Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4429-4429

Abstract: Introduction Chronic lymphocytic leukemia (CLL) is a disease of the elderly patient with a median age of 72 years at diagnosis. In addition to a generally increased obesity prevalence, higher age is also associated with increased body fat contents, and currently 22.5% of men and 31.8% of women above 65 years in Germany qualify as obese (body mass index [BMI] ≥30 kg/m²). While high BMI values are regarded as a risk factor for certain cancers, the impact of obesity on treatment outcomes is controversial and differs between genders. In aggressive B-cell lymphoma the prognosis of obese elderly women was worse following R-CHOP chemoimmunotherapy (CIT). With this meta-analysis the question whether obesity has an impact in CLL was addressed. Methods We analyzed pooled data from three prospective phase III trials (CLL4, CLL8, CLL10) of the German CLL study group (GCLLSG). With the aim to assess the effect of rituximab, patients treated with fludarabine monotherapy (F) or bendamustine and rituximab (BR) were excluded from this analysis. Underweighted patients (BMI 〈 18.5 kg/m², n=10) were excluded as well. Finally, the total analysis cohort comprised 1237 previously untreated patients receiving fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). We analyzed progression-free survival (PFS) and overall survival (OS) according to baseline BMI (normal weight (NW) 18.5-24.9 kg/m²; overweight (OW) 25-29.9 kg/m²; obese (OB) ≥ 30 kg/m²), gender and treatment regimen. Kaplan-Meier curves were plotted and compared by non-stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression modelling. Results In this combined cohort 560 (45.3%) patients received FC and 677 (54.7%) received FCR. 319 (25.8%) patients were female, 918 (74.2%) were male, median age was 60 years (range 30-81). The cohort comprised 497 (40.2%) NW patients, 521 (42.1%) OW patients and 219 (17.7%) OB patients. Median BMI was 25.1 kg/m² (range 18.6-45.0) in the female and 26.0 kg/m² (range 18.7-45.2) in the male study population. Clinical characteristics, in particular CLL-IPI risk groups and other prognostic factors, were equally distributed between BMI subgroups. Median observation time was 68.4 (range 0.4-151.3) months. OB patients received lower CIT doses compared to NW patients with regard to planned doses based on body surface area (Table 1). Medians of given dose intensities were for fludarabine: NW 95.1% (range 10.8-124.7) vs. OB 84.0% (range 9.2-121.0), for cyclophosphamide: NW 93.5% (range 11.1-105.7) vs. OB 84.0% (range 9.2-102.3), and for rituximab: NW 98.2% (range 0.1-108.7) vs. OB 88.9% (range 26.8-101.3). This difference was observed in male and female patients. We found significantly increased creatinine clearance rates in OB patients of both genders calculated by three different methods including the Salazar/Corcoran method that adjusts for obesity. PFS and OS according to the three BMI groups were not different in the entire cohort comprising both genders or males only. However, obese females had significantly worse outcomes following FCR treatment compared to NW females: median PFS was 44.6 in OB vs. 73.0 months in NW females (HR 1.743 [1.022-2.973]; p=0.041) and the median OS was 83.7 months compared to not reached in the female NW group (HR 3.013 [1.345-6.752] ; p=0.007) (Figure 1). These survival differences could not be detected in FC treated females (Figure 2). Conclusions Our data suggest that obesity is associated with significantly shorter PFS and OS in female CLL patients undergoing FCR chemoimmunotherapy but not conventional FC chemotherapy without rituximab. Therefore we assume that lower relative chemotherapy dose exposition that OB females received was not the major contributing factor to this survival difference. In contrast, we assume lower rituximab exposure in OB females treated with FCR due to obesity-associated increased clearance rates as described before. The significantly increased creatinine clearance rates in OB female patients might have additionally contributed to this effect, however the detailed mechanisms remain to be characterized. Our results are in line with recently published data on obesity as a survival risk factor in female patients with aggressive B-cell lymphoma undergoing R-CHOP CIT. Taken together, this warrants closer metabolic and anthropometric status evaluation in future immunotherapeutic studies. Disclosures Hopfinger: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Honoraria, Research Funding. Fink:Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel geants; Roche: Other: travel grants; Mundipharma: Other: travel grants. Al-Sawaf:Roche: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Langerbeins:Sunesis: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Mundipharma: Consultancy, Other: Travel grants; Roche: Consultancy, Other: Travel grants, Research Funding. Cramer:Mundipharma: Other: Travel grants; Roche: Honoraria, Other: Travel grants, Research Funding; Acerta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Gilead: Other: Travel grants, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grants, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel grants, Research Funding. Von Tresckow:Celgene: Consultancy, Other: Travel grants; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Janssen-Cliag: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria. Kutsch:Janssen: Other: Travel support; AbbVie: Other: Travel support; Mundipharma: Other: Travel support; Gilead: Research Funding. Hoechstetter:Hexal: Other: Travel Grants; Abbvie: Other: Travel Grants; Gilead Sciences: Consultancy, Other: Travel Grants. Dreyling:Gilead: Consultancy, Honoraria; Mundipharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Acerta: Consultancy; Sandoz: Consultancy. Kneba:AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Stilgenbauer:Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding. Döhner:AbbVie: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding. Hensel:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jaeger:Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria. Wendtner:Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding. Goede:Janssen: Honoraria, Other: Travel grants; Abbvie: Consultancy; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel grants. Fischer:Roche: Other: Travel support. Hallek:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113257

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 526-526

Abstract: Introduction FCR is the current standard first line treatment regimen in advanced CLL (Hallek et al., Lancet, 2010), but is associated with significant side effects. The GCCLSG initiated an international phase III study in order to test the non-inferiority regarding efficacy and potentially better tolerability of BR compared to FCR in first-line therapy of physically fit pts without del(17p). Methods and Patients 688 CLL pts from 158 sites in five countries (Germany, Austria, Switzerland, Denmark and Czech Republic) were screened centrally for immunophenotype, genomic aberrations by FISH, IGHV sequenzing, comorbidity burden and renal function. 564 CLL pts with CIRS score ≤ 6, creatinine clearance 〉 70 ml/min and without del(17p) were enrolled between October 2008 and June 2011. Pts were randomly assigned to receive 6 courses of either FCR (N= 284; F 25mg/m2 i.v. d1–3, C 250 mg/m2 i.v. d1–3, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days) or BR (N=280; B 90mg/m2 i.v. d1+2, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days). The intent-to-treat population consisted of 561 pts, because three patients were excluded due to deferred treatment (1 pt decision, 1 treatment before randomization, 1 misdiagnosis). 22 % were Binet A, 38 % Binet B and 40 % Binet C. The median age was 62 years (yrs) (range 33 to 82), median CIRS score 2 (range 0-6). There were significantly more pts with unmutated IGVH in the BR arm (68%) in comparison to the FCR arm (55%; p=0.003). All other characteristics including median age were well balanced. A mean number of 5.27 courses was given in the FCR arm versus 5.41 courses in the BR arm (p=0.022). 70.6% (FCR) and 80.3% (BR) of pts received 6 courses (p=0.008). Dose was reduced by more than 10% in 27.3% (FCR) and 31.6% (BR) of all courses given (p = 0.012). Results The median observation time was 27.9 months (mo) in all pts alive. While response evaluation was missing in 14 pts, 547 pts (274 FCR; BR 273) were evaluable for response and all 561 pts (282 FCR; 279 BR) for progression-free survival (PFS), event-free survival (EFS) and OS. The overall response rate was identical in both arms with 97.8% (p=1.0). The complete response rate (CRR) (confirmed by central immunhistology) with FCR was 47.4% as compared to 38.1% with BR (p=0.031). MRD data were available at interim analysis from 192 pts (99 FCR; 93 BR) of the first 300pts. 71.7% of pts in the FCR and 66.7% in the BR arms achieved MRD-levels below 10-4 in peripheral blood at final staging (p=0.448). The complete MRD data set will be available by November. PFS was 85.0% at 2 yrs in the FCR arm and 78.2% in the BR arm (p=0.041). EFS was 82.6% at 2 yrs in the FCR arm and 75.7% in the BR arm (p=0.037).There was no difference in OS rate for the FCR vs BR arm (94.2% vs 95.8% at 2 years p=0.593). Hazard Ratio for PFS, EFS and OS was 1.385, 1.375 and 0.842 respectively. PFS was assessed in pts 〈 65 yrs and ≥ 65 yrs. While there was a significant difference in pts 〈 65 yrs between both treatment arm (median PFS for BR 36.5 mo vs not reached for FCR; p=0.016), the difference disappeared in elderly pts (not reached vs. 45.6 mo; p=0.757). A multivariate analysis including treatment arm, Binet stage, age, sex, comorbidity, serum TK, serum beta2-microglobulin (Beta2M), del(11q) and IGHV status identified treatment arm, Beta2M, del(11q) and IGHV as independent prognostic factors for PFS and EFS. FCR treated pts had significantly more frequent severe, CTC grade 3 to 5, adverse events during the whole observation period (90.8% vs 78.5%; p 〈 0.001). Especially severe hematotoxicity was more frequent in the FCR arm (90.0% vs 66.9%, p 〈 0.001). The higher rate of severe neutropenia (81.7% vs 56.8%, p 〈 0.001) resulted in a significantly higher rate of severe infections (39.0% vs 25.4%, p=0.001) in the FCR arm, especially in the elderly (FCR: 47.4% vs BR: 26.5%; p=0.002). Treatment related mortality occurred in 3.9% (n=11) in the FCR and 2.1% (n=6) in the BR arm. Conclusion The results of this planned interim analysis show that FCR seems more efficient than BR in the first-line treatment of fit CLL pts with regard to higher CRR, as well as longer PFS and EFS. These advantages might be balanced by a higher rate of severe adverse events, in particular neutropenia and infections, associated with FCR. In light of these results, no firm recommendation of one regimen over the other can be given at the present time regarding the first-line use in CLL pts with good physical fitness. Disclosures: Eichhorst: Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Gregor:Roche: Consultancy, Honoraria, Travel Support Other; Mundipharma: Travel Support, Travel Support Other. Plesner:Mundipharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Fischer:Roche: Travel grants Other; Mundipharma: Travel grants, Travel grants Other. Kneba:Roche: Consultancy, Research Funding. Wendtner:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Kreuzer:Roche: Honoraria; Mundipharma: Honoraria. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Böttcher:Roche: Honoraria, Research Funding. Hallek:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.526.526

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4430-4430

Abstract: Introduction: In CLL, chemoimmunotherapies (CIT) and combinations with novel agents have proven to be highly effective with regard to eradication of minimal residual disease (MRD), while complete remissions (CR) are frequently not achieved due to residual lymphadenopathy. We have previously reported that minimal residual disease (MRD) negativity after CIT is a prognostic factor irrespective of the clinical response (Kovacs et al., JCO 2016). Because inferior outcome was observed in small subgroups of patients (pts) with residual lymphadenopathy, we analyzed the prognostic value of residual lymphadenopathy after CIT in comparison to MRD detection in a larger pt population. Methods: We included 361 pts receiving frontline CIT within 3 prospective clinical trials of the GCLLSG (CLL2M: 23 pts, CLL8: 113 pts, CLL10: 225 pts) with available CT/MRI scans to assess abdominal lymphadenopathy at the final restaging (FR; 2 months after the end of last treatment cycle). Pts with available data on all classical lymph node regions (N=217) were analyzed separately (Figure 1). Enlarged lymph nodes (LN+) were defined as 〉 1.5 cm in the longest diameter according to iwCLL 2008 guidelines regardless of the investigator-assessed response category. MRD levels in peripheral blood (PB) were assessed at FR. PFS and OS was analyzed from time point of radiological assessment. Kaplan-Meier curves were plotted and compared using the log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression modelling. Results: Of the 361 pts included in this analysis, 227 (62.9%) received fludarabine, cyclophosphamide and rituximab (FCR) and 134 (37.1%) pts received bendamustine and R (BR). Median age was 60 years (range, 34-79); median observation time was 55.8 months (mo) (3.2-85.5). 62 (17.2%) pts had residual abdominal LN+, 299 (82.8%) had no residual abdominal lymphadenopathy (LN-) at FR. Of 217 pts with documented CT/MRI of all LN regions at FR, 48 (22.1%) pts had residual LN+ in at least one LN region and 169 (77.9%) showed no residual LN in any of the regions. Baseline characteristics were equally distributed between pts with and without available radiological assessments, between pts with radiological assessments of all regions or only abdominal and between LN+ and LN- pts. MRD in PB was available for 231 (64.0%) pts in this analysis group; of these, 165 pts (71.4%) showed MRD negativity (MRD-) at FR. PFS and OS were analyzed for different LN size categories (≤1 cm; 〉 1 & ≤2 cm; 〉 2 & ≤3 cm; 〉 3 cm). Patient outcome decreased with larger residual abdominal LN size at FR with regard to PFS (median, 52.9 mo vs. 24.6 mo vs. 30.5 mo vs. 10.6 mo; p 〈 0.001) and OS (median, NR vs. 63.2 mo vs. 57.0 mo vs. 45.9 mo; p 〈 0.001). However, the iwCLL guideline cut-off at 1.5 cm was found to be appropriate. Using this 1.5 cm cut-off, PFS and OS were significantly worse in abdominal LN+ pts compared to abdominal LN- pts (median PFS: 20.4 mo vs. 52.5 mo; HR 2.806; CI=2.030-3.879; p 〈 0.001; median OS: 57 mo vs. not reached [NR]; HR 4.294; CI=2.600-7.091; p 〈 0.001). In pts with residual lymphadenopathy 〉 1.5 cm in any lymph node region, PFS and OS was significantly worse compared to LN- pts (median PFS: 27.3 mo vs. 60.4 mo; HR 2.409; CI=1.622-3.577; p 〈 0.001; median OS: 60.7 mo vs. NR; HR 4.445; CI=2.208-8.947; p 〈 0.001). In a multivariate analysis, abdominal LN size at FR was an independent prognostic factor for PFS and OS, while LN size in any lymph node region failed to show independent prognostic value (Table 1). In the MRD- group, PFS was significantly shorter in MRD-/LN+ pts compared to MRD-/LN- pts (abdominal LN: median, 34.7 mo vs. 75.6 mo; HR 2.150; CI=1.190-3.883; p=0.011; any LN: median, 34.7 mo vs. 75.6 mo; HR 2.343; CI=1.221-4.497; p=0.01). This observation was confirmed for OS (abdominal LN: 5-year survival, 52.9% vs. 88.8%; HR 3.153; CI=1.183-8.407; p=0.022; any LN: 5-year survival, 61.9% vs. 94.3%; HR 4.213; CI=1.179-15.016; p=0.027) (Figures 2 & 3). Conclusions: Residual abdominal lymphadenopathy at FR is an independent prognostic factor for PFS and OS regardless of MRD negativity. It remains to be determined whether these findings can be transferred to novel targeted agents such as kinase inhibitors, venetoclax, novel CD20 antibodies or combinations of these. Residual disease in the lymph node compartment may identify a pt population which might benfit from strategies using consolidation therapies. Disclosures Bahlo: Roche: Honoraria, Other: Travel Grants. Fink:Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel geants; Roche: Other: travel grants; Mundipharma: Other: travel grants. Dreyling:Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sandoz: Consultancy; Acerta: Consultancy; Gilead: Consultancy, Honoraria. Hess:CTI: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritgen:Roche: Honoraria, Research Funding; abbvie: Research Funding. Kneba:AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Döhner:Bristol Myers Squibb: Research Funding; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Astellas: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Pfizer: Research Funding; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; AbbVie: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding. Stilgenbauer:AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Mundipharma: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding. Goede:Roche: Consultancy, Honoraria, Other: Travel grants; Janssen: Consultancy, Honoraria, Other: Travel grants; Gilead: Consultancy, Honoraria; AbbVie: Consultancy. Fischer:Roche: Other: Travel support. Böttcher:Genentech: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Research Funding. Hallek:Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113280

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 4 ( 2020-04), p. 1177-1181

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-019-0630-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: HemaSphere, Ovid Technologies (Wolters Kluwer Health), Vol. 4, No. 1 ( 2020-01-27), p. e336-

Type of Medium: Online Resource

ISSN: 2572-9241

URL: Article

DOI: 10.1097/HS9.0000000000000336

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2020

detail.hit.zdb_id: 2922183-3

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 19-19

Abstract: Introduction: For physically fit CLL pts with low comorbidity burden FCR is the standard frontline regimen in advanced CLL. The CLL10 study, an international phase III study evaluated the efficacy and tolerance of BR in comparison to FCR in frontline therapy of fit pts without del(17p). Methods and Patients: 158 sites in five countries (Germany, Austria, Switzerland, Denmark and Czech Republic) registered 688 CLL pts for central screening including immunophenotyping, FISH, comorbidity burden and renal function. 564 CLL pts with CIRS score ≤ 6, creatinine clearance 〉 70 ml/min and without del(17p) were enrolled between 10/2008 and 6/2011. Pts were randomly assigned 1:1 to receive 6 courses of FCR (N= 284; F 25mg/m2 i.v. d1–3, C 250 mg/m2 i.v. d1–3, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days) or BR (N=280; B 90mg/m² i.v. d1+2, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days). A general prophylactic use of antibiotics or growth factors was not recommended. Three patients (2 FCR, 1 BR) were excluded because of deferred treatment. The median CIRS score was 2. There was no difference in median age (61.6 years (yrs) for all pts), but a significantly higher proportion of pts ≥ 70 yrs was included in the BR arm (22% vs 14%, p=0.020). Binet A was present in 22%, Binet B in 38 % and Binet C in 40 %. Unmutated IGHV status was not balanced between both groups (68% in BR versus 55% in FCR arm; p=0.003). All other characteristics showed no differences. The mean number of administered FCR courses was 5.27 courses vs 5.41 BR course (p=0.017). Results: The median observation time for all patients was 35.9 months (mo). 547 pts (FCR 274 ; BR 273) were evaluable for response and all pts (282 FCR ; 279 BR) included for progression-free survival (PFS) and overall survival (OS) analysis. The overall response rate in both arms was 97.8% (p=1.0). The complete response (CR) rate according to IWCLL and confirmed by central bone marrow immunohistology was 40.7% with FCR compared to 31.5% with BR (p=0.026). Four-colour-flow MRD data from peripheral blood (sensitivity 10-4) were available from 355 pts (185 FCR; 170 BR) at final staging. In the FCR arm 74.1% and 62.9% in the BR arm respectively of all evaluated pts were MRD negative (p=0.024). Bone marrow samples, available in 129 FCR and 98 BR pts, were MRD negative in 58.1% and 31.6% of pts, respectively (p 〈 0.001). At 12 mo follow-up 58.2% of the pts in the FCR arm (46/79) were still MRD negative in comparison to 26.3% (20/76) after BR (p 〈 0.001). At 18 mo there were 53.8% (35/65) MRD negative cases versus 24.6% (16/65; p=0.006). Median PFS was 53.7 mo in the FCR arm and 43.2 mo in the BR arm (HR=1.589, 95% CI 1.25-2.079; p=0.001). While PFS was statistically not significant different between both arm in pts with mutated IGHV, pts with unmutated IGHV status had a median time to progression of 43.9 mo after FCR compared to 34.0 mo after BR (p=0.015). Physically fit subgroups (CIRS max 3, only one CIRS item, age 〈 65 yrs) benefited most from FCR therapy. The difference in PFS was statistically not significant between both arms in pts ≥ 65 years, CIRS 4-6 or 〉 1 CIRS item. Multivariate analysis identified treatment arm, age ≥ 65 yrs, male sex, high serum TK, del(11q), absence of del(13q) and IGHV status as independent prognostic factors for PFS. No difference in OS was observed (at 36 mo 90.6% for FCR vs 92.2% for BR; HR=1.030, 95% CI 0.618-1.717; p=0.910). For OS male gender, age ≥ 60 yrs, high serum TK and IGHV status were assessed as independent prognostic factors. Severe neutropenia was more often observed in the FCR arm (87.7% vs 67.8%, p 〈 0.001), but no significant difference in the incidence of anemia (14.2% vs. 12.0%; p=0.46) or thrombocytopenia (22.4% vs 16.5%; p=0.096) was documented. Severe infections occurred significantly more frequent (39.8% vs 25.4%, p=0.001) in the FCR arm during treatment phase until 6 months follow-up, especially in older pts (48.4% vs 26.8%; p=0.001). Treatment related mortality was 3.9% (FCR) and 2.1% (BR), respectively. Conclusion: The final analysis of the CLL10 study shows that FCR remains the standard therapy in very fit CLL patients, because it yields higher CR rates, more MRD negativity and longer PFS in comparison to BR. However, in elderly fit pts high toxicity rates and infection rates result into dose reductions leading to similar efficacy between both arms. Elderly fit pts or pts with previous infections might benefit from BR as alternative regimen. Disclosures Eichhorst: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant Other; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Off Label Use: The Combination of Bendamustine and Rituximab is not approved for frontline chemoimmunotherapy of CLL. Fink:Celgene: Other. Maurer:Mundipharma: Travel grant Other. Kiehl:Roche: Membership on an entity's Board of Directors or advisory committees. Gregor:Roche: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria. Trneny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fischer:Roche: Other. Döhner:Roche: Research Funding. Kneba:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Wendtner:Mundipharma: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding. Klapper:Hoffmann-La Roche: Research Funding; Takeda/Millenium: Research Funding. Kreuzer:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Böttcher:Roche: Honoraria, Research Funding, Travel grant Other. Hallek:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.19.19

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: European Journal of Haematology, Wiley

Abstract: Long‐term data of chronic lymphocytic leukemia (CLL) patients with favorable risk who were treated with fludarabine, cyclophosphamide, and rituximab (FCR) within clinical trials show good efficacy. We here report long‐term data collected within the GCLLSG registry. Altogether, 417 CLL patients who received first‐line treatment with FCR were analyzed, of which 293 (70.3%) were treated outside of clinical trials. The median observation time from first‐line was 95.8 (interquartile range 58.7–126.8) months. Focusing on data of 194 (46.5%) patients who received FCR first‐line treatment after 2013 (start of data collection within GCLLSG registry), responses were documented in 85% of the patients, non‐responses in 15%, and for 3.6% the assessment was missing. Median event‐free survival (EFS, time until disease progression, subsequent treatment, or death) was 60.2 months with a 5‐year EFS‐rate of 50.6%. Patients with higher‐risk disease, characterized by unmutated IGHV ( N = 78), had a median EFS of 45.4 months with a 5‐year EFS rate of 36.3%, while the median EFS was 77.5 months with a 5‐year EFS rate of 60.3% in patients with mutated IGHV ( N = 40). Median overall survival was not reached with a 5‐year survival rate of 92.7%. In summary, first‐line FCR was associated with long EFS, especially in patients exhibiting a mutated IGHV status.

Type of Medium: Online Resource

ISSN: 0902-4441 , 1600-0609

URL: Article

DOI: 10.1111/ejh.14220

Language: English

Publisher: Wiley

Publication Date: 2024

detail.hit.zdb_id: 2027114-1