ALBERT

Description: Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p

Description: BACKGROUND The prior Australasian Leukaemia and Lymphoma Group (ALLG) CLL5 Study showed dose-reduced oral fludarabine and cyclophosphamide plus rituximab (FCR3) was safe, tolerable and effective in fit elderly patients for front-line therapy for CLL. The German CLL11 Study showed chlorambucil plus obinutuzumab (Cbl+G) was superior to chlorambucil alone or with rituximab in unfit patients requiring initial therapy. We conducted a randomized study to assess the safety, tolerability, and efficacy of dose-reduced FC + obinutuzumab (G) (FC+G) versus Cbl+G in unfit (i.e. with comorbidity), elderly patients with CLL. METHODS Patients aged ≥65 years and considered "unfit" defined by co-morbidities using the Cumulative Illness Rating Scale [CIRS] ≥6 were eligible for the ALLG CLL7 study. Patients with any single organ system score ≥4 were excluded. Previously untreated patients with progressive CLL aged ≥65 and CIRS ≥6 were randomised to one of 2 therapy arms: (i) Chlorambucil 0.5mg/kg D1+15 p.o. + obinutuzumab ("G") (i.v. 1000mg/m2 cycle 1, Day 1, 8, 15, and 1000mg/m2 D1 cycles 2-6), or (ii) FC(rd)+G: F-24mg/m2 p.o. and C-150mg/m2 p.o. D1-3 + G (same schedule above) at 4 weekly intervals for planned 6 cycles. Early stopping for toxicity was mandated: treatment could be delayed for 2 weeks for grade 3+ toxicity, but if unresolved by 2 weeks, patients were taken off study. The primary end-point was grade 3+ non-hematological, and grade 4 hematological adverse events. Secondary objectives were overall response rate (ORR), complete remission (CR), partial remission (PR), progression-free survival (PFS) and overall survival (OS) and minimal residual disease (MRD) negativity. Final staging was performed between 2-3 months following final treatment cycle. RESULTS Patient characteristics Patient recruitment was terminated early due to poor recruitment. At the time of study closure, there were 32 patients, with 15 on Cbl+G and 17 on FC(rd)+G. The mean age was 74.2 years (range 66-85 years) with 23 females (71.9%) and 9 males (28.1%). The CIRS score was 6 in 4 patients (12.5%), 6-8 in 14 (43.8%), 8-10 in 11 (34.4%) and 〉10 in 3 (9.4%). Binet stage at registration was stage A 18.2%, B 27.3% and C 54.5%. Tolerability Both therapies were tolerable with 15/17 (88.2%) completing all 6 cycles of FC(rd)+G and 12/15 (92.3%) completing six cycles of Cbl+G. Toxicity Most toxicity was hematological and manageable. Grade 3/4 hematological toxicity was more common with FC(rd)+G than Cbl+G occurring in 60% with FC(rd)+G and 38.5% with Cbl+G (Table 1). There was one death due to progressive CLL on the FC(rd)+G arm. Response rate A complete remission (CR), confirmed by bone marrow (BM) trephine, was achieved in 86.6% of patients on FC(rd)+G versus (vs) 53.9% on Cbl+G, partial response (PR/nPR) in 1 (6.7%) on FC(rd)+G, and 6 (46.2%) on Cbl+G, and either stable or progressive disease (SD or PD) on 1 on FC(rd)+G, and nil on Cbl+G. BM MRD-negativity rates were 3/17 (20.0%) FC(rd)+G vs 1/15 (7.7%) Cbl+G (Table 2). CONCLUSION This randomized trial of dose-reduced FC(rd)+G vs Cbl+G in elderly patients aged ≥65 and with co-morbidities (CIRS ≥6) was terminated early due to poor recruitment. Due to the dose-reduced FC, and early stopping rule, treatment was safe and tolerable and most patients completed all 6 cycles of planned therapy. Grade 3/4 toxicity was mainly hematological and manageable, with higher rates of neutropenia with the FC (60%) vs Cbl (35.7%) backbone. FC(rd)+G compared to Cbl+G resulted a higher CR rate of 86.6%% versus 53.9%, and higher MRD-negativity (20% vs 7.7%). Progression-free and overall survival are being evaluated. Disclosures Badoux: Roche: Research Funding. Cull:Takeda Australia: Other: Travel Expenses; Amgen Australia: Other: Travel Expenses; AbbVie (Australia): Membership on an entity's Board of Directors or advisory committees. Tam:Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: 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; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background Cytogenetic characterization by fluorescence in-situ hybridization (FISH) identifies subgroups of patients with chronic lymphocytic leukemia likely to have poor responses or short remission duration following standard frontline chemoimmunotherapy. Next-generation sequencing (NGS) has identified new molecular targets associated with refractory or poorly responsive disease (eg. Notch1, SF3B1 or BIRC3) independent of cytogenetic abnormalities. We have performed genetic and molecular characterization of fit, elderly patients enrolled on the Australasian Leukemia and Lymphoma Group (ALLG) CLL5 randomized clinical trial of oral fludarabine, cyclophosphamide and rituximab (ACTRN12608000404325). Methods Pre-treatment peripheral blood and bone marrow aspirate samples were obtained from patients enrolled on a phase II randomized clinical trial investigating oral fludarabine, oral cyclophosphamide and intravenous rituximab (poFCivR) tolerance in previously untreated fit elderly patients with CLL (ALLG CLL5 study). Fitness was defined as Cumulative Illness Rating Scale (CIRS) score of ²6. Bone marrow aspirate samples were analysed for CLL-associated genomic changes with a Vysis CLL FISH probe kit (Abbott, Des Moines, IL) and ranked according to Dohner hierarchical classification. DNA was extracted from peripheral blood lymphocytes and we performed targeted exome sequencing of genes including TP53, ATM, NOTCH1, SF3B1, BIRC3, MYD88 and FBXW7 using a TruSeq Custom Amplicon Design Panel on a MiSeq DNA sequencer as per manufacturerÕs protocol (Illumina, San Diego, CA). Gene mutations were confirmed by Sanger sequencing. Data was analyzed using Illumina proprietary software, annotated using ANNOVAR software and compared to COSMIC and other genomic mutation databases. Results Of 116 analyzable patients enrolled on the clinical trial, 78 pts had available FISH results and 76 patients DNA sequencing. The ORR and CR for all patients on study were 96% and 56% respectively. There was no significant difference in ORR between cytogenetic risk groups (Table 1); however, only 1 of 9 patients with ATM deletion achieved CR (11%, p=0.0095). We identified 8 pts with TP53 mutations, only one patient (12.5%) achieved a CR (p=0.0084). CR rate for patients with mutations in ATM (n=9, CR 44%), NOTCH1 (n=10, CR 60%), SF3B1 (n=11, CR 91%), BIRC3 (n=2, CR 0%), XPO1 (n=6, CR 33%), myd88 (n=5, 100%) were not significantly different to patients without the respective mutations. Of 14 pts with normal FISH, 10 pts (71%) had molecular abnormalities identified by NGS (Figure 1). Median follow-up of patients is 20 months, with 91% patients alive at last follow up. At the time of analysis, there was no significant difference in progression free survival (PFS) between different FISH cytogenetic risk groups (Figure 1). Multivariable analysis identified patients with TP53 mutations (HR 4.3, p=0.04) and XPO1 mutations (HR 3.2, p=0.035) as independently associated with shorter PFS. Our analysis was limited by the small subgroups of patients with individual molecular mutations and currently relatively short follow-up of this study. Conclusions Molecular characterization by DNA sequencing increases the yield of pre-treatment genetic alterations discovered in CLL patients. In this randomized clinical trial of elderly patients requiring first line therapy of CLL, we identified a high proportion of genomic alterations. Identification of genomic mutations may help further risk stratify CLL patients undergoing chemoimmunotherapy. Table 1 N CR (n) CR (%) ORR (n) ORR (%) All patients 116 65 56 111 96 FISH 17p deletion 19 10 52 17 89 11q deletion 9 1 11 8 89 Trisomy 12 15 9 60 14 93 13q deletion 33 18 55 32 97 No abnormal 16 13 81 16 100 Not Done 24 14 81 24 100 NGS All Available 76 44 58 72 95 mutations TP53 8 1 13 7 87.5 ATM 9 4 44 9 100 NOTCH1 10 6 60 9 90 SF3B1 11 10 91 10 91 BIRC3 2 0 0 2 100 XPO1 6 2 33 5 83 Myd88 5 5 100 5 100 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Badoux: Roche: Honoraria. Mulligan:Roche, Abbvie: Consultancy, Honoraria. Kuss:Roche: Research Funding; Sanofi: Research Funding.

Description: Dysregulation of cancer cell bioenergetics is one of the hallmarks of cancer. The Warburg effect is one such documented change. However, glucose metabolism is not universally increased in cancer cells. Uptake of radiolabelled glucose in chronic lymphocytic leukaemia (CLL) fails as a marker of proliferation and the underlying reason is not well elucidated [Conte et al, 2014]. Using proteomic and comprehensive lipid analyses, the preferred metabolic pathways of CLL cells have been identified. We have previously shown by proteomic analysis that circulating peripheral blood CLL cells demonstrate a significant increase in the expression of proteins pivotal in endogenous lipid synthesis pathways compared to B-cells from healthy individuals. These include fatty acid synthase (+3.84 fold), farnesyl diphosphate synthase (+2.17 fold), ATP-citrate lyase (+4.63 fold), citrate synthase (+2.45 fold) and acetyl-CoA acetyltransferase 1 (+5.84 fold). Conversely, analysis of the proliferation centres in CLL lymph nodes reveals increased expression of proteins involved in beta-oxidation, such as hydroxyacyl-CoA dehydrogenase (+2.02 fold). Additionally CLL cells shows a large increase in the levels of phospholipids found associated with lipid droplets compared to healthy B-cells, including phosphatidylinositol and phosphatidylethanolamine. Our current studies have expanded these observations in an attempt to determine if CLL cells have a preponderance for endogenous synthesis of lipids or exogenous uptake. We performed a comprehensive analysis of CLL cells from the bone marrow and peripheral blood using a variety of techniques. Transmission electron microscopy (TEM) images demonstrate striking morphological differences between normal B-cells and CLL cells with the inclusion of lipid droplets in the cytoplasm of CLL cells (Figure 1A) which was most evident in peripheral CLL samples. These were confirmed to be lipid droplets by the specific marker Bodipy 493/503 on flow cytometry (Fig. 1B) and confocal microscopy imaging with ReZolveL1 which targets neutral lipids (Fig. 1C). These showed a substantially higher level of lipid droplet staining in CLL cells compared to normal B-cells. Additionally there was higher expression of CD36 in CLL cells which is the receptor for exogenous lipid uptake into cells (Fig 1D). TEM analysis also revealed a high number of lysosomes in CLL cells, which was confirmed with lysotracker imaging on confocal microscopy (Fig. 1E). Lysosomes are now emerging as key players in lipid transport and biogenesis [Thelen and Zoncu, 2017]. Lipid droplets may be broken down by a process called autophagy mediated lipid degradation, or lipophagy, which relies on autophagosomes delivering lipid droplets to lysosomes. Autophagosomes were observed in several further bone marrow samples (Fig. 1F). The bone marrow samples also showed evidence of 'condensed mitochondria', indicative of high rates of beta-oxidation [Rossignol et al, 2004]. qPCR was then carried out on 90 genes involved in lipid metabolism. These results revealed significant differences between healthy B-cells and CLL cells. All CLL samples analysed demonstrated high expression of PLIN1, which protects lipid droplets from degradation, and low expression of APOC1, which prevents fatty acid uptake. From these observations we propose that peripheral CLL cells scavenge lipids from the periphery, mainly by uptake via the CD36 receptor, and increased endogenous lipid synthesis pathways. These results underpin a model for metabolism and enhanced survival for CLL cells in the hypoxic and potentially nutrient poor bone marrow/lymph node microenvironments. Peripheral CLL cells scavenge lipids; these excess lipids, which are toxic to the cell, are stored in lipid droplets which are protected from degradation by a high expression of PLIN proteins. Once these cells circulate back to the bone marrow and lymph nodes to proliferate, the lipid droplets are degraded, likely by lipophagy and neutral lipolysis which frees fatty acids to be used in beta oxidation in the mitochondria to sustain cell proliferation in the bone marrow and lymph node compartments. Our results begin to unravel CLL bioenergetics and dysregulation of cellular metabolism that occurs in this disease. We are now investigating whether the manipulation of these pathways, particularly lipophagy, may represent a novel therapeutic approach in CLL. Disclosures No relevant conflicts of interest to declare.

Description: Background : Ibr is the only once-daily inhibitor of Bruton tyrosine kinase with significant overall survival benefit demonstrated in 2 randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). Both Ibr and Ven, an oral inhibitor of BCL2, are approved in the US for treatment of CLL/SLL. The combination of Ibr + Ven may have synergistic anti-tumor activity given the capacity of Ibr to mobilize CLL cells from protected niches within lymphoid tissue to the blood where they may have greater dependence on BCL2 for survival. Recent clinical studies of Ibr + Ven in patients (pts) with CLL or mantle cell lymphoma show high rates of remission with undetectable minimal residual disease (uMRD) (Jain, NEJM 2018; Hillmen, JCO 2019; Tam, NEJM 2018). CAPTIVATE (PCYC-1142) is a multi-center phase 2 study (NCT02910583) evaluating the combination of Ibr + Ven to achieve deep response, including uMRD, in first-line treatment of CLL/SLL. We present results from the MRD cohort with 12 cycles of Ibr + Ven prior to MRD-guided randomized treatment discontinuation (data not yet available). Methods : Pts aged

Description: Abstract 699 Background: Combination immunochemotherapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free and overall survival compared to FC in the German CLL8 Study. The median age in CLL8 was 61 years compared to a median age for overall CLL patients of 72 years. There is ongoing debate regarding the tolerability and safety of FCR in elderly patients. Arbitrary dose reductions are common practice. Oral FC is more convenient for many older patients. Methods: Previously untreated patients with progressive CLL aged ≥65 were randomised to one of three treatment regimens FR5, FCR3 and FCR5 as follows: (i) F 24mg/m2 po D1-5 + R (375 mg/m2 C1, 500mg/m2 C2-6) iv D1 (FR5), (ii) F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 (FCR3) or (iii) F 24mg/m2 po + C 150mg/m2 po D1-5 + R iv D1 (FCR5), all given at monthly intervals for an intended 6 cycles. The dosage of FCR5 is equivalent to standard intravenous FCR in the CLL8 Study. Patients were administered their therapy arm with no dose reduction. Fludarabine dosing was reduced according to renal function by calculated GFR. Therapy was delayed by 2 weeks if there was any grade 3 or 4 toxicity. If this was unresolved after 2 weeks, patients were taken off study. If toxicity resolved to grade 2 or less, therapy proceeded. Results: Over half the planned patients (65 of 120) were recruited by 1 August, 2010 from 21 centres in Australia and New Zealand with the study having been open for 18 months. Median age is 72 (range 65–85) years. Binet stage at registration was progressive A – 11 (16.9%), B – 32 (49.2%) and C – 22 (33.8%). Randomisations are FR5 – 22, FCR3 – 22 and FCR5 – 21. FISH data is available on 50 patients: 25 with 13q-, 9 with 12+, 4 with 11q−, and 6 with 17p−. P53 functional analysis is available on 15 patients. Interim reasons for cessation of treatment, dose delay and clinical responses are shown in tables 1, 2 and 3 respectively for the total patient cohort. Cessations for reasons other than toxicity occurred in 7 patients: intercurrent illness (N=2) with acute myocardial infarction (AMI) and recurrent episodes of amnesia, and other reasons (N=5). Deaths were recorded for 2 patients due to infection and AMI. Conclusions: Oral F(C)R therapy appears generally safe and well tolerated to date in CLL patients aged ≥65 years requiring first-line treatment. Using stringent stopping criteria with delay of 2 weeks for recovery of grade 3 or 4 toxicity but no dose reduction, about half the patients will stop early due to toxicity or intercurrent illness. Nevertheless, response rates are high. Accrual is ongoing. Disclosures: Mulligan: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Schering, now Genzyme: Honoraria. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Chronic lymphocytic leukaemia (CLL) is an inherently heterogeneous disease in which founding lesions and cell of origin remain a subject of debate. This case of truly biclonal CLL provides evidence of the presence of a pre-leukaemic stem cell, supporting other lines of evidence that pathogenic genetic and epigenetic lesions in CLL arise early in haematopoiesis. An individual with trisomy 12 containing CLL, present at a frequency of 30%, was identified. Two distinct CD5/19-positive CLL clones were separated by flow cytometry, based on bimodal expression of CD49d. Each leukaemic clone was subjected to targeted immunoglobulin heavy chain variable region gene (IGHV) sequencing, whole exome sequencing (WES) and single-nucleotide polymorphism (SNP) microarray. CD5-positive T cells and a non-malignant superficial skin biopsy sample from the same individual were analysed as comparators. The CD49d-positive and CD49d-negative fractions harboured completely different IGHV rearrangements and mutational statuses (V4-34*02, hypermutated, and V3-21*02, unmutated, respectively) indicative of two unique leukaemic clones. Furthermore, trisomy 12, a relatively common aneuploidy in CLL, was present at high frequency (89.9%) in the CD49d-positive fraction but was absent in the CD49-negative and T-cell fractions. A mutation in the known CLL driver SF3B1 (c.1866G〉T) was present in the CD49-negative, unmutated clone alone, along with a 17p deleted subclone in around 20% of this fraction. The presence of a 17p deletion is highly clinically relevant in this disease, and it is noteworthy that this subclone was not detected by routine fluorescence in situ hybridisation (FISH) at diagnosis. Two putative driver mutations in KMT2D and BCL11B were detected in the CD49d-positive, trisomy 12 clone alone (c.15256C〉T and c.1387G〉A respectively). A TET2 mutation (c.3609C〉G) was found in all three fractions. The mutation in this epigenetic regulator has previously been described in clonal haematopoiesis of indeterminate potential (CHIP) and was hypothesised to have been acquired in a haematopoietic stem cell predisposing the individual to the development of haematological malignancy. However, the presence of this mutation was confirmed by Sanger sequencing of genomic DNA extracted from the skin sample, and is therefore of germline origin. The role of germline TET2 variants has not been described in lymphoid malignancy. Importantly, eight coding mutations were found common to both leukaemic clones but were absent from T-cells, implicating a common cell of origin prior to IGHV rearrangement but following B-lineage commitment (that is, a putative pre-leukaemic stem cell). One of these mutations was a disruptive 123 base pair deletion (c.4824_4946del) in MDC1 (mediator of DNA damage checkpoint 1) and was present at a variant allele frequency (VAF) of approximately 50% in both CLL clones, suggesting it was a founder mutation prior to subclone divergence. MDC1 is a mediator in the Ataxia Telangiectasia Mutated (ATM)-dependent DNA damage repair pathway and has not been previously implicated in CLL pathogenesis unlike ATM, which is frequently lost in del11q CLL. The proposed evolution of CLL in this case is presented in Figure 1. In summary, this highly unusual case of CLL provides insights into the evolution of CLL and adds another line of evidence to support the proposed early origins of CLL in haematopoiesis. The role that MDC1 may contribute to CLL pathogenesis, in particular its association with ATM dysregulation, remains to be elucidated. Further work to delineate critical pathways based on the discovered mutations is underway, and includes global transciptomic analysis of the purified leukaemic clones by RNAseq. Disclosures No relevant conflicts of interest to declare.

Description: Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range,

Description: BACKGROUND: Fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free (PFS) and overall survival (OS) versus (vs) FC in the CLL8 Study. The median age in CLL8 was 61 years compared to 72 years for CLL overall. We aimed to assess the safety, tolerability and efficacy of FCR based therapy in elderly patients (pts). METHODS: Previously untreated pts with progressive CLL aged ≥65 were randomised to one of 3 therapy arms: (i) FR5: F 24mg/m2 po D1-5 + R (375mg/m2 cycle 1, 500mg/m2 cycles 2-6) iv D1, (ii) FCR3: F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 or (iii) FCR5: F 24mg/m2 po+ C 150mg/m2 po D1-5 + R iv D1 all at 4 weekly intervals for an intended 6 cycles. Cycles could be delayed up to 2 weeks for grade 3+ toxicity, and if unresolved by 2 weeks, pts were taken off study. All analyses were by intention to treat (ITT) and adjusted for pre-treatment Binet stage. RESULTS: Recruitment of 120 pts was completed in July 2012. 117 fulfilled eligibility and 1 had no treatment or follow-up reducing the cohort to 116. Median age was 71 (range 65-82) years; 78 males (67%) and 39 females (33%). Binet stage was progressive A - 19 (16.2%), B – 55 (47.0%), C – 43 (36.8%). Response data are shown in table 1 and grade 3+ toxicity in table 2. All 6 protocol cycles were completed in 69% but less on FCR5 44% vs FR5 89% and FCR3 76% (p

Description: Abstract 436 Background: Combination immunochemotherapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free and overall survival compared to FC in the CLL8 Study. The median age in CLL8 was 61 years compared to a median age for overall CLL patients of 72 years. There is ongoing debate regarding the tolerability and safety of FCR in elderly patients, and what are the most appropriate criteria for selection of therapy. Methods: Previously untreated patients with progressive CLL aged ≥65 were randomised to one of three treatment regimens FR5, FCR3 and FCR5 as follows: (i) F 24mg/m2 po D1-5 + R (375 mg/m2 C1, 500mg/m2 C2-6) iv D1 (FR5), (ii) F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 (FCR3) or (iii) F 24mg/m2 po + C 150mg/m2po D1-5 + R iv D1 (FCR5), all given at 4 weekly intervals for an intended 6 cycles. The dosage of FCR5 is equivalent to standard 3 day IV FCR in the CLL8 Study. Patients were administered their therapy arm with no dose reduction but fludarabine dose was reduced if the eGFR was 50–69ml/min. Therapy was delayed up to 2 weeks if there was grade 3 or 4 toxicity, and if unresolved after 2 weeks, patients were taken off study. If toxicity resolved to grade 2 or less, therapy proceeded. Results: Recruitment of all 120 randomised patients was completed in July 2012. An analysis was performed with a cut-off date of 5 May, 2012 at which time there were 117 of 120 recruited from 29 centres in Australia and New Zealand. Median age was 71.7 (range 65–83) years. Binet stage at registration was progressive A – 20 (17.1%), B – 55 (47.0%) and C – 42 (35.9%). Response data are shown in table 1 for the total patient cohort - no analysis has been performed to date by treatment arm. Analysis of grade 3 and 4 toxicity events by Cumulative Illness Rating Scale (CIRS) score and age are shown in Tables 2 and 3 with data available at the cut-off date. Conclusions: Oral F(C)R therapy appears generally safe and well tolerated in CLL patients aged ≥65 years requiring first-line treatment according to data available at end of recruitment. Using stringent stopping criteria with delay of 2 weeks for recovery of grade 3 or 4 toxicity but no dose reduction, ∼40% of patients stop early due to toxicity, intercurrent illness or patient choice. Based on the 66 patients with completed Final Pathological Staging 2 months after end of therapy, response rates appear high with an overall response rate (ORR) of 92.3%. For this relatively fit elderly patient cohort, neither a CIRS score of 0 to 6, nor age predicted for grade 3 and 4 toxicity. Disclosures: Mulligan: Roche: Consultancy, Research Funding, Speakers Bureau; Genzyme: Consultancy, Research Funding, Speakers Bureau.