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In: Blood, American Society of Hematology, Vol. 123, No. 21 ( 2014-05-22), p. 3247-3254

Abstract: Independent prognostic impact of biological markers, notably TP53 and SF3B1 mutations, in CLL patients requiring therapy. NOTCH1 mutation as a predictive factor for reduced benefit from the addition of rituximab to FC chemotherapy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2014-01-546150

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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. 4394-4394

Abstract: Introduction Chemoimmunotherapy with FCR is the current standard for physically fit CLL patients (pts) without TP53 deletion/mutation. Due to better tolerability, BR should be considered in pts aged ≥ 65. Data from studies in CLL and other lymphomas suggest that women might have a better overall survival (OS) than male pts. The aim of this study was to evaluate the impact of gender on progression-free (PFS) and OS as well as on the rate of toxicities during and after therapy with FCR or BR. Methods Data from three clinical trials (phase II/III) of the GCLLSG including 1078 treatment naïve pts were analyzed. 683 pts received FCR (404 in CLL8 [FCR vs FC], 279 in CLL10 [FCR vs BR] ) and 395 received BR (278 in CLL10, 117 in CLL2M). Laboratory markers, genetic parameters as well as event-related data were pooled. 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. Independent prognostic factors for PFS and OS were identified by multivariate analyses using Cox regression modelling with stepwise selection procedures. Results Median age was 61 years (y) (30-81). 291 (27%) pts were female, 787 (73%) were male. Distribution of Binet stages was similar between women and men, as well as age, frequency of unfavorable genetic aberrations and mutations (17p deletion, 11q deletion, unmutated IGHV) or elevated serum parameters (thymidine kinase [TK], β2-microglobulin [B2M] ) except for trisomy 12 (18.7% in female vs 9.8% in male). Median observation time was 69.7 months in the CLL8 trial, 42.7 in CLL2M and 58.2 in CLL10 and 63.6 in the overall cohort. The CR rate with FCR treatment was 50% in female pts vs 41.9% in male pts and 29.5 vs 29.1% with BR treatment. At final restaging, 66.4% of female pts were MRD negative in peripheral blood (defined as & lt;10-4) vs 66.7% of male pts. 45.2% of female pts achieved MRD negativity in bone marrow vs 44.9% of male pts. 5-y-PFS was higher for women after FCR (52.5% vs 45.5%; HR=1.197 [0.949-1.510]; p =0.13) as well as after BR (44.8% vs 23.2%; HR=1.523 [1.124-2.063] ; p=0.007). While BR was significantly inferior to FCR in male pts (5-y-PFS 23.2% vs. 45.5%; HR=1.644 [1.359-1.988]; p & lt;0.001) the difference was not statistically significant in female pts (5-y-PFS 44.8% vs. 52.5%; HR=1.277 [95%CI 0.912-1.788]; p=0.154). Median OS for all groups was not yet reached. 5-y-OS after BR was 84.6% in women vs 74.7% in men (HR=1.705 [95%CI, 0.965-3.014]; p=0.07) and 80% vs 79.6% after FCR (HR=1.179 [0.831-1.673] ; p=0.36). OS according to gender did not differ significantly between men and women (5-y-OS 78.4 % vs 81.8%; HR=1.301 [0.966-1.752]; p=0.083), while PFS did differ significantly (5-y-PFS 38.6 % vs 50.1%; HR=1.283 [1.067-1.542] ; p=0.008). In multivariate analyses, independent adverse prognostic factors for PFS were BR treatment, male gender, TK ( & gt;10.0 U/l), unmutated IGHV, deletion 17p and deletion 11q. Factors associated with OS were age ( & gt;65y), B2M ( & gt;3.5 mg/l), TK ( & gt;10.0 U/l), unmutated IGHV and deletion 17p, but not gender. CTC grade 3 and 4, hematological adverse events (AE) were more frequent in female pts treated with FCR, particularly anemia (8.6% vs 5.6% in male), leukopenia (51.4% vs 41.0%) and neutropenia (57.3% vs 46.0%), but not thrombocytopenia (11.4% vs 11.8%). Frequency of dose reductions and median number of administered treatment cycles did not differ. Though frequency of hematological AEs was lower with BR compared to FCR, female pts experienced more severe anemia (10.4 % vs 8.7%), leukopenia (50% vs 36.3%), neutropenia (50.9% vs 39.8%), but not thrombocytopenia (15.1% vs 15.2%) compared to male pts. The rate of infections and infestations did not differ between genders during FCR (18.9 % vs 20.9%) as well as BR (12.3% vs 15.6%). After 5 years less female pts developed second primary malignancies (SPM) after FCR compared to male pts (6.7% vs 12.8%), while the rate of SPM after BR was similar between both genders (13.8% vs 13.1%). Conclusions Based on this pooled analysis of three prospective clinical trials in CLL, women had longer PFS than men after chemoimmunotherapy with either FCR or BR although the rate of hematological toxicities during therapy was higher. Understanding the causes of this observation can enable a more tailored, gender-specific approach in CLL treatment. Figure Overall survival (A) and progression free survival (B) according to treatment and gender. Figure. Overall survival (A) and progression free survival (B) according to treatment and gender. Disclosures Al-Sawaf: Gilead: Other: Travel grants. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Fink:Mundipharma: Other: Travel grants; AbbVie: Other: Travel grants; Celgene: Research Funding; Roche: Honoraria, Other: Travel grants. Cramer:Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; Gilead: Other: Travel grants, Research Funding; GlaxoSmithKline/Novartis: Research Funding; Janssen-Cilag: Honoraria, Other: Travel grants, Research Funding; Astellas: Other: Travel grants; Mundipharma: Other: Travel grants. Maurer:Mundipharma: Other: Travel grants. Bergmann:Mundipharma: Honoraria; Roche: Consultancy, Honoraria; Celgene: Honoraria; Glaxo-SmithKline: Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kneba:Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: Travel grants; Gilead: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants; Glaxo-SmithKline: Other: Travel grants; Amgen: Research Funding. Stilgenbauer:Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding. Kiehl:Roche: Consultancy, Other: Travel grants, Speakers Bureau. Jäger:Roche: Other: Personal fees, Research Funding. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; Glaxo-SmithKline: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Fischer:Roche: Other: travel grants. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: 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; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Eichhorst:Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Hopfinger:Mundipharma: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Takeda: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4394.4394

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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. 136, No. Supplement 1 ( 2020-11-5), p. 2-4

Abstract: Background: Aggressive hematological malignancies in relapsed/refractory setting bear a dire prognosis with low cure rates and short survival. Matching these patients to therapies is challenged by complexity due to spatial and temporal tumor evolution and incomplete understanding of genotype to phenotype correlations. Direct functional testing could address these impediments. The EXALT trial is an interventional, one-arm study designed to assess the clinical value of next generation functional drug screening (ngFDS). An interim analysis on 17 patients suggested a clinical benefit (Snijder et al., Lancet Hematol. 2017). Methods: We applied image-based ngFDS to quantify differential ex-vivo sensitivity of primary patient tumor cells to respective non-tumor cells towards 136 small molecule drugs, including EMA approved for any indication or experimental. We screened bone marrow, peripheral blood or lymph node material from 143 patients who suffered from late stage aggressive hematological malignancies (acute leukemias, aggressive B- and T-cell lymphomas) , discussed the results in a multidisciplinary tumor board and recommended treatments to physicians (A). The primary endpoint of this study was the percentage of patients reaching a PFS-ratio (PFS(ngFDS treatment)/PFS(previous treatment)) of ≥1.3 with an H0 hypothesis & lt; 15% patients. The secondary endpoint was overall response rate (ORR) defined as proportion of patients reaching complete remission (CR) or partial remission (PR). Additionally, we performed a post hoc analysis to evaluate the matching of ngFDS to drugs used in actual treatment (matching score of received treatment). Results: 56 (39%) patients were evaluable and treated according to ngFDS based recommendations. With 30 of 56 (54%) ngFDS guided patients experiencing a PFS ratio of ≥1.3, the primary study endpoint was reached. 11 patients (37%) had ongoing response at censoring date (B). The median follow-up was 718 days. The median number of days from sampling to treatment was 21 (range 4-77). The ngFDS treatment regimens consisted of a median of 2 drugs (range: 1-6). ORR was 55% for all evaluable ngFDS treated patients, 60% for the lymphoid subgroup and 41% for the myeloid subgroup. Patients on ngFDS guided treatment with performance status ECOG ≤ 1 had a median PFS of 207 days compared to a median PFS of 29 days for patients with higher ECOG (p & lt; 0.001, C). 24 of 39 (62%) patients with ECOG ≤ 1 had a PFS ratio of ≥1.3 (D). In disease specific subgroup analysis median PFS of T-cell lymphoma patients was 235 days versus 60 days for B-cell lymphoma patients (p = 0.018, E). Age (≤60 vs. & gt;60), sex, lineage (myeloid vs. lymphoid), number of previous treatment lines (≤2 vs. & gt;2), and clinical presentation (leukemia vs. lymphoma) did not have an impact on PFS of ngFDS guided treatment. Post hoc analysis including additional 17 non-ngFDS treated patients demonstrated that only patients receiving treatment with a positive ngFDS matching score demonstrated clinical benefit (HR: 0.53, p=0.005; vs. HR: 1.4, p=0.4). ngFDS matched treatments resulted in higher PFS for patients with tumor samples that had a cancer cell fraction of 10-50% in comparison to patients with samples of lower or higher cancer cell percentage (HR:0.35, p=0.01). Conclusion: ngFDS could be integrated in the routine clinical work flow. ngFDS guided treatments led to high rates of PFS prolongation compared to previous treatments of individual patients. ngFDS guided treatment is feasible and effective in patients with late stage aggressive hematological malignancies. These results prompted a prospective randomized trial comparing treatment guidance based on ngFDS or comprehensive genomic profiling or physician's choice (EXALT-2 trial, NCT04470947). Figure Disclosures Vladimer: Allcyte GmbH: Current Employment, Current equity holder in private company, Other: Founder. Jaeger:Karyopharm: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; True North: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding; F. Hoffmann-La Roche: Honoraria, Research Funding; Infinity: Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Krall:Allcyte GmbH: Current Employment, Current equity holder in private company, Other: Founder. Valent:Allcyte GmbH: Research Funding; Cellgene: Honoraria, Research Funding; Pfizer: Honoraria. Wolf:Celgene: Honoraria, Research Funding. Zielinski:MSD: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Imugene: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Merrimack: Consultancy, Honoraria, Speakers Bureau; Merck KGaA: Consultancy, Honoraria, Speakers Bureau; Fibrogen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Tesaro: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; Eli Lilly: Consultancy, Honoraria, Speakers Bureau; Athenex: Consultancy, Honoraria, Speakers Bureau. Superti-Furga:Allcyte GmbH: Current equity holder in private company, Other: Founder. Snijder:Allcyte GmbH: Current equity holder in private company, Other: Founder. Staber:Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Celgene/ BMS: Consultancy, Honoraria; msd: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-140831

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 625-625

Abstract: Background: Early stage CLL is a heterogeneous disease with a prognosis ranging from an overall survival of a few months to two decades. Prognostic markers helping to predict the individual course of CLL are highly warranted. The CLL1 trial was initiated to investigate all major prognostic parameters used at the time of its initiation for prediction of the course of CLL. Patients: From 1997 to 2004 877 Binet A pts (median age 60 yrs) were enrolled. The median follow up was 45 months (mo). Risk stratification was possible for 788 pts. Pts with high risk (HR) were defined by elevated thymidine kinase (TK) or beta-2-microglobulin (beta-2-MG)) and either short lymphocyte doubling time (LDT, 〈 12 months)) or diffuse bone marrow infiltration (BMI). 99 pts were not eligible due to trial violation. HR pts were randomized to W & W vs. immediate therapy with fludarabine. Treated pts (n=104) were excluded from this analysis. Analyses on PFS and OS on 585 pts are presented. Progression was defined by slightly modified NCI-WG criteria. Results: 114 pts (19.5%) were stratified to HR, 471 pts (80.5%) to low risk (LR). At enrolment there was no significant difference with regard to age, performance state, comorbidity. Significantly more male pts were assigned to HR (p=0.03). Beside parameters for stratification the cohorts differed in leukocyte/lymphocyte count (p 〈 0.001), cervical and inguinal lymphadenopathy (LN) (p=0.001 resp. 0.005) and splenomegaly (p=0.02). B symptoms, hemoglobin, platelets, hepatomegaly and axillary LN were similar distributed in both groups. The median PFS for all was 57.3 mo. The median PFS for HR was significantly shorter than for LR (88 vs.18 mo; p 〈 0,001). Although the median OS was not reached for both, HR had significantly shorter OS time (p 〈 0,001). Pts had a significantly shorter PFS (25 vs. 88 mo; p 〈 0.001) if they had TK 〉 7 U/L, beta-2-MG 〉 3.5 mg/L (13 vs. 75 mo; p 〈 0.001) or LDT 〈 12 mo (20 vs. 75 mo; p 〈 0.001). For these parameters OS was also significantly shorter for HR, although the median OS was not reached. Pts with diffuse BMI had shorter PFS (49 vs. 75 mo; p=0.003), but OS was not different (p=0.2). Furthermore lymphocyte counts 〉 30 G/L (PFS 17 vs. 88 mo; p 〈 0.001) or non-smouldering CLL (PFS 46 mo vs. n.r.; p 〈 0.001) predicted shorter PFS/OS. Male pts had shorter PFS (49 mo vs. n.r.; p=0.001), but not OS (p=0.08). OS was significantly shorter for older pts than 55 (p=0.014) or 65 yrs (p 〈 0.001), while PFS was not different. A multivariate Cox analysis revealed that TK, LDT, beta-2-MG, absolute lymphocyte count, sex and age were independent variables for PFS, while LDT, beta-2-MG, lymphocytes and age were also independent for OS. Conclusion: This prospective trial defined clinical and biological factors (TK, LDT, beta-2-MG, absolute lymphocyte count, age, sex) which help to predict progression in early CLL. Our model for risk stratification reliably separated between HR and LR. Due to the weak impact of BMI we do not further recommend the use of BM biopsy for assessment of prognosis in CLL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.625.625

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 1 ( 2014-07-03), p. 49-62

Abstract: Prognostic tool for CLL patients with high discriminatory power compared with conventional clinical staging systems. Prognostication on the individual patient level independent of clinical stage.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2014-02-556399

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 8678-8679

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-159221

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

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. 4127-4127

Abstract: Chronic lymphocytic leukemia (CLL) is typically diagnosed at an early stage and a watch & wait (W & W) strategy is applied. Only when the disease progresses to a more active, symptomatic form, treatment is indicated. The prospective CLL1 trial was designed to evaluate the benefit of early risk-adapted therapy with fludarabine (F) monotherapy, and to document the natural course of the disease from diagnosis. Here we present follow-up data to assess overall survival from the time point of treatment indication. Methods At enrolment, risk stratification was performed based on bone marrow (BM) infiltration pattern, lymphocyte doubling time (LDT), serum beta2-microglobulin (ß2-MG), and serum thymidine kinase (TK). Pts were “high-risk” (HR) if they had diffuse BM infiltration pattern and/or LDT 〈 12 months (mo) combined with TK 〉 7.0 U/L and/or ß2-MG 〉 3.5 mg/L at enrolment. HR pts were randomized in a 1:1 ratio to early F (HR-F), or to W & W until classical treatment indication (HR-W & W), which was also applied to all low-risk (LR) pts. Results Between 1997 and 2004, 710 pts with Binet A stage CLL were enrolled and underwent risk stratification (RS) per protocol. Median time from diagnosis to enrolment was 3.2 mo (range 0-33.7) and median follow-up time was 8.5 years (yrs) (range 0-13.9). 521 pts (73%) were stratified to LR and 189 pts (27%) to HR, of whom 93 pts (49%) were randomized to HR-F and 96 pts (51%) to HR-W & W. Median age was 60 (range 32-75) yrs, 61% were male, 34% had unmutated IGHV status; high-risk cytogenetic features (17p- and 11q-) had 3% and 8% of pts, respectively. Early intervention with F among HR pts significantly prolonged progression-free survival (PFS) (30 vs. 13 mo; p 〈 .001) and treatment-free survival (TFS) (74 vs. 41 mo; p=0.036) but did not significantly impact overall survival (OS) (127 mo vs. not reached; p=0.75). 303 patients had received treatment due to disease progression. 23% of patients received combination chemotherapy, 22% chemoimmunotherapy, 18% monotherapy with chlorambucil, and 15% monotherapy with purine analogues. Median OS for all pts was 91 mo (95% CI, 86 to 101 mo) from start of first treatment due to active disease. Patients with high risk (HR) for disease progression according to risk stratification had a significant shorter OS from start of first treatment than patients with low risk (LR) (71 mo vs. not reached; p=0.001). Early treatment with F did not show a significant impact on survival, when patients progressed after risk-adapted F, but showed a trend to a more favorable outcome for the watch and wait arm receiving their first therapy only when they had progressed to active disease (HR-F: median OS 51 mo versus HR-W & W not reached; p=0.055). Multivariate analyses on 237 pts identified 17p-, 11q-, unmutated IGHV, ß2-MG 〉 3.5 mg/L, and age 〉 60 yrs as independent prognostic factors for OS for patients with progressive, active disease and treatment indication. Conclusions Monotherapy with fludarabine is not superior to the W & W approach for the management of early stage CLL pts, since early F did not improve OS or outcome following subsequent therapies. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.4127.4127

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. 95, No. 3 ( 2000-02-01), p. 1086-1092

Abstract: Polytrauma (PT) leads to systemic activation of polymorphonuclear neutrophils (PMNs). Organ damage commonly found in these patients is ascribed to respiratory bursts of activated PMNs. With the use of sodium dodecyl sulfate–polyacrylamide gel electrophoresis, PMN extracts from PT patients were found to contain a clear protein band not seen in control PMNs from healthy volunteers. This band was identified by amino acid sequencing and Western blotting as pyruvate kinase (PK). Enzymatic assays revealed a 600-fold increase in PK activity in PMNs of PT patients, with the highest levels occurring between the fifth and seventh posttraumatic day. In lymphocytes, no such increase was detectable. As PK is a major regulatory enzyme in glycolysis, glucose-dependent lactate production in PMNs from PT patients was assayed. These cells showed a higher glycolytic lactate production than controls. It was additionally demonstrated that acute activation of respiratory burst activity depends mainly on breakdown of glucose to lactate via the pentose-phosphate pathway and glycolysis. In PMNs from PT patients, this glucose-dependent respiratory burst activity was more than twofold higher than in controls. The increase in expression and activity of PK in PMNs from PT patients may contribute to the high glucose-dependent respiratory burst activity seen in these cells.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V95.3.1086.003k09_1086_1092

Language: English

Publisher: American Society of Hematology

Publication Date: 2000

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7