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We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time 10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0–99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care “watch and wait” for these patients.

The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death. Multivariate analysis identified six independent factors associated with overall survival (OS) and time-to-first treatment (TTFT): del(17p), unmutated IGHV, del(11q), ß2-microglobulin3.5 mg/dL, lymphocyte doubling time (LDT)12 months, and age60 years. These factors were integrated into the CLL1-PM, which stratified patients into four risk groups. The CLL1-PM was prognostic for OS and TTFT, e.g., the risk of treatment at 5 years was 85.9, 51.8, 27.6, and 11.3% for very low (0-1.5), low (2-4), high (4.5-6.5), and very high-risk (7-14) scores, respectively (P 0.001). Notably, in addition to factors comprising CLL-IPI, we substantiated del(11q) and LDT as prognostic factors in early CLL. Altogether, our findings would be useful to effectively stratify Binet stage A patients, particularly within the scope of clinical trials evaluating novel agents.

Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B-cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinico-biological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: (i) early-stage patients ('watch and wait' arm of the CLL1 trial) (n=592); (ii) patients in need of treatment, enrolled in three phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1,861). Subset #1 was associated with del(11q), higher CLL International Prognostic Index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (hazard ratio [HR]: 4.2, confidence interval [CI]: 2-8.6, P

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group

Objective Measuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5. Methods To investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times. Results A comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies. Conclusions The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.

Introduction Although the median (med) age at diagnosis of CLL is 72 years (yrs), 11% are less than 55 yrs of age (SEER database). For this significant proportion of younger patients (pts), there exists a paucity of published data, particularly with regards to long-term follow up and safety. In recent years, single-centre retrospective analyses of younger CLL pts have been published (Parikh et al. 2015, Getta et al. 2018.) but this is the first study using data from international prospective randomised multi-centre trials, representing a large and diverse cohort of pts. Methods We performed a pooled analysis of pts receiving first-line treatment in seven phase II or III clinical trials conducted by the GCLLSG. This includes two phase III trials for early stage (CLL1 and CLL7), four phase III trials for advanced stages (CLL4, CLL8, CLL10 and CLL11) and one phase II trial (CLL2M). All trials evaluated chemotherapy or chemo-immunotherapy (CIT). Only patients who received treatment were included in this analysis. Using clinical and laboratory data, we compared baseline characteristics, treatments, efficacy and causes of death of pts in the age groups of ≤ 55 yrs and > 55 yrs. An age cut-off of 55 yrs has been selected based on similar historical studies. Further subgroup analyses were performed; (i) separating younger (≤ 55 yrs) pts into > 45 - ≤ 55 yrs and ≤ 45 yrs and (ii) pts with advanced stage CLL (including CLL4, CLL8, CLL10, CLL11 and CLL2M). Time to event was analysed by Kaplan-Meier method and hazard ratios (HR) with confidence intervals (CI) calculated using Cox regression model. Results In total, 2904 pts were included in this meta-analysis, 650 (22.4%) pts were younger (≤ 55 yrs) and 2254 (77.6%) were older (> 55 yrs), the med age being 63 yrs with a med observation period of 67.7 months. Baseline characteristics are shown in table 1 and frontline therapies in table 2. All six cycles of therapy were completed in 80.5% of the younger pts and 75.3% of the older pts. The best overall response (CR/PR) was 92.8% for younger pts and 85.8% for older pts. 33.8% and 25.7% achieved a CR respectively. Minimal residual disease negativity (< 10-4) was achieved in 22.3% and 16.2% respectively, with missing results in 56.4% of total, as per intention to treat approach. The med duration of response was 25.3 months in older pts as compared to 36.1 in younger pts (HR: 1.353, 95% CI: 1.205-1.520). Med progression-free survival (PFS) was 32.7 months in older pts as compared to 41.3 in younger pts (HR: 1.292, 95% CI: 1.160-1.438) respectively (figure 1a), with similar results in the pts with advanced disease. No significant difference in PFS was found within the two groups less than 55 yrs of age ( > 45 - ≤ 55 yrs and ≤ 45 yrs). Med time to next treatment (TTNT) was similar between the ≤ 55 yrs cohort and > 55 yrs (62.5 month and 59.1 months). Med overall survival (OS) was 85.8 months in the > 55 aged pts as compared to 122.7 months in the ≤ 55 year old pts (HR: 2.023, 95% CI: 1.698-2.411) (figure 1b), with similar results in the advanced CLL pts. PFS and OS for younger and older pts, was significantly better, when FCR was administered in comparison to all other treatments, including fludarabine (F), F + cyclophosphamide(FC), bendamustine and rituximab (BR), chlorambucil (CLB) alone and CLB + R, CLB + obinutuzumab (G) ( figures 2a and 2b). Death, as determined by investigator, was CLL-related in 50.3% of younger pts and 46% of older pts. In the younger group; CLL-related death was due to progressive disease (PD) in 46.7%, infection 40% and Richter transformation (RT) 12%. Amongst the older pts, death was attributed to PD in 62.2%, infection in 31% and RT in 6%. CLL-unrelated deaths (22.8%) occurred in younger pts; due to co-morbid conditions in 47.1%, secondary malignancy in 38.2% and adverse events (AEs) in 11.8%. In the older pts, Co-morbid conditions (39.1%), AEs (35.6%) and secondary malignancy (23.6%) resulted in the CLL-unrelated deaths. Conclusions This meta-analysis of younger CLL pts, demonstrated that being aged 55 yrs or younger has a significant impact on OS and PFS. While pts younger than 55 yrs respond better to therapy and show a longer PFS, they clearly suffer from an elevated rate of late complications. In this regards, a higher rate of death due to secondary malignancy in the younger pts is of particular interest. The data define the need for first-line treatments with reduced long-term toxicity and warrant long-term outcome analyses in younger pts treated with novel agents. Disclosures Cramer: mundipharma: Other: travel support; Roche: Honoraria, Other: travel support, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Gilead: Other: travel support, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fink:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: travel grants; Celgene: Research Funding. Fischer:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: travel grants. Goede:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau; janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Herling:Roche: Other: travel grants, Research Funding. Wendtner:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria, Research Funding; Janssen-CILAG: Consultancy, Honoraria, Research Funding; GILEAD Science: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Hallek:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Eichhorst:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Clinical management of chronic lymphocytic leukaemia (CLL) in patients aged >= 80 years is based on limited evidence due to the lack of published information. Therefore, we analysed CLL patients aged >= 80 years using data from seven phase III clinical trials of the German CLL Study Group. Among 3552 participants, 152 were >= 80 years old at initiation of first-line study treatment. Median age was 82 years (range 80-90). Concomitant diseases were present in 99% of the patients, with a median cumulative illness rating scale score of 8 (0-18). Chemoimmunotherapy with chlorambucil-obinutuzumab (CLB-OB) or chlorambucil-rituximab (CLB-R) was administered to 61 (40%) and 56 (37%) patients. The remaining patients received CLB (n = 19) or fludarabine (F, n = 10), F/cyclophosphamide (FC, n = 1), FC/rituximab (FCR, n = 2) or bendamustine/rituximab (BR, n = 3). Rates of grade 3 or 4 neutropenia and infections were 35% and 13%. Overall response rate was 77% with 13% complete remissions. Median progression-free survival and treatment-free survival were 17.2 and 32.3 months, respectively. Median overall survival was 48.3 months; adverse events (22%) and progressive CLL (16.4%) were the most frequent causes of death. These findings suggest that anti-leukaemic treatment including chemoimmunotherapy is feasible and efficacious in >= 80-year-old CLL patients. However, this group of patients lives for a shorter time than age-matched controls of the general population.

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 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.

Introduction: Idelalisib is a first-in-class PI3Kδ-inhibitor. In clinical studies idelalisib demonstrated significant efficacy in patients with CLL, including patients with TP53 aberrations (del17p and/or TP53m). On this basis national and international guidelines in Europe recommend idelalisib as one treatment option in this high-risk CLL patient population. However, it is unclear how efficacy reported in clinical studies translates into real world experience. Considering the importance of such data, we initiated a real world study soon after market authorization of idelalisib in the European Union prospectively investigating efficacy and safety of idelalisib in routine clinical practice. Concomitant PJP prophylaxis is a risk minimization measure that was introduced after market authorization of idelalisib. Nevertheless, the impact on patient outcomes in routine clinical practice has not been studied in detail. We therefore also analyzed the impact of PJP prophylaxis on overall survival (OS) within this real world cohort. Methods: A prospective, two-cohort, multicenter, non-interventional post-authorization safety study (PASS) reporting real world safety and efficacy data on the use of idelalisib in Germany. Inclusion of patients was based on the physician's decision to initiate treatment with idelalisib in accordance with the European Summary of Product Characteristics. Descriptive statistics were used for data analysis. Results: This analysis included 84 CLL patients with a median age of 74 years. 88% of patients were older than 65 years, 70% were male and 86% presented with one or more co-morbidities. Binet stage A, B, C was reported in 25%, 33% and 37% of patients, respectively. The median time from diagnosis to start of idelalisib therapy was 89.5 months and patients received a median number of two prior lines of therapy, including treatment with the BTK inhibitor ibrutinib in 11 patients (13%). With a median observation time of 11.5 months the median overall survival (OS) for the entire CLL patient population was not reached. Our CLL cohort included 24 patients (29%) that did not receive PJP prophylaxis for idelalisib therapy. We therefore compared OS in patients with and without concomitant PJP prophylaxis. In patients receiving PJP prophylaxis survival rates were higher in the first 6-12 months of therapy, with 6-month and 12-month survival rates in patients with vs without PJP prophylaxis of 98% vs 76% and 84% vs 76%, respectively (Figure 1). 19% of CLL patients (n=16) had documented TP53 aberrations, including five patients that received idelalisib as first-line treatment. In patients with TP53 aberrations the overall response rate (ORR) was 77% compared to 67% in patients without TP53 aberrations. Importantly, the 12-month survival rates for patients with and without TP53 aberrations were similar with 81% and 83%, respectively. Median OS was not reached for either patient population (Figure 2). Conclusion: This prospective real world study started collecting data on the efficacy and safety of idelalisib in routine clinical practice soon after market authorization of idelalisib in Europe. Results demonstrate similar efficacy of idelalisib irrespective of the patients' TP53 status confirming the efficacy previously reported in pivotal clinical studies. Additionally, our results provide evidence that PJP prophylaxis is an effective risk minimization measure impacting on survival. Disclosures Hoechstetter: Hexal: Other: Travel Grants; Abbvie: Other: Travel Grants; Gilead Sciences: Consultancy, Other: Travel Grants. Eissmann:Gilead Sciences: Employment. Hucke:Gilead Sciences: Employment. van Troostenburg:Gilead Sciences: Employment. Ramroth:Gilead Sciences: Employment. Knauf:Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy; Janssen: Consultancy; Mundipharma: Consultancy; Roche: Consultancy; Amgen: Consultancy, Honoraria; AbbVie: Consultancy.