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In: Cancer, Wiley, Vol. 119, No. 12 ( 2013-06-15), p. 2258-2267

Type of Medium: Online Resource

ISSN: 0008-543X

URL: Article

DOI: 10.1002/cncr.27972

Language: English

Publisher: Wiley

Publication Date: 2013

detail.hit.zdb_id: 1479932-7

detail.hit.zdb_id: 1429-1

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 671-671

Abstract: Telomeres are sequences at the ends of each chromosome that confer genomic stability. The presence of dysfunctional telomeres is associated with increased genomic abnormalities and tumorigenesis. In CLL, telomere length has been described as an independent prognostic factor (e.g. Roos et al., Blood 2008) but these analyses have been performed on heterogeneous patient cohorts and have not yet been confirmed within clinical trials. Here, we studied the impact of telomere length on outcome in the international CLL8 trial of the GCLLSG evaluating first-line treatment with fludarabine and cyclophosphamide (FC) versus FC with rituximab (Anti-CD20). Telomere length was analyzed using quantitative PCR of DNA (in triplicates) from baseline samples of 620 patients enrolled on CLL8, and this cohort was representative of the full trial population. The technique was validated using terminal restriction fragment length analysis (TRF) (R2=0.859, P 〈 0.001) in an independent control sample set (n=18) and 6 of these samples were included in every batch as controls. Telomere length was found to be highly variable in CLL (1.94 kb – 33.56 kb), whereas normal B-cells from age matched healthy probands (n=20) showed limited variability (5.39 – 9.60 kb; median 7.54 kb). Analysis of paired CD19+ (malignant) and CD19- (non-malignant) fractions (n=48) showed that telomere shortening in CLL was restricted to the malignant cell population (median: CD19+ 3.37 kb vs. CD19- 5.42 kb; P 〈 0.001). Comparison of clinical characteristics between the groups defined by short and long telomeres (cut-off at the median of 4.54 kb) showed no significant associations with age (P=0.931), sex (P=0.116), presence of B-symptoms (P=0.297), ECOG status (P=0.288), CIRS score (P=0.438) and ß2-MG (P=0.586). Short telomeres were significantly associated with high WBC (≥50 Giga/L; P=0.004), high thymidine kinase levels (≥10.0 U/L; P 〈 0.001) and presence of larger lymph nodes ( 〉 5cm; P=0.048). Also, unmutated IGHV (P 〈 0.001), ZAP70+ (≥20%; P=0.005), del(17p) (P 〈 0.001) and del(11q) (P 〈 0.001) were significantly more frequent in the group with short telomeres. Interestingly, cases with Binet C stage were significantly associated with long telomeres (P=0.007). After a median follow up time of 69.97 months, there were 423 events for progression free survival (PFS) and 209 for overall survival (OS). Short telomeres were significantly associated in both treatment arms with poor PFS (FC: median 27.4 vs. 44.0 months, P 〈 0.001; FCR: median 44.3 vs. 70.0 months, P 〈 0.001) (Figure) and OS (FC: median 35.1 vs. 62.5 months, P 〈 0.001; FCR: median 79.5 vs. 86.2 months, P=0.010). Multivariable analysis by Cox regression with backward selection was performed for the identification of independent prognostic factors, including as variables the treatment arms, age, sex, stage, ECOG status, B-symptoms, WBC, thymidine kinase, ß2-MG, CIRS, del(11q), +(12q), del(13q), del(17p), mutation status of IGHV, TP53, NOTCH1, SF3B1 and telomere length. Regarding PFS, we identified the following independent prognostic markers: FCR (HR 0.493; P 〈 0.001), male sex (HR 1.330; P=0.035), ECOG status 〉 0 (HR 1.256; P=0.037), thymidine kinase 〉 10 (HR 1.312; P=0.042), del(11q) (HR 1.378; P=0.012), del(17p) (HR 3.225; P 〈 0.001), unmutated IGVH (HR 1.478; P=0.007), TP53 mutation (HR 2.031; P=0.001) and short telomere length (HR 1.425; 95% CI 1.109-1.832; P=0.006). Regarding OS, the following independent prognostic markers were identified: FCR (HR 0.657; P=0.007), age ≥65 years (HR 1.453; P=0.021), ECOG status 〉 0 (HR 1.617; P=0.003), thymidine kinase 〉 10 (HR 1.850; P=0.007), beta2 microglobulin (HR 1.486; P=0.016), del(17p) (HR 2.716; P 〈 0.001), unmutated IGHV (HR 2.001; P=0.001) and TP53 mutation (HR 3.034; P=0.001). When not including NOTCH1, SF3B1 and TP53 in the multivariable models, short telomeres where identified as independent prognostic markers for PFS (HR 1.543; P 〈 0.001) and OS (HR 1.473; P=0.029). In conclusion, the characterization of telomere length in the CLL8 trial revealed significant associations with other biological high-risk features and an independent prognostic impact on outcome after FC or FCR treatment. This points to a role of telomere dysfunction in CLL pathogenesis, progression and response to therapy. Further study of telomere dysfunction in the evolution of CLL and in the context of novel non-genotoxic treatments is warranted. Disclosures: Wenger: F. Hoffmann-La Roche: Employment, Ownership interests (including stock options) in a start-up company, the stock of which is not publicly traded Other. Fingerle-Rowson:F. Hoffmann-La Roche : Employment. Wendtner:Hoffmann-La Roche: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Fischer:Roche: Travel grants Other; Mundipharma: Travel grants, Travel grants Other. Hallek:Roche: Consultancy, Honoraria, Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.671.671

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. 128, No. 22 ( 2016-12-02), p. 4401-4401

Abstract: Introduction: There are a growing number of therapeutic options for elderly patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, thus making clinical aids necessary to choose between available treatments. CLL-IPI is a validated tool for prognostication of overall survival in CLL (with age, stage, beta2-microglobulin, 17p deletion / TP53 mutation, and IGHV mutational status used as weighted factors to stratify patients for low, intermediate, high, or very high risk of death). We here evaluated CLL-IPI in a large sample of elderly patients with comorbidities. Methods: CLL-IPI was analyzed in the population of the CLL11 study, a randomized trial having enrolled 781 patients with previously untreated CLL and increased comorbidity burden for treatment with obinutuzumab (formerly GA101) plus chlorambucil (G-Clb, n=333), rituximab plus chlorambucil (R-Clb, n=330), or chlorambucil alone (Clb, n=118). Patients with all five CLL-IPI factors available were stratified into CLL-IPI risk groups. Overall survival (OS) was estimated for low, intermediate, high, and very high risk. Additionally, risk-specific time to next treatment (TTNT) and progression-free survival (PFS) were assessed. Methods included Kaplan-Meier curve, log-rank test, and Cox regression analyses. Results: Among 781 patients enrolled in the CLL11 study, 691 were evaluable in this analysis while 90 had to be excluded due to missing information for beta2-microglobulin, 17p deletion / TP53 mutation, or IGHV mutational status. Of the 691 patients, 299 were treated with G-Clb, 294 with R-Clb, and 98 with Clb. Median age, cumulative illness rating scale (CIRS), and ECOG performance status were 74 years, 8 and 1, respectively. Median observation time was 41.8 months. Stratification according to CLL-IPI was as follows: 62 (9%) low risk, 206 (30%) intermediate risk, 361 (52%) high risk, 62 (9%) very high risk. In a pooled analysis of all 691 evaluable patients, OS was significantly different between CLL-IPI risk groups (p 〈 0.001, Figure), with statistically satisfying values regarding both discrimination and calibration (C-statistics: C=0.633, 95%-CI 0.596-0.676; Hosmer-Lemeshow-Test: p=0.716). Similarly, graduating differences in OS between CLL-IPI risk groups were found in the subset of patients treated with chemoimmunotherapy and subsets of patients of each antibody arm, respectively. TTNT and PFS also differed between CLL-IPI risk groups. Favorable risk as assessed by CLL-IPI was associated with greater likelihood of OS benefit from treatment with G-Clb versus R-Clb (HR 0.232, 95%-CI, 0.027-1.983 for low risk; HR 0.540, 95%-CI 0.249-1.170 for intermediate risk; HR 0.884, 95%-CI 0.595-1.315 for high risk; HR 0.830, 95%-CI 0.372-1.852 for very high risk). Previously observed TTNT and PFS benefits from G-Clb versus R-Clb were maintained across CLL-IPI risk groups. Conclusions: This is the first validation study of CLL-IPI in elderly patients with previously untreated CLL in need of therapy and comorbidities. Results suggest good performance of the CLL-IPI in this patient population. CLL-IPI may provide help to physicians to choose between available treatment options in these patients. Figure OS by CLL-IPI risk groups in the analyzed CLL11 study sample (n=691) Figure. OS by CLL-IPI risk groups in the analyzed CLL11 study sample (n=691) Disclosures Goede: F- Hoffmann-LaRoche: Consultancy, Honoraria, Other: Travel grants; Gilead: Consultancy; Janssen: Consultancy, Other: Travel grants; Glaxo Smith Kline: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Bristol Myer Squibb: Honoraria. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Fischer:Roche: Other: travel grants. Fink:Mundipharma: Other: Travel grants; AbbVie: Other: Travel grants; Roche: Honoraria, Other: Travel grants; Celgene: Research Funding. Fingerle-Rowson:Roche: Employment. Stilgenbauer:Mundipharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genzyme: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding. Bergmann:Janssen: Honoraria; Gilead: Consultancy, Honoraria; Glaxo-SmithKline: Honoraria; Celgene: Honoraria; Roche: Consultancy, Honoraria; Mundipharma: Honoraria. Eichhorst:Mundipharma: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4401.4401

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 9 ( 2012-03-20), p. 980-988

Abstract: To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial. Patients and Methods MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- ( 〈 10 −4 ), intermediate- (≥ 10 −4 to 〈 10 −2 ), and high-level (≥ 10 −2 ) groups. Results Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P 〈 .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P 〈 .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC. Conclusion MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2011.36.9348

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2012

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3327-3327

Abstract: Introduction: Chemoimmunotherapy with the glycoengineered type II anti-CD20 antibody obinutuzumab plus the alkylating drug chlorambucil (G-Clb regimen) has been investigated in the CLL11 study and demonstrated clinical benefit in patients with previously untreated CLL and comorbidities. Whether G-Clb is also an active treatment in patients with refractory CLL after frontline therapy with Clb alone has been explored in the subpopulation of CLL11 subjects treated with such salvage therapy. Methods: Thirty patients who received Clb alone as initial study treatment, but developed progressive CLL within up to 6 months after end of Clb treatment were offered G-Clb as optional salvage therapy. The dosing schedule for obinutuzumab was 100 mg intravenously on day 1, 900 mg on day 2, and 1000 mg on day 8 and 15 of cycle 1, and 1000 mg on day 1 of cycles 2-6. Clb was administered orally with 0.5 mg/kg body weight on day 1 and 15 of each 28-day cycle. Results: The median age in the crossover patient population (n=30) was 72 years. The comorbidity burden was high as assessed at study entry (median cumulative illness rating scale total score 8), and renal function was reduced (median calculated creatinine clearance 67 mL/min). Deletions of 11q and 17p were present in 12% and 20% of the patients, respectively; and 64% had unmutated IGHV genes. When crossing over to G-Clb, the majority (93%) had not responded to the initial study treatment with Clb while two patients had responded transiently to Clb with a partial remission, but had relapsed early (median time from start of Clb to crossover: 9.7 months). After crossover, all but one patient completed the 6 cycles of salvage therapy with G-Clb; one subject discontinued after the first infusion of obinutuzumab due to an infusion-related reaction (IRR). Grade 3 or 4 IRRs occurred in 17% of the patients. Grade 3 or 4 neutropenia, anemia, thrombocytopenia, and infection were reported in 33%, 7%, 10%, and 13% of the patients, respectively. Response rates at the end of crossover treatment with G-Clb are given in the table. Negativity for minimal residual disease in bone marrow and/or peripheral blood after crossover treatment was achieved in 23% of the patients. The median progression-free survival from start of crossover treatment was 17.2 months (95% CI 14.2; 22.4 months) (median observation time: 23 months). Conclusions: These results suggest that, besides its established role as frontline treatment of CLL, chemoimmunotherapy with G-Clb could be a safe and active treatment for patients with CLL refractory to prior chlorambucil chemotherapy. Table: Clinical response to G-Clb after failure of Clb alone n (%) Responders 26 (87) Complete response 2 (7) Complete response incomplete 1 (3) Partial response 23 (77) Non-Responders 4 (13) Stable disease 2 (7) Progressive disease 1 (3) Not evaluable* 1 (3) * Due to early treatment discontinuation after IRR Disclosures Goede: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other. Off Label Use: Obinutuzumab (GA101, Gazyva); approved for 1st line treatment of CLL; paper includes results / discussion of drug use in 2nd line treatment of CLL. Engelke:Roche: Travel grants Other. Langerak:Roche: Research Funding. Ritgen:Roche: Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding. Asikanius:Roche: Employment. Humphrey:Roche: Employment. Wenger:Genentech: Employment. Fingerle-Rowson:Roche: Employment. Hallek:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3327.3327

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Leukemia, Springer Science and Business Media LLC, Vol. 33, No. 9 ( 2019-9), p. 2183-2194

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-019-0446-4

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2019

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 535-535

Abstract: Abstract 535 Introduction: In 2008, first results of a multicenter, international randomized phase III trial (CLL8) were presented, showing superiority of FCR chemoimmunotherapy for response rates and progression-free survival (PFS) when compared to FC chemotherapy. We now report updated results with a longer median observation time of 37.7 months (mo). Methods and Patients: 817 treatment-naïve patients (pts) with good physical fitness and CD20-positive CLL randomly (1:1) received treatment with 6 courses of either FCR or FC therapy. Both treatment arms were well balanced with regard to sex, age, stage, genomic aberrations and IGVH gene status. The median age was 61 years (range 30 to 81), 25.7% pts were female in both arms, 64.1% were Binet B, 31% Binet C and 4.9% Binet A. The median cumulative illness rating scale (CIRS) score was 1 (range 0-8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively. A mean number of 5.2 treatment courses were delivered in the FCR arm vs 4.8 courses in the FC arm (p=0.006). Dose reductions by more than 10% in at least one treatment course were performed in 47% (FCR) and 27% (FC) of pts (p 〈 0.001), respectively. 74% (FCR) and 67% (FC) of pts received 6 cycles (p=0.02). The total median cumulative dose applied per pt was 775 mg for F and 7712 mg for C, with no statistically significant difference among the two treatment arms. Pts in Binet stages A and B received more treatment cycles (5.31) than Binet C pts (4.52; p 〈 0.001). Only 57.1% (FC) and 60.3% (FCR) Binet C pts received 6 cycles. Dose reductions by more than 10% were observed in 49% of FCR pts (vs 28% FC (p=0.001). Results: As of June 2009, the median observation time was 37.7 (mo). 761 pts (FCR 388; FC 371) were evaluable for response, 790 pts (FCR 401; FC 389) for PFS and all for OS. FCR induced a higher overall response rate than FC (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p 〈 0.001). Median PFS was 32.8 mo for FC and 51.8 mo for FCR pts (p 〈 0.001, Hazard Ratio (HR) 0.56, CI 95% 0.460-0.689). The largest benefit for FCR was observed in Binet stage A and B for CR, ORR and PFS (Binet A: p=0.08, HR 0.423 CI 95%, 0.157-1.135, Binet B: p 〈 0.001 HR: 0.504 CI 95%, 0.390-0.651, Binet C: p=0.08, HR 0.732 CI 95%, 0.514-1.041). In Binet C, the median PFS was 14 mo for pts treated with up to 3 courses FC, but 44 mo for pts that received 4 courses or more (p 〈 0.001). Median PFS for pts treated with up to 3 cycles FCR was 12.5 mo, while for pts with 4 cycles or more, median PFS has not been reached (p 〈 0.001). Statistically significant differences were observed in OS between the two treatment arms. The OS rate at 37.7 mo was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01). In both arms, the median OS has not been reached. Only patients in Binet stages A and B showed a superior OS after FCR treatment (Binet A: HR 0.19, CI 95%, 0.023-1.613 p=0.09; Binet B: HR 0.45, CI 95%, 0.296-0.689, p 〈 0.001; Binet C HR1.4, CI 95%, 0.843-2.620, p=0.168). As previously reported more hematologic adverse events, particularly neutropenia, were observed with FCR treatment, but this did not result in an increased infection rate. More deaths have occurred in the FC arm (86/396, 21.7%) than in the FCR arm (65/404, 16.1%). In the majority of cases, the underlying cause of death was progressive disease (FC 48/86, FCR 33/65), secondary malignancies (FC 13/86, FCR 5/65) or unrelated causes of death such as myocardial infarction (FC 15/86, FCR 17/65). Treatment related mortality occurred in 8 (2.0%) of pts in each arm. Of these, 7 FC-treated pts and 5 FCR-treated pts died from infections related to treatment. In 7 pts (3 FC vs. 4 FCR), treatment was discontinued before the third treatment course due to fatal toxicity. Multivariate analysis was performed to evaluate factors predicting outcome. Age, sex, FCR-treatment, response, number of cycles (0-3), 17p-deletion, increased serum levels of thymidine kinase and β2-microglobulin and unmutated IGVH genes were independent prognostic factors predicting OS or PFS. Conclusion: Treatment with FCR chemoimmunotherapy is more effective than FC chemotherapy. The partial failure to demonstrate a benefit for FCR in Binet stage C patients may be related to an insufficient treatment intensity in these patients with higher tumor load. To our knowledge, this is the first time that a randomized trial is able to demonstrate that a specific first-line treatment for CLL results in an improved overall survival. The results corroborate the recommendation to use FCR as standard therapy in physically fit pts with CLL requiring therapy. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding. Fingerle-Rowson:Roche: Honoraria, travel grants. Fink:Roche: Travel grants. Mayer:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy; Fresenius: Consultancy; Roche: Research Funding; Pfizer: Research Funding. Hensel:Roche: Honoraria, Travel Grants; Bayer: Honoraria. Hopfinger:Roche: Membership on an entity's Board of Directors or advisory committees. Hess:Roche: Honoraria. Bergmann:Roche: Honoraria for monitoring and CRFs. Catalano:Roche: Honoraria, Research Funding, Travel grants. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Berrebi:Roche: travel grants. Jaeger:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants. Trneny:Roche: Honoraria, Research Funding. Westermann:Roche: Travel Grants. Wendtner:Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Eichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Staib:Roche: Research Funding. Boettcher:Roche: Honoraria, Research Funding, Travel grants. Ritgen:Roche: Research Funding. Mendila:Roche: Employment. Kneba:Roche: Honoraria, Research Funding. Doehner:Roche: Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding, travel grants. Fischer:Mundipharma: Research Funding; Roche: travel grants.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.535.535

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3227-3227

Abstract: BACKGROUND The CLL11 trial evaluated front line treatment with Clb vs. R-Clb vs. G-Clb in 781 physically unfit patients. Genomic aberrations, IGHV and TP53 mutation status are established prognostic factors in CLL, while NOTCH1, SF3B1, ATM and othersare recurrently mutated genes of potential prognostic and/or predictive value. METHODS We performed amplicon-based targeted next generation sequencing of all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3, XPO1, POT1) or hotspots (NOTCH1 exons 33/34, SF3B1 exons 14-16/18) via Illumina TSCA™ in a representative subset of 689 (88.2%) patients of the CLL11 trial at baseline. Mean read depth was 1363x (range 636-1879) and a variant allele frequency 〉 5% was determined as mutation. RESULTS Incidences of gene mutations were: ATM 19.6%, NOTCH1 18.6%, SF3B1 12.9%, TP53 10.7%, POT1 7.3%, XPO1 6.8%, BIRC3 5.2%, FBXW7 3.8%, and MYD88 3.3%. We found several significant associations with clinical and genetic baseline characteristics including most prominently IGHVunmut with ATMmut (p=0.013), NOTCH1mut (p 〈 0.001), POT1mut (p=0.026), XPO1mut (p 〈 0.001), and MYD88wt (p 〈 0.001). ATMmut and NOTCH1mut were more frequent in Binet stage B/C (p=0.011, p=0.001, resp.). POT1mut showed significantly higher and FBXW7mut lower WBC (p=0.033, p=0.002, resp.). Finally, we found associations of ATMmut with del11q, TP53mut with del17p, NOTCH1mut and FBXW7mut with +12q (p 〈 0.001, each), BIRC3mut and POT1wt with +12q (p=0.003, p=0.014, resp.). Regarding response to treatment, TP53mut was associated with reduced ORR for R-Clb (p 〈 0.001) and G-Clb (p=0.002), BIRC3mut for R-Clb (p=0.001) and FBXW7mut for G-Clb (p=0.045) only. MRD negativity ( 〈 10-4) at the end of treatment was more frequently achieved by G-Clb as compared with R-Clb in the subgroups ATMmut (p 〈 0.001), BIRC3mut (p=0.007), NOTCH1mut (p 〈 0.001) and FBXW7mut (p=0.047). At a median observation time of 41.9 months, there were 529 (76.8%) events for PFS and 195 (28.3%) events for OS in the cohort studied. G-Clb prolonged PFS as compared to R-Clb in the overall cohort (median 27.1 vs. 15.7 months, HR 0.49, p 〈 0.001) and in all gene mutation subgroups, except for FBXW7mut. Subgroups defined by ATMmut and TP53mut (Fig. 1) had significantly reduced PFS in both R-Clb and G-Clb (ATMmut HR 1.41, p=0.029/HR 1.67, p=0.004; TP53mut HR 3.36/HR 2.28, p 〈 0.001, each). For SF3B1mut and XPO1mut a non-significant trend was observed for shorter PFS in both treatment arms. Notably, NOTCH1mut (Fig. 2)was associated with decreased PFS only in the R-Clb arm (HR 1.42, p=0.03), but not in Clb monotherapy (HR 1.52, p=0.103) or G-Clb arm (HR 1.08, p=0.697). Similarly, POT1mut (HR 1.69, p=0.043) and BIRC3mut (HR 1.69, p=0.023) affected PFS only in the R-Clb arm, and FBXW7mut exclusivelyin the G-Clb arm (HR 2.35, p=0.028). We performed multivariable Cox regression analysis including clinical and genetic prognostic parameters that were significant in univariate analyses to evaluate their independent prognostic value for PFS and OS. For PFS we identified G-Clb vs. Clb (HR 0.21, p 〈 0.001), G-Clb vs. R-Clb (HR 0.42, p 〈 0.001), 17p- (HR 1.57, p=0.038), IGHVunmut (HR 2.19, p 〈 0.001), TP53mut (HR 2.19, p 〈 0.001), ATMmut (HR 1.33, p=0.009), and serum thymidine kinase (TK) 〉 10 U/l (HR 1.22, p=0.037) as independent prognostic factors. Regarding OS, 17p- (HR 2.57, p 〈 0.001), 11q- (HR 1.58, p=0.015), IGHVunmut (HR 2.0, p 〈 0.001), POT1mut (HR 2.17, p=0.001), age 〉 80 years (HR 1.68, p=0.006), Binet stage C (HR 2.1, p 〈 0.001), ECOG ≥1 (HR 1.6, p=0.007), and TK 〉 10 U/l (HR 1.59, p=0.004) were identified as independent adverse prognostic factors, while G-Clb vs. Clb (HR 0.61, p=0.022) and G-Clb vs. R-Clb (HR 0.69, p=0.029) correlate with a better OS. CONCLUSION The advent of targeted next generation sequencing has led to a more comprehensive molecular characterization of CLL patients and can provide the basis for genotype specific treatment concepts. G-Clb improves treatment outcome as compared to R-Clb for most subgroups defined by gene mutations and overcomes NOTCH1mut-associated Rituximab resistance. In particular, addition of G achieved more MRD negativity in NOTCH1mut, ATMmut, BIRC3mut and FBXW7mut patients. Both ATMmut and TP53mut remain strong prognostic factors. New treatment regimens with novel agents should be considered for patients with adverse independent prognostic factors for PFS and OS, most notably 17p-, 11q-, IGHVunmut and TP53mut. Figure 1 Figure 1. Disclosures Tausch: Gilead: Other: Travel support, Speakers Bureau; Amgen: Other: Travel support; Celgene: Other: Travel support. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Goede:Glaxo Smith Kline: Consultancy, Honoraria; F- Hoffmann-LaRoche: Consultancy, Honoraria, Other: Travel grants; Janssen: Consultancy, Other: Travel grants; Gilead: Consultancy; Mundipharma: Consultancy, Honoraria; Bristol Myer Squibb: Honoraria. Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Langerak:InVivoScribe Technologies: Patents & Royalties: Royalties are provided to European Network (EuroClonality); F. Hofmann-LaRoche, Genentech: Research Funding. Fingerle-Rowson:F. Hoffmann-LaRoche: Employment. Kneba:Amgen: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants; Janssen-Cilag: Consultancy, Honoraria, Other: Travel grants; Glaxo-SmithKline: Other: Travel grants; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding. Fischer:Roche: Other: travel grants. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3227.3227

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: American Journal of Hematology, Wiley, Vol. 94, No. 9 ( 2019-09), p. 1002-1006

Abstract: In CLL, progressive disease (PD) following remission after first line treatment can present with varying phenotypes. We hypothesized that the mode of PD correlates with clinical outcomes. Data from three phase III trials of the German CLL Study Group (GCLLSG) (CLL8, CLL10, CLL11) including a total of 2159 patients receiving first line (immuno)‐chemotherapy (FCR, FC, CLB, CLB‐R, CLB‐Ob) were analyzed. Patients were categorized as “ALC” if PD was due to increasing absolute lymphocyte count, or as “Ly” if due to lymphadenopathy. A group of 241 patients progressed with ALC, and 727 progressed with Ly, including 329 who progressed on both modalities. In fit patients, median TTNT after PD in the Ly group was 12.3 months vs 17.0 months in the ALC group (HR 1.299 [1.036‐1.628]; P = .024). Median OS after PD was 45.1 months in the Ly group and 42.4 months in the ALC group (HR=1.023 [0.753‐1.389]; P = .885). For unfit patients, median TTNT in the Ly group was 11.7 months vs 21.4 months in the ALC group (HR 1.357 [1.051‐1.753]; P = .019). Median OS was 42.8 months in the Ly group and not reached in the ALC group (HR 1.851 [1.280‐2.677]; P = .001). Patients in the Ly group more frequently showed impairment of quality of life (QoL). This analysis demonstrates that patients with progressive lymphadenopathy have a significantly shorter TTNT, OS and less favorable QoL. Our findings might help physicians to better estimate the clinical course of a progressing CLL patient.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v94.9

DOI: 10.1002/ajh.25561

Language: English

Publisher: Wiley

Publication Date: 2019

detail.hit.zdb_id: 1492749-4

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 325-325

Abstract: Introduction: Previous phase II studies have suggested that a combination of FCR may increase the outcome of both untreated and relapsed CLL pts. In order to validate this concept the German CLL study group (GCLLSG) initiated a multicentre, multinational phase III trial, CLL8, to evaluate the efficacy and tolerability of FCR versus FC for the first-line treatment of pts with advanced CLL. Methods and Patients: 817 pts with good physical fitness as defined by a cumulative illness rating scale (CIRS) score (Extermann et al., JCO 1998) of up to 6 and a creatinine clearance (cr cl) □d 70 ml/min were enrolled between July 2003 and March 2006. Pts were randomly assigned to receive 6 courses of either FC (N=409; F 25mg/m2 i.v. d1–3 and C 250 mg/m2 i.v. d1–3; q 28 days) or FC plus R (N=408; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days). Both treatment arms were well balanced with regard to age, stage, genomic aberrations and VH status. 64% were Binet B, 32% Binet C and 5% Binet A. The median age was 61 years (range 30 to 81), the median CIRS score was 1 (range 0–8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively, with no statistically significant differences between treatment arms. A mean number of 5.2 courses was given in the FCR arm versus 4.8 courses in the FC arm (p=0.006). 74% (FCR) and 67% (FC) of pts received 6 cycles. Dose was reduced by more than 10% in at least one treatment course in 43% (FCR) and 30% (FC) of pts, and in 21% (FCR) and 17% (FC) of all treatment courses given. 17 pts did not receive any study medication, 10 due to violation of enrolment criteria (4 decreased renal function, 2 active secondary malignancies, 2 active infections, 1 autoimmune thrombocytopenia, 1 pt not requiring treatment), 3 due to withdrawal of consent, 2 due to worsened concomitant diseases. 2 pts were lost before start of treatment. 56 pts were not evaluable for response: 17 did not receive any study medication, 16 withdrew consent before interim staging, 7 due to violation of enrolment criteria, 4 discontinued treatment due to toxicity and 12 due to early death (caused by toxicity, progression or secondary malignancy). Prophylactic use of antibiotics or growth factors was not generally recommended in the protocol. Results: At the time of analysis, June 2008, the median observation time was 25.5 months (mo). 761 pts (FCR 390; FC 371) were evaluable for response, 787 pts (FCR 400; FC 387) for PFS and all for OS. The overall response rate (ORR) was significantly higher in the FCR arm (95%; 370/390) compared to FC (88%; 328/371 (p=0.001). The complete response rate of the FCR arm was 52% as compared to 27.0% in the FC arm (p & lt;0.0001). PFS was 76.6% at 2 years in the FCR arm and 62.3% in the FC arm (p & lt;0.0001). There was a trend for an increased OS rate in the FCR arm (91% vs 88% at 2 years p=0.18). Hazard Ratio for PFS was 0.59, for OS 0.76. The largest benefit for FCR was observed in Binet stage A and B with regard to CR, ORR and PFS (A: p=0.01, B: p & lt;0.0001). FCR treatment was more frequently associated with CTC grade 3 and 4 adverse events (47% of FC vs 62% of FCR treated pts). Severe hematologic toxicity occurred in 55% (FCR) versus 39% (FC) of all patients. Significant differences were observed for neutropenia (FCR 33,6%; FC 20,9% p=0.0001) and leukocytopenia (FCR 24%; FC 12,1% p & lt;0.0001) but not for thrombocytopenia (FCR 7,4%; FC 10,8% p=0.09) and anemia (FCR: 5,4% FC 6,8% p=0.42). The incidence of CTC grade 3 or 4 infections was not significantly increased in the FCR arm (18,8% versus 14,8% in the FC arm, p=0.68). Tumor lysis syndrome (FCR 0,2% FC 0,5%) and cytokine release syndrome (FCR 0,2% FC 0,0%) were rarely observed in both arms. Treatment related mortality occurred in 2.0% in the FCR and 1.5% in the FC arm. Multivariate analyses were performed to evaluate factors predicting outcome. Amongst these variables age, sex, Binet stage, CIRS score, renal function (cr cl & lt; 70 ml/min) were independent prognostic factors predicting OS or PFS. Conclusion: Treatment with FCR chemoimmunotherapy improves response rates and PFS when compared to the FC chemotherapy. FCR caused more neutropenia/leukopenia without increasing the incidence of severe infections. These results suggest that FCR chemoimmunotherapy might become the new standard first-line treatment for physically fit CLL patients.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.325.325

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7