`[1], with a yearly incidence of about 120,000 cases in the USA [1], with a yearly incidence of about 120,000 cases in the USA [1], with a yearly incidence of about 120,000 cases in the USA [1], with a yearly incidence of about 120,000 cases in the USA
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`and Europe. As CLL often shows an indolent course and still and Europe. As CLL often shows an indolent course and still and Europe. As CLL often shows an indolent course and still and Europe. As CLL often shows an indolent course and still
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`remains an incurable disease in the vast majority of patients, remains an incurable disease in the vast majority of patients, remains an incurable disease in the vast majority of patients, remains an incurable disease in the vast majority of patients,
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`therapeutic interventions are generally restricted to symptom-therapeutic interventions are generally restricted to symptom-therapeutic interventions are generally restricted to symptom-therapeutic interventions are generally restricted to symptom-
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`atic patients. For many years, single alkylating agents such as atic patients. For many years, single alkylating agents such as atic patients. For many years, single alkylating agents such as atic patients. For many years, single alkylating agents such as
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`chlorambucil were the cornerstone of first-line therapy. Dur-chlorambucil were the cornerstone of first-line therapy. Dur-chlorambucil were the cornerstone of first-line therapy. Dur-chlorambucil were the cornerstone of first-line therapy. Dur-
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`ing the last two decades, the quality of tumor remissions could ing the last two decades, the quality of tumor remissions could ing the last two decades, the quality of tumor remissions could ing the last two decades, the quality of tumor remissions could
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`be raised distinctly by the introduction of purine analogues, be raised distinctly by the introduction of purine analogues, be raised distinctly by the introduction of purine analogues, be raised distinctly by the introduction of purine analogues,
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`e.g. fludarabine, and monoclonal antibodies are no purine e.g. fludarabine, and monoclonal antibodies are no purine e.g. fludarabine, and monoclonal antibodies are no purine e.g. fludarabine, and monoclonal antibodies are no purine
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`analouges. However, a clear impact of these more aggressive analouges. However, a clear impact of these more aggressive analouges. However, a clear impact of these more aggressive analouges. However, a clear impact of these more aggressive
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`Abstract Bendamustine demonstrated clinical activity in Abstract Bendamustine demonstrated clinical activity in
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`Abstract Bendamustine demonstrated clinical activity in Abstract Bendamustine demonstrated clinical activity in
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`pre-treated hematological malignancies due to its unique pre-treated hematological malignancies due to its unique
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`pre-treated hematological malignancies due to its unique pre-treated hematological malignancies due to its unique
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`mechanism of action distinct from standard alkylating agents. mechanism of action distinct from standard alkylating agents.
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`mechanism of action distinct from standard alkylating agents. mechanism of action distinct from standard alkylating agents.
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`This study assessed its efficacy in patients with chronic lym-This study assessed its efficacy in patients with chronic lym-
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`This study assessed its efficacy in patients with chronic lym-This study assessed its efficacy in patients with chronic lym-
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`phocytic leukemia pre-treated with an alkylator, in compari-phocytic leukemia pre-treated with an alkylator, in compari-
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`phocytic leukemia pre-treated with an alkylator, in compari-phocytic leukemia pre-treated with an alkylator, in compari-
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`son to fludarabine. Patients with relapsed chronic lymphocytic son to fludarabine. Patients with relapsed chronic lymphocytic
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`son to fludarabine. Patients with relapsed chronic lymphocytic son to fludarabine. Patients with relapsed chronic lymphocytic
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`leukemia requiring treatment after one previous systemic leukemia requiring treatment after one previous systemic
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`leukemia requiring treatment after one previous systemic leukemia requiring treatment after one previous systemic
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`regimen (usually chlorambucil-based) were randomized to regimen (usually chlorambucil-based) were randomized to
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`regimen (usually chlorambucil-based) were randomized to regimen (usually chlorambucil-based) were randomized to
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`either receive bendamustine 100 mg/m2 on days 1 and 2 of either receive bendamustine 100 mg/m2 on days 1 and 2 of
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`either receive bendamustine 100 mg/m2 on days 1 and 2 of either receive bendamustine 100 mg/m2 on days 1 and 2 of
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`a 4-week cycle or standard fludarabine treatment consisting a 4-week cycle or standard fludarabine treatment consisting
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`a 4-week cycle or standard fludarabine treatment consisting a 4-week cycle or standard fludarabine treatment consisting
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`Presented in abstract form at the 151h Congress of the European Presented in abstract form at the 151h Congress of the European
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`Presented in abstract form at the 151h Congress of the European Presented in abstract form at the 151h Congress of the European
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`CanCer Organisation and 34th Congress of the European Society for CanCer Organisation and 34th Congress of the European Society for
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`CanCer Organisation and 34th Congress of the European Society for CanCer Organisation and 34th Congress of the European Society for
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`Medical Oncology, Berlin, Germany, September 20-24,2009. Medical Oncology, Berlin, Germany, September 20-24,2009.
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`Medical Oncology, Berlin, Germany, September 20-24,2009. Medical Oncology, Berlin, Germany, September 20-24,2009.
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`N. Niederle (M). D. Megdenberg N. Niederle (M). D. Megdenberg
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`N. Niederle (M). D. Megdenberg N. Niederle (M). D. Megdenberg
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`Medizinische Klinik 111, Klinikum Leverkusen gGinbIL Medizinische Klinik 111, Klinikum Leverkusen gGinbIL
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`Medizinische Klinik 111, Klinikum Leverkusen gGinbIL Medizinische Klinik 111, Klinikum Leverkusen gGinbIL
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`Am Gesundheitspark 11, Am Gesundheitspark 11, Am Gesundheitspark 11, Am Gesundheitspark 11,
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`D-51375 Leverkusen, Germany D-51375 Leverkusen, Germany D-51375 Leverkusen, Germany D-51375 Leverkusen, Germany
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`e-mail: niederie@klinikum-lev.de e-mail: niederie@klinikum-lev.de
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`e-mail: niederie@klinikum-lev.de e-mail: niederie@klinikum-lev.de
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`L. Balleisen L. Balleisen
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`L. Balleisen L. Balleisen
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`Medizinische Klinik 1, Ev. Krankenhaus Hamm, Germany Medizinische Klinik 1, Ev. Krankenhaus Hamm, Germany
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`Medizinische Klinik 1, Ev. Krankenhaus Hamm, Germany Medizinische Klinik 1, Ev. Krankenhaus Hamm, Germany
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`W. Heil W. Heil
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`W. Heil W. Heil
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`Fiamatologicurn, Essen, Germany Fiamatologicurn, Essen, Germany Fiamatologicurn, Essen, Germany Fiamatologicurn, Essen, Germany
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`W. Knauf W. Knauf
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`W. Knauf W. Knauf
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`Onkologische Gemeinschaftspraxis, Frankfurt, Germany Onkologische Gemeinschaftspraxis, Frankfurt, Germany Onkologische Gemeinschaftspraxis, Frankfurt, Germany Onkologische Gemeinschaftspraxis, Frankfurt, Germany
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`J. WeiB J. WeiB J. WeiB J. WeiB
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`Praxis tiir Hiimatologie and intemistisehe Onkologie. Weiden, Praxis tiir Hiimatologie and intemistisehe Onkologie. Weiden, Praxis tiir Hiimatologie and intemistisehe Onkologie. Weiden, Praxis tiir Hiimatologie and intemistisehe Onkologie. Weiden,
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`Germany Germany
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`Germany Germany
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`W. Freier W. Freier
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`W. Freier W. Freier
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`Onkologische Schwerpunktpraxis, Ifildesheim, Germany Onkologische Schwerpunktpraxis, Ifildesheim, Germany Onkologische Schwerpunktpraxis, Ifildesheim, Germany Onkologische Schwerpunktpraxis, Ifildesheim, Germany
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`A. Hinke • S. Ibach A. Hinke • S. Ibach
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`A. Hinke • S. Ibach A. Hinke • S. Ibach
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`WiSP Research Institute, Langcnfeld, Germany WiSP Research Institute, Langcnfeld, Germany WiSP Research Institute, Langcnfeld, Germany WiSP Research Institute, Langcnfeld, Germany
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`H. Eimennacher H. Eimennacher H. Eimennacher H. Eimennacher
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`Onkologische Schwerpunktprax is, Olpe, Germany Onkologische Schwerpunktprax is, Olpe, Germany Onkologische Schwerpunktprax is, Olpe, Germany Onkologische Schwerpunktprax is, Olpe, Germany
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`I Springer I Springer I Springer I Springer
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`CEPHALON, INC. -- EXHIBIT 2019 001
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`654 (cid:9)654 (cid:9)
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`654 (cid:9)654 (cid:9)
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`Ann llenlatol (2013) 92:653-660 Ann llenlatol (2013) 92:653-660
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`Ann llenlatol (2013) 92:653-660 Ann llenlatol (2013) 92:653-660
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`treatment approaches on overall survival could not be proven treatment approaches on overall survival could not be proven
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`treatment approaches on overall survival could not be proven treatment approaches on overall survival could not be proven
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`as yet; although, there are promising preliminary results on as yet; although, there are promising preliminary results on
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`as yet; although, there are promising preliminary results on as yet; although, there are promising preliminary results on
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`rituximab-containing regimes [2, 3]. Nevertheless, the search rituximab-containing regimes [2, 3]. Nevertheless, the search
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`rituximab-containing regimes [2, 3]. Nevertheless, the search rituximab-containing regimes [2, 3]. Nevertheless, the search
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`for further treatment options in advanced CLL is warranted. for further treatment options in advanced CLL is warranted.
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`for further treatment options in advanced CLL is warranted. for further treatment options in advanced CLL is warranted.
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`Bendamustine, first synthesized back in the 1960s in Bendamustine, first synthesized back in the 1960s in
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`Bendamustine, first synthesized back in the 1960s in Bendamustine, first synthesized back in the 1960s in
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`the former German Democratic Republic [4], consists of a the former German Democratic Republic [4], consists of a
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`the former German Democratic Republic [4], consists of a the former German Democratic Republic [4], consists of a
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`nitrogen—mustard moiety bound to a purine-like benzimid-nitrogen—mustard moiety bound to a purine-like benzimid-
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`nitrogen—mustard moiety bound to a purine-like benzimid-nitrogen—mustard moiety bound to a purine-like benzimid-
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`azole ring. Originally, bendamustine was considered to act azole ring. Originally, bendamustine was considered to act
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`azole ring. Originally, bendamustine was considered to act azole ring. Originally, bendamustine was considered to act
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`similarly to cytostatics such as cyclophosphamide or similarly to cytostatics such as cyclophosphamide or
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`similarly to cytostatics such as cyclophosphamide or similarly to cytostatics such as cyclophosphamide or
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`chlorambucil. However, several preclinical and clinical chlorambucil. However, several preclinical and clinical
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`chlorambucil. However, several preclinical and clinical chlorambucil. However, several preclinical and clinical
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`findings suggested that the activity profile and the mech-findings suggested that the activity profile and the mech-
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`findings suggested that the activity profile and the mech-findings suggested that the activity profile and the mech-
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`anism of action of the drug significantly differ from anism of action of the drug significantly differ from
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`anism of action of the drug significantly differ from anism of action of the drug significantly differ from
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`classical alkylators [5]. Recently, thorough comparative classical alkylators [5]. Recently, thorough comparative
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`classical alkylators [5]. Recently, thorough comparative classical alkylators [5]. Recently, thorough comparative
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`examinations on the mechanism of action revealed unique examinations on the mechanism of action revealed unique
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`examinations on the mechanism of action revealed unique examinations on the mechanism of action revealed unique
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`effects of bendamustine and major differences in cytotoxic effects of bendamustine and major differences in cytotoxic
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`effects of bendamustine and major differences in cytotoxic effects of bendamustine and major differences in cytotoxic
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`effects in vitro [6]. Consequently, a lack of cross-resistance to effects in vitro [6]. Consequently, a lack of cross-resistance to
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`effects in vitro [6]. Consequently, a lack of cross-resistance to effects in vitro [6]. Consequently, a lack of cross-resistance to
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`chlorambucil and other DNA-damaging cytotoxic drugs could chlorambucil and other DNA-damaging cytotoxic drugs could
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`chlorambucil and other DNA-damaging cytotoxic drugs could chlorambucil and other DNA-damaging cytotoxic drugs could
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`be detected. be detected.
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`be detected. be detected.
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`Bendamustine has been shown to be clinically active in Bendamustine has been shown to be clinically active in
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`Bendamustine has been shown to be clinically active in Bendamustine has been shown to be clinically active in
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`the treatment of numerous hematological and solid malig-the treatment of numerous hematological and solid malig-
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`the treatment of numerous hematological and solid malig-the treatment of numerous hematological and solid malig-
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`nancies [7]. Based on the favorable findings of phase I and nancies [7]. Based on the favorable findings of phase I and
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`nancies [7]. Based on the favorable findings of phase I and nancies [7]. Based on the favorable findings of phase I and
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`II trials in non-Hodgkin's lymphoma (NHL) and CLL [4, II trials in non-Hodgkin's lymphoma (NHL) and CLL [4,
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`II trials in non-Hodgkin's lymphoma (NHL) and CLL [4, II trials in non-Hodgkin's lymphoma (NHL) and CLL [4,
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`8-10], both with single drug and combination treatment, 8-10], both with single drug and combination treatment,
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`8-10], both with single drug and combination treatment, 8-10], both with single drug and combination treatment,
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`several randomized trials were initiated to compare bend-several randomized trials were initiated to compare bend-
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`several randomized trials were initiated to compare bend-several randomized trials were initiated to compare bend-
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`amustine to standard therapies. amustine to standard therapies.
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`amustine to standard therapies. amustine to standard therapies.
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`Design and methods Design and methods
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`Design and methods Design and methods
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`carcinoma or cervical cancer). The study was approved by carcinoma or cervical cancer). The study was approved by
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`carcinoma or cervical cancer). The study was approved by carcinoma or cervical cancer). The study was approved by
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`all ethical committees responsible for the participating study all ethical committees responsible for the participating study
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`all ethical committees responsible for the participating study all ethical committees responsible for the participating study
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`centers. All patients gave written informed consent before centers. All patients gave written informed consent before
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`centers. All patients gave written informed consent before centers. All patients gave written informed consent before
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`entering the study, in accordance with the Declaration of entering the study, in accordance with the Declaration of
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`entering the study, in accordance with the Declaration of entering the study, in accordance with the Declaration of
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`Helsinki, Edinburgh version, 2000. Helsinki, Edinburgh version, 2000.
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`Helsinki, Edinburgh version, 2000. Helsinki, Edinburgh version, 2000.
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`Study design and treatment Study design and treatment
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`Study design and treatment Study design and treatment
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`The study was designed as an open-label, multi-center, The study was designed as an open-label, multi-center,
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`The study was designed as an open-label, multi-center, The study was designed as an open-label, multi-center,
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`randomized phase Ill trial. After registration at the central randomized phase Ill trial. After registration at the central
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`randomized phase Ill trial. After registration at the central randomized phase Ill trial. After registration at the central
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`study office, patients were randomly assigned to treatment, study office, patients were randomly assigned to treatment,
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`study office, patients were randomly assigned to treatment, study office, patients were randomly assigned to treatment,
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`consisting either of fludarabine or bendamustine monother-consisting either of fludarabine or bendamustine monother-
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`consisting either of fludarabine or bendamustine monother-consisting either of fludarabine or bendamustine monother-
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`apy. Computer-generated randomization lists, created by a apy. Computer-generated randomization lists, created by a
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`apy. Computer-generated randomization lists, created by a apy. Computer-generated randomization lists, created by a
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`block randomization method with variable block size, were block randomization method with variable block size, were
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`block randomization method with variable block size, were block randomization method with variable block size, were
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`used. Patients were stratified according to Binet stage B or C used. Patients were stratified according to Binet stage B or C
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`used. Patients were stratified according to Binet stage B or C used. Patients were stratified according to Binet stage B or C
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`and study center. For therapy, patients received either bend-and study center. For therapy, patients received either bend-
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`and study center. For therapy, patients received either bend-and study center. For therapy, patients received either bend-
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`amustine 100 mWrn2 body surface on days l and 2 or amustine 100 mWrn2 body surface on days l and 2 or amustine 100 mWrn2 body surface on days l and 2 or amustine 100 mWrn2 body surface on days l and 2 or
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`fludarabine 25 mg/m2 body surface on days 1 to 5 of each fludarabine 25 mg/m2 body surface on days 1 to 5 of each fludarabine 25 mg/m2 body surface on days 1 to 5 of each fludarabine 25 mg/m2 body surface on days 1 to 5 of each
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`28-day treatment cycle. Treatment cycles were repeated 28-day treatment cycle. Treatment cycles were repeated 28-day treatment cycle. Treatment cycles were repeated 28-day treatment cycle. Treatment cycles were repeated
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`until confirmation of best response to treatment, with a until confirmation of best response to treatment, with a until confirmation of best response to treatment, with a until confirmation of best response to treatment, with a
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`maximum of eight cycles. The duration of cycles could maximum of eight cycles. The duration of cycles could maximum of eight cycles. The duration of cycles could maximum of eight cycles. The duration of cycles could
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`be extended if required for resolution of treatment-be extended if required for resolution of treatment-be extended if required for resolution of treatment-be extended if required for resolution of treatment-
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`induced neutropenia or thrombocytopenta. Furthermore, induced neutropenia or thrombocytopenta. Furthermore, induced neutropenia or thrombocytopenta. Furthermore, induced neutropenia or thrombocytopenta. Furthermore,
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`dose reduction was applied in case of duration of grade dose reduction was applied in case of duration of grade dose reduction was applied in case of duration of grade dose reduction was applied in case of duration of grade
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`4 neutropenia for >5 days, platelet nadir <20 x 109 per 4 neutropenia for >5 days, platelet nadir <20 x 109 per 4 neutropenia for >5 days, platelet nadir <20 x 109 per 4 neutropenia for >5 days, platelet nadir <20 x 109 per
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`liter, creatinine >2.0 mg/d1, or other organ toxicities of liter, creatinine >2.0 mg/d1, or other organ toxicities of liter, creatinine >2.0 mg/d1, or other organ toxicities of liter, creatinine >2.0 mg/d1, or other organ toxicities of
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`grade 3 or higher. Grade 4 neurologic toxicity resulted in grade 3 or higher. Grade 4 neurologic toxicity resulted in grade 3 or higher. Grade 4 neurologic toxicity resulted in grade 3 or higher. Grade 4 neurologic toxicity resulted in
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`permanent termination of treatment. Bendamustine dose permanent termination of treatment. Bendamustine dose permanent termination of treatment. Bendamustine dose permanent termination of treatment. Bendamustine dose
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`was decreased by increments of 20 mg/m2 (but not more was decreased by increments of 20 mg/m2 (but not more was decreased by increments of 20 mg/m2 (but not more was decreased by increments of 20 mg/m2 (but not more
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`than 40 mg/m2), fludarabine by increments of 5 mg/m2 than 40 mg/m2), fludarabine by increments of 5 mg/m2 than 40 mg/m2), fludarabine by increments of 5 mg/m2 than 40 mg/m2), fludarabine by increments of 5 mg/m2
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`(but not more than 10 mg/m2). (but not more than 10 mg/m2). (but not more than 10 mg/m2). (but not more than 10 mg/m2).
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`The primary objective was to evaluate, whether CLL The primary objective was to evaluate, whether CLL The primary objective was to evaluate, whether CLL The primary objective was to evaluate, whether CLL
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`treatment with bendamustine shows equivalent efficacy treatment with bendamustine shows equivalent efficacy treatment with bendamustine shows equivalent efficacy treatment with bendamustine shows equivalent efficacy
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`compared to treatment with fludarabine, with regard to compared to treatment with fludarabine, with regard to compared to treatment with fludarabine, with regard to compared to treatment with fludarabine, with regard to
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`progression-free survival. Secondary objectives of the trial progression-free survival. Secondary objectives of the trial
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`progression-free survival. Secondary objectives of the trial progression-free survival. Secondary objectives of the trial
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`were the comparison of antineoplastic efficacy by evalua-were the comparison of antineoplastic efficacy by evalua-
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`were the comparison of antineoplastic efficacy by evalua-were the comparison of antineoplastic efficacy by evalua-
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`tion of remission rates and overall survival, as well as the tion of remission rates and overall survival, as well as the
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`tion of remission rates and overall survival, as well as the tion of remission rates and overall survival, as well as the
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`comparison of tolerability by evaluation of frequency and comparison of tolerability by evaluation of frequency and
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`comparison of tolerability by evaluation of frequency and comparison of tolerability by evaluation of frequency and
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`grade of toxicity influencing treatment feasibility (dose grade of toxicity influencing treatment feasibility (dose
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`grade of toxicity influencing treatment feasibility (dose grade of toxicity influencing treatment feasibility (dose
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`reductions, cycle delays). Furthermore, frequency and dura-reductions, cycle delays). Furthermore, frequency and dura-reductions, cycle delays). Furthermore, frequency and dura-reductions, cycle delays). Furthermore, frequency and dura-
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`tion of hospitalizations, blood transfusions, and supportive tion of hospitalizations, blood transfusions, and supportive tion of hospitalizations, blood transfusions, and supportive tion of hospitalizations, blood transfusions, and supportive
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`medications were evaluated. medications were evaluated. medications were evaluated. medications were evaluated.
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`Assessments Assessments Assessments Assessments
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`Baseline assessments consisted of clinical examination, tu-Baseline assessments consisted of clinical examination, tu-Baseline assessments consisted of clinical examination, tu-Baseline assessments consisted of clinical examination, tu-
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`mor evaluation (clinical, by sonography and radiological mor evaluation (clinical, by sonography and radiological mor evaluation (clinical, by sonography and radiological mor evaluation (clinical, by sonography and radiological
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`imaging), and standard hematology and blood chemistry imaging), and standard hematology and blood chemistry imaging), and standard hematology and blood chemistry imaging), and standard hematology and blood chemistry
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`parameters including Coombs test. Additional radiologic parameters including Coombs test. Additional radiologic parameters including Coombs test. Additional radiologic parameters including Coombs test. Additional radiologic
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`evaluation could be performed as indicated and was left to evaluation could be performed as indicated and was left to evaluation could be performed as indicated and was left to evaluation could be performed as indicated and was left to
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`investigator's discretion. Bone marrow biopsy and aspira-investigator's discretion. Bone marrow biopsy and aspira-investigator's discretion. Bone marrow biopsy and aspira-investigator's discretion. Bone marrow biopsy and aspira-
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`tion were required if not performed within 3 months prior to tion were required if not performed within 3 months prior to tion were required if not performed within 3 months prior to tion were required if not performed within 3 months prior to
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`inclusion. Standard blood counts had to be repeated once inclusion. Standard blood counts had to be repeated once inclusion. Standard blood counts had to be repeated once inclusion. Standard blood counts had to be repeated once
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`This trial was registered at ClinicalTrials.gov (NCT01423032). This trial was registered at ClinicalTrials.gov (NCT01423032). This trial was registered at ClinicalTrials.gov (NCT01423032). This trial was registered at ClinicalTrials.gov (NCT01423032).
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`Patients Patients
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`Patients Patients
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`Patients with histologically or immunologically confirmed Patients with histologically or immunologically confirmed Patients with histologically or immunologically confirmed Patients with histologically or immunologically confirmed
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`chronic B cell leukemia in refractory (i.e., no response or chronic B cell leukemia in refractory (i.e., no response or chronic B cell leukemia in refractory (i.e., no response or chronic B cell leukemia in refractory (i.e., no response or
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`progression during initial chemotherapy) or relapsed situa-progression during initial chemotherapy) or relapsed situa-progression during initial chemotherapy) or relapsed situa-progression during initial chemotherapy) or relapsed