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1. Looking down in the ancestral selection graph: A probabilistic approach to the common ancestor type distribution

Author

Lenz, Ute, Kluth, Sandra, Baake, Ellen, and Wakolbinger, Anton

Subjects
Quantitative Biology - Populations and Evolution, Mathematics - Probability, 92D15, 60J28, 60J60
Abstract

In a (two-type) Wright-Fisher diffusion with directional selection and two-way mutation, let $x$ denote today's frequency of the beneficial type, and given $x$, let $h(x)$ be the probability that, among all individuals of today's population, the individual whose progeny will eventually take over in the population is of the beneficial type. Fearnhead [Fearnhead, P., 2002. The common ancestor at a nonneutral locus. J. Appl. Probab. 39, 38-54] and Taylor [Taylor, J. E., 2007. The common ancestor process for a Wright-Fisher diffusion. Electron. J. Probab. 12, 808-847] obtained a series representation for $h(x)$. We develop a construction that contains elements of both the ancestral selection graph and the lookdown construction and includes pruning of certain lines upon mutation. Besides being interesting in its own right, this construction allows a transparent derivation of the series coefficients of $h(x)$ and gives them a probabilistic meaning., Comment: Theoretical Population Biology, in press

Published
2014
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2. The Moran model with selection: Fixation probabilities, ancestral lines, and an alternative particle representation

Author

Kluth, Sandra and Baake, Ellen

Subjects
Quantitative Biology - Populations and Evolution, Mathematics - Probability, 92D15, 60J28
Abstract

We reconsider the Moran model in continuous time with population size $N$, two allelic types, and selection. We introduce a new particle representation, which we call the labelled Moran model, and which has the same distribution of type frequencies as the original Moran model, provided the initial values are chosen appropriately. In the new model, individuals are labelled $1,2, \dots, N$; neutral resampling events may take place between arbitrary labels, whereas selective events only occur in the direction of increasing labels. With the help of elementary methods only, we not only recover fixation probabilities, but also obtain detailed insight into the number and nature of the selective events that play a role in the fixation process forward in time., Comment: 21 pages, 8 figures

Published
2013

3. The common ancestor process revisited

Author

Kluth, Sandra, Hustedt, Thiemo, and Baake, Ellen

Subjects
Quantitative Biology - Populations and Evolution, Mathematics - Probability, 92D15, 60J28
Abstract

We consider the Moran model in continuous time with two types, mutation, and selection. We concentrate on the ancestral line and its stationary type distribution. Building on work by Fearnhead (J. Appl. Prob. 39 (2002), 38-54) and Taylor (Electron. J. Probab. 12 (2007), 808-847), we characterise this distribution via the fixation probability of the offspring of all individuals of favourable type (regardless of the offspring's types). We concentrate on a finite population and stay with the resulting discrete setting all the way through. This way, we extend previous results and gain new insight into the underlying particle picture., Comment: 25 pages, 4 figures

Published
2013
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4. Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy

Author

Herling, Carmen Diana, Klaumünzer, Marion, Rocha, Cristiano Krings, Altmüller, Janine, Thiele, Holger, Bahlo, Jasmin, Kluth, Sandra, Crispatzu, Giuliano, Herling, Marco, Schiller, Joanna, Engelke, Anja, Tausch, Eugen, Döhner, Hartmut, Fischer, Kirsten, Goede, Valentin, Nürnberg, Peter, Reinhardt, Hans Christian, Stilgenbauer, Stephan, Hallek, Michael, and Kreuzer, Karl-Anton

Published
2016
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7. Mutations driving CLL and their evolution in progression and relapse

Author

Landau, Dan A., Tausch, Eugen, Taylor-Weiner, Amaro N., Stewart, Chip, Reiter, Johannes G., Bahlo, Jasmin, Kluth, Sandra, Bozic, Ivana, Lawrence, Mike, Bottcher, Sebastian, Carter, Scott L., Cibulskis, Kristian, Mertens, Daniel, Sougnez, Carrie L., Rosenberg, Mara, Hess, Julian M., Edelmann, Jennifer, Kless, Sabrina, Kneba, Michael, Ritgen, Matthias, Fink, Anna, Fischer, Kirsten, Gabriel, Stacey, Lander, Eric S., Nowak, Martin A., Dohner, Hartmut, Hallek, Michael, Neuberg, Donna, Getz, Gad, Stilgenbauer, Stephan, and Wu, Catherine J.

Subjects
Gene mutations -- Observations, Metastasis -- Genetic aspects, Chronic lymphocytic leukemia -- Genetic aspects -- Development and progression, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome., In recent years, unbiased massively parallel sequencing of whole exornes (WES) in chronic lymphocytic leukaemia (CLL) has yielded fresh insights into the genetic basis of this disease (1-4). Two important [...]

Published
2015
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8. Efficacy of antineoplastic treatment is associated with the use of antibiotics that modulate intestinal microbiota

Author

Pflug, Natali, Kluth, Sandra, Vehreschild, Joerg J., Bahlo, Jasmin, Tacke, Daniela, Biehl, Lena, Eichhorst, Barbara, Fischer, Kirsten, Cramer, Paula, Fink, Anna-Maria, von Bergwelt-Baildon, Michael, Stilgenbauer, Stephan, Hallek, Michael, Cornely, Oliver A., Vehreschild, Maria J. G. T., Pflug, Natali, Kluth, Sandra, Vehreschild, Joerg J., Bahlo, Jasmin, Tacke, Daniela, Biehl, Lena, Eichhorst, Barbara, Fischer, Kirsten, Cramer, Paula, Fink, Anna-Maria, von Bergwelt-Baildon, Michael, Stilgenbauer, Stephan, Hallek, Michael, Cornely, Oliver A., and Vehreschild, Maria J. G. T.

Abstract

Reduced anticancer efficacy of cyclophosphamide and platinum salts has been reported in animals treated with anti-Gram-positive antibiotics. These effects were related to translocation of Gram-positive bacteria during mucositis with subsequent induction of cytotoxic oxygen reactive species and tumor invasion by pathogenic Th17 cells. To assess these hypotheses in a clinical setting, we identified patients receiving cyclophosphamide for chronic lymphocytic leukemia (CLL) and cisplatin for relapsed lymphoma. Data originated from the CLL8 trial (NCT00281918) and the Cologne Cohort of Neutropenic Patients (NCT01821456). Relevant antibiotics were defined as compounds with primary activity against Gram-positive bacteria. We evaluated their impact on response, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier methodology and Cox proportional hazards regression analysis. Among 800 available CLL patients, those receiving anti-Gram-positive antibiotics (n = 45/800) achieved a significantly lower overall response rate (OR 74.3% vs. 90.2%, p = 0.007). Patients with anti-Gram-positive antibiotics progressed significantly earlier, had a reduced OS (median PFS 14.1 vs. 44.1 mo, p < 0.001; median OS 56.1 vs. 91.7 mo, p < 0.001) and multivariate analysis showed that administration of anti-Gram-positive antibiotic treatment was independently associated with reduced PFS (Hazard ratio (HR) 2.090, p = 0.001) and OS (HR 2.966, p < 0.001). Of 122 patients with relapsed lymphoma, those treated with anti-Gram-positive antibiotics (n = 21/122) achieved a significantly lower OR rate (70.3% vs. 42.9%, p = 0.016). Patients with anti-Gram-positive antibiotics progressed significantly earlier than others (median PFS 2.3 vs. 11.5 mo, p = 0.001). As for multivariate analysis, the use of anti-Gram-positive antibiotics was independently associated with reduced PFS (HR 2.237, p = 0.012) and OS (HR 7.831, p < 0.001). Our data supports a potential negative impact of anti-Gram-pos

Published
2016

9. Bendamustine and rituximab in combination with lenalidomide in patients with chronic lymphocytic leukemia

Author

Maurer, Christian, Pflug, Natali, Bahlo, Jasmin, Kluth, Sandra, Rhein, Christina, Cramer, Paula, Gross-Ophoff, Carolin, Langerbeins, Petra, Fink, Anna-Maria, Eichhorst, Barbara, Kreuzer, Karl-Anton, Fischer, Norbert, Tausch, Eugen, Stilgenbauer, Stephan, Boettcher, Sebastian, Doehner, Hartmut, Kneba, Michael, Dreyling, Martin, Binder, Mascha, Hallek, Michael, Wendtner, Clemens-Martin, Bergmann, Manuela, Fischer, Kirsten, Maurer, Christian, Pflug, Natali, Bahlo, Jasmin, Kluth, Sandra, Rhein, Christina, Cramer, Paula, Gross-Ophoff, Carolin, Langerbeins, Petra, Fink, Anna-Maria, Eichhorst, Barbara, Kreuzer, Karl-Anton, Fischer, Norbert, Tausch, Eugen, Stilgenbauer, Stephan, Boettcher, Sebastian, Doehner, Hartmut, Kneba, Michael, Dreyling, Martin, Binder, Mascha, Hallek, Michael, Wendtner, Clemens-Martin, Bergmann, Manuela, and Fischer, Kirsten

Abstract

PurposeA phase I/II trial to assess safety and efficacy of the combination bendamustine, rituximab, and lenalidomide (BRL) in patients with chronic lymphocytic leukemia (CLL). Patients and MethodsSeventeen relapsed or refractory (R/R) and five previously untreated (FL) CLL patients were enrolled in the trial. In the R/R cohort, four different dose levels of lenalidomide (maximum 15 mg/d) were used. In the FL cohort, lenalidomide was dose escalated from 5 mg/d to 15 mg/d. Bendamustine was used at doses of 50 or 90 mg/m(2) for R/R or FL treatment, respectively. 375 mg/m(2) Rituximab were used for the first and 500 mg/m(2) for subsequent treatment courses. Treatment consisted of up to six courses of 28 d. ResultsThe maximal tolerable dose of lenalidomide was 5 mg/d. The response rate was 47.1% in R/R and 60% in FL patients. Median progression-free survival was 8.0 months. Median overall survival was 22.9 and 12.3 months, respectively, in R/R and FL patients. Grade 3/4 hematological toxicity was observed in 71.4%, and severe infections in 47.6% of patients. Due to high toxicity and low response rate of BRL, the trial was closed prematurely. ConclusionBRL was associated with a high toxicity rate, a high number of treatment interruptions, and a low remission rate. Therefore, BRL cannot be considered an appropriate treatment option for patients with CLL.

Published
2016

11. Efficacy of antineoplastic treatment is associated with the use of antibiotics that modulate intestinal microbiota

Author

Pflug, Natali, primary, Kluth, Sandra, additional, Vehreschild, Jörg J., additional, Bahlo, Jasmin, additional, Tacke, Daniela, additional, Biehl, Lena, additional, Eichhorst, Barbara, additional, Fischer, Kirsten, additional, Cramer, Paula, additional, Fink, Anna-Maria, additional, von Bergwelt-Baildon, Michael, additional, Stilgenbauer, Stephan, additional, Hallek, Michael, additional, Cornely, Oliver A., additional, and Vehreschild, Maria J. G. T., additional

Published
2016
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12. Quantitative Clonal Dynamics Define Mechanisms of CLL Evolution in Response to Combination Chemotherapy

Author

Landau, Dan A., Tausch, Eugen, Boettcher, Sebastian, Stewart, Chip, Bozic, Ivana, Leischner, Iganty, Rosebrock, Daniel, Taylor-Weiner, Amaro, Mertens, Daniel, Sougnez, Carrie, Kless, Sabrina, Kneba, Michael, Ritgen, Matthias, Kluth, Sandra, Bahlo, Jasmin, Fink, Anna-Maria, Fischer, Kirsten, Gabriel, Stacey, Lander, Eric, Dohner, Hartmut, Hallek, Michael, Neuberg, Donna S., Nowak, Martin, Getz, Gad, Stilgenbauer, Stephan, Wu, Catherine J., Landau, Dan A., Tausch, Eugen, Boettcher, Sebastian, Stewart, Chip, Bozic, Ivana, Leischner, Iganty, Rosebrock, Daniel, Taylor-Weiner, Amaro, Mertens, Daniel, Sougnez, Carrie, Kless, Sabrina, Kneba, Michael, Ritgen, Matthias, Kluth, Sandra, Bahlo, Jasmin, Fink, Anna-Maria, Fischer, Kirsten, Gabriel, Stacey, Lander, Eric, Dohner, Hartmut, Hallek, Michael, Neuberg, Donna S., Nowak, Martin, Getz, Gad, Stilgenbauer, Stephan, and Wu, Catherine J.

Published
2015

13. Prognostic Impact and Risk Factors of Reducing Prescribed Doses of Fludarabine, Cyclophosphamide and Rituximab (FCR) during Frontline Treatment of Chronic Lymphocytic Leukemia (CLL)

Author

Kovacs, Gabor, Bahlo, Jasmin, Kluth, Sandra, Cramer, Paula, Fink, Anna-Maria, Fischer, Kirsten, Gross-Ophoff-Mueller, Carolin, Langerbeins, Petra, Maurer, Christian, von Tresckow, Julia, Wendtner, Clemens-Martin, Stilgenbauer, Stephan, Hallek, Michael, Eichhorst, Barbara, Goede, Valentin, Kovacs, Gabor, Bahlo, Jasmin, Kluth, Sandra, Cramer, Paula, Fink, Anna-Maria, Fischer, Kirsten, Gross-Ophoff-Mueller, Carolin, Langerbeins, Petra, Maurer, Christian, von Tresckow, Julia, Wendtner, Clemens-Martin, Stilgenbauer, Stephan, Hallek, Michael, Eichhorst, Barbara, and Goede, Valentin

Published
2015

14. The Moran model with selection (and mutation) : fixation probabilities, ancestral lines, and an alternative particle representation

Author

Kluth, Sandra

Subjects
labelled Moran model, fixation probability, common ancestor process, ancestral line, defining event, Moran model
Abstract

This thesis is devoted to a classical model of population genetics, namely, the Moran model in continuous time with two allelic types, (fertility) selection, and mutation. We concentrate on the ancestral line and its stationary type distribution. Building on work by Fearnhead (2002) and Taylor (2007), this distribution may be characterised via the fixation probability of the offspring of all individuals of favourable type (regardless of the offspring's types). Both approaches employ the diffusion limit from the very beginning. The resulting expression for the stationary distribution does not have an obvious interpretation in terms of the graphical representation of the model. Therefore, we concentrate on a finite population and stay with the resulting discrete setting all the way through. This way, we extend previous results and gain new insight into the underlying particle picture. As a further approach we restrict ourselves on a Moran model with selection. We introduce a new particle representation, which we call the labelled Moran model, and which has the same distribution of type frequencies as the original Moran model, provided the initial values are chosen appropriately. In the new model, each individual is characterised by a label; neutral resampling events may take place between arbitrary labels, whereas selective events only occur in the direction of increasing labels. We recover fixation probabilities and obtain detailed insight into the number and nature of selective events that play a role in the fixation process forward in time. The distribution of these events establishes a link to the work of Fearnhead and Taylor.

Published
2013

15. Quantitative Clonal Dynamics Define Mechanisms of CLL Evolution in Response to Combination Chemotherapy

Author

Landau, Dan A., primary, Tausch, Eugen, additional, Böttcher, Sebastian, additional, Stewart, Chip, additional, Bozic, Ivana, additional, Leischner, Iganty, additional, Rosebrock, Daniel, additional, Taylor-Weiner, Amaro, additional, Mertens, Daniel, additional, Sougnez, Carrie, additional, Kless, Sabrina, additional, Kneba, Michael, additional, Ritgen, Matthias, additional, Kluth, Sandra, additional, Bahlo, Jasmin, additional, Fink, Anna-Maria, additional, Fischer, Kirsten, additional, Gabriel, Stacey, additional, Lander, Eric, additional, Dohner, Hartmut, additional, Hallek, Michael, additional, Neuberg, Donna S, additional, Nowak, Martin, additional, Getz, Gad, additional, Stilgenbauer, Stephan, additional, and Wu, Catherine J., additional

Published
2015
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16. Value of Minimal Residual Disease (MRD) Negative Status at Response Evaluation in Chronic Lymphocytic Leukemia (CLL): Combined Analysis of Two Phase III Studies of the German CLL Study Group (GCLLSG)

Author

Kovacs, Gabor, Boettcher, Sebastian, Bahlo, Jasmin, Kluth, Sandra, Ritgen, Matthias, Fink, Anna Maria, Stodden, Irene, Cramer, Paula, von Tresckow, Julia, Maurer, Christian, Doehner, Hartmut, Stilgenbauer, Stephan, Kneba, Michael, Fischer, Kirsten, Hallek, Michael, Eichhorst, Barbara, Kovacs, Gabor, Boettcher, Sebastian, Bahlo, Jasmin, Kluth, Sandra, Ritgen, Matthias, Fink, Anna Maria, Stodden, Irene, Cramer, Paula, von Tresckow, Julia, Maurer, Christian, Doehner, Hartmut, Stilgenbauer, Stephan, Kneba, Michael, Fischer, Kirsten, Hallek, Michael, and Eichhorst, Barbara

Published
2014

17. Subclonal Driver Mutations Predict Shorter Progression Free Survival in Chronic Lymphocytic Leukemia Following First-Line Chemo(immuno) Therapy: Results from the CLL8 Trial

Author

Landau, Dan A., Tausch, Eugen, Taylor-Weiner, Amaro N., Bottcher, Sebastian, Bahlo, Jasmin, Stewart, Chip, Edelmann, Jennifer, Kluth, Sandra, Mertens, Daniel, Kneba, Michael, Kless, Sabrina, Sougnez, Carrie, Fischer, Kirsten, Ritgen, Matthias, Gabriel, Stacey, Lander, Eric, Dohner, Hartmut, Hallek, Michael, Getz, Gad, Neuberg, Donna, Stilgenbauer, Stephan, Wu, Catherine J., Landau, Dan A., Tausch, Eugen, Taylor-Weiner, Amaro N., Bottcher, Sebastian, Bahlo, Jasmin, Stewart, Chip, Edelmann, Jennifer, Kluth, Sandra, Mertens, Daniel, Kneba, Michael, Kless, Sabrina, Sougnez, Carrie, Fischer, Kirsten, Ritgen, Matthias, Gabriel, Stacey, Lander, Eric, Dohner, Hartmut, Hallek, Michael, Getz, Gad, Neuberg, Donna, Stilgenbauer, Stephan, and Wu, Catherine J.

Published
2014

18. Value of Minimal Residual Disease (MRD) Negative Status at Response Evaluation in Chronic Lymphocytic Leukemia (CLL): Combined Analysis of Two Phase III Studies of the German CLL Study Group (GCLLSG)

Author

Kovacs, Gabor, primary, Boettcher, Sebastian, additional, Bahlo, Jasmin, additional, Kluth, Sandra, additional, Ritgen, Matthias, additional, Fink, Anna Maria, additional, Stodden, Irene, additional, Cramer, Paula, additional, von Tresckow, Julia, additional, Maurer, Christian, additional, Doehner, Hartmut, additional, Stilgenbauer, Stephan, additional, Kneba, Michael, additional, Fischer, Kirsten, additional, Hallek, Michael, additional, and Eichhorst, Barbara, additional

Published
2014
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19. Subclonal Driver Mutations Predict Shorter Progression Free Survival in Chronic Lymphocytic Leukemia Following First-Line Chemo(immuno)Therapy: Results from the CLL8 Trial

Author

Landau, Dan A., primary, Tausch, Eugen, additional, Taylor-Weiner, Amaro N, additional, Bottcher, Sebastian, additional, Bahlo, Jasmin, additional, Stewart, Chip, additional, Edelmann, Jennifer, additional, Kluth, Sandra, additional, Mertens, Daniel, additional, Kneba, Michael, additional, Kless, Sabrina, additional, Sougnez, Carrie, additional, Fischer, Kirsten, additional, Ritgen, Matthias, additional, Gabriel, Stacey, additional, Lander, Eric, additional, Dohner, Hartmut, additional, Hallek, Michael, additional, Getz, Gad, additional, Neuberg, Donna, additional, Stilgenbauer, Stephan, additional, and Wu, Catherine J., additional

Published
2014
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22. Complex karyotypes and KRASand POT1mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy

Author

Herling, Carmen Diana, Klaumünzer, Marion, Rocha, Cristiano Krings, Altmüller, Janine, Thiele, Holger, Bahlo, Jasmin, Kluth, Sandra, Crispatzu, Giuliano, Herling, Marco, Schiller, Joanna, Engelke, Anja, Tausch, Eugen, Döhner, Hartmut, Fischer, Kirsten, Goede, Valentin, Nürnberg, Peter, Reinhardt, Hans Christian, Stilgenbauer, Stephan, Hallek, Michael, and Kreuzer, Karl-Anton

Abstract

Genetic instability is a feature of chronic lymphocytic leukemia (CLL) with adverse prognosis. We hypothesized that chromosomal translocations or complex karyotypes and distinct somatic mutations may impact outcome after first-line chemoimmunotherapy of CLL patients. We performed metaphase karyotyping and next-generation sequencing (NGS) of 85 genes in pretreatment blood samples obtained from 161 patients registered for CLL11, a 3-arm phase 3 trial comparing frontline chlorambucil (Clb) vs Clb plus rituximab (Clb-R) or Clb plus obinutuzumab in CLL patients with significant comorbidity. Chromosomal aberrations as assessed by karyotyping were observed in 68.8% of 154 patients, 31.2% carried translocations, and 19.5% showed complex karyotypes. NGS revealed 198 missense/nonsense mutations and 76 small indels in 76.4% of patients. The most frequently mutated genes were NOTCH1, SF3B1, ATM, TP53, BIRC3, POT1, XPO1,and KRAS. Sole chemotherapy, treatment with Clb-R, or genetic lesions in TP53(9.9% of patients) and KRAS(6.2% of patients) were significantly associated with nonresponse to study therapy. In multivariate models, complex karyotypes and POT1mutations (8.1% of patients) represented significant prognostic factors for an unfavorable survival, independently of IGHVmutation status, Binet stage, and serum β-2-microglobuline. Patients with the copresence of complex karyotypes and deletions/mutations involving TP53demonstrated a particularly short survival. In summary, this is the first prospective, controlled study in CLL patients that shows a role of complex karyotype aberrations as an independent prognostic factor for survival after front-line therapy. Moreover, the study identifies mutations in KRASand POT1as novel determinants of outcome after chemoimmunotherapy using chlorambucil and anti-CD20 treatment.

Published
2016
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23. Bendamustine and rituximab in combination with lenalidomide in patients with chronic lymphocytic leukemia.

Author

Maurer C, Pflug N, Bahlo J, Kluth S, Rhein C, Cramer P, Gross-Ophoff C, Langerbeins P, Fink AM, Eichhorst B, Kreuzer KA, Fischer N, Tausch E, Stilgenbauer S, Böttcher S, Döhner H, Kneba M, Dreyling M, Binder M, Hallek M, Wendtner CM, Bergmann M, and Fischer K

Subjects
Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride administration & dosage, Chromosome Aberrations, Drug Administration Schedule, Female, Humans, Lenalidomide, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Maximum Tolerated Dose, Middle Aged, Mutation, Neoplasm Staging, Prognosis, Rituximab administration & dosage, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Abstract

Purpose: A phase I/II trial to assess safety and efficacy of the combination bendamustine, rituximab, and lenalidomide (BRL) in patients with chronic lymphocytic leukemia (CLL)., Patients and Methods: Seventeen relapsed or refractory (R/R) and five previously untreated (FL) CLL patients were enrolled in the trial. In the R/R cohort, four different dose levels of lenalidomide (maximum 15 mg/d) were used. In the FL cohort, lenalidomide was dose escalated from 5 mg/d to 15 mg/d. Bendamustine was used at doses of 50 or 90 mg/m(2) for R/R or FL treatment, respectively. 375 mg/m(2) Rituximab were used for the first and 500 mg/m(2) for subsequent treatment courses. Treatment consisted of up to six courses of 28 d., Results: The maximal tolerable dose of lenalidomide was 5 mg/d. The response rate was 47.1% in R/R and 60% in FL patients. Median progression-free survival was 8.0 months. Median overall survival was 22.9 and 12.3 months, respectively, in R/R and FL patients. Grade 3/4 hematological toxicity was observed in 71.4%, and severe infections in 47.6% of patients. Due to high toxicity and low response rate of BRL, the trial was closed prematurely., Conclusion: BRL was associated with a high toxicity rate, a high number of treatment interruptions, and a low remission rate. Therefore, BRL cannot be considered an appropriate treatment option for patients with CLL., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2016
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