ALBERT

Description: Background ITP is an autoimmune disorder characterized by isolated thrombocytopenia in the absence of other causes. Although the pathogenetic mechanisms may vary between cases, in common is the accelerated peripheral destruction of platelets due to a failure of self-tolerance and a complex interplay between autoantibodies, autoreactive T cells, antigen-presenting cells and the reticuloendothelial system. Conventional therapies such as glucocorticoids and rituximab target only one or some of these players in autoimmunity. Aims To demonstrate the safety and efficacy of a triple therapy approach to targeting all three major agents for autoimmunity in ITP: B-cells, T-cells and antigen-presenting cells. Simultaneous suppression of these three cell lines may benefit responders with prolonged relapse free survival without the burden of significant additional toxicity. Methods A total of 26 patients with ITP were enrolled into two separate sites with three separate triple therapy protocols (TT4, R1 and R2). Eligibility criteria, definitions and toxicity are as per IWG criteria and CTCAE 4.02. Results 25/26 patients completed treatment as planned. Three required salvage glucocorticoids/IVIG during the first four weeks of therapy. One patient additionally required splenectomy and completed triple therapy. There was only one therapy-related Grade III-IV ASE in all of the treatment protocols: hypertension in a patient with a prior history. All therapy-related Grade I-II ASE listed with numbers of patients affected: hirsuitism and dyspepsia 4; headache, insomnia, nausea and tremor 2; hypertension, blurred vision, diarrhea, peripheral oedema, myalgia, parasthesiae, gum hypertrophy, cramps, chills and mood swings 1. There were no therapy-related SAE although five patients required hospital admission: three during treatment phase (social 1, bleeding due to thrombocytopenia 2) and two over 12 months following therapy (atrial fibrillation with prior history and acute renal failure due to non-steroidal anti-inflammatory drugs). One male patient aged 85 was diagnosed with prostate cancer 18 months following treatment with TT4 and has been successfully treated. Other therapy-unrelated AE included renal colic, gum bleeding, easy bruising, back pain and menorrhagia. Conclusions We report on the efficacy, safety and tolerability of a triple therapy approach to treating adult ITP. Notwithstanding the bias of non-random patient selection, we targeted B-cells, T-cells and antigen-presenting cells without the introduction of serious adverse events over the median follow-up period of 15.8 months across all arms. Overall, the 6 month response rate of 75% appears to be maintained beyond 12 months. Ongoing studies are required to confirm the safety of triple therapy approach to ITP. Although the median 7 days time to response seen in triple therapy compares favourably with other regimens, three patients required salvage therapy while awaiting their final doses of rituximab highlighting the need to further optimise sequential dosing strategies in future studies. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 206 Lenalidomide is an immunomodulatory agent that has clinical activity in CLL. In patients (pts) with relapsed/refractory CLL treatment with single agent lenalidomide induces an overall response rate of 32–47% when used as monotherapy (Chanan-Khan A.A. et al. 2006; Ferrajoli A. et al. 2008). Rituximab has modest activity as monotherapy, but significally synergizes with chemotherapy agents when administered to pts with CLL. The addition of rituximab to lenalidomide resulted in clinical responses in a small number of pts with CLL that had progressed while on lenalidomide monotherapy (Chanan-Khan A.A. et al. 2006). Because lenalidomide stimulates NK cell proliferation (Wu et al. 2008) we hypothesized that lenalidomide will enhance the activity of rituximab. We, therefore, designed a phase II study to evaluate the combination of lenalidomide and rituximab in pts with relapsed CLL. Pts with CLL and active disease were eligible if they had received prior treatment with purine analog-based therapy. Standard inclusion criteria were required in terms of organ function and performance status, and pts with any ANC or platelet count were eligible. All pts received rituximab (375 mg/m2) intravenously on days 1, 8, 15 and 22 of cycle 1, and then once every 4 weeks during cycles 3–12. Lenalidomide was given orally at the dose of 10 mg/day starting on day 9 of cycle 1 and continued daily for 12 cycles. Each cycle consisted of 28 days of treatment. During the first two weeks of therapy, allopurinol at the dose of 300 mg daily was prescribed as prophylaxis for tumor lysis. Sixty pts were accrued between October 2008 and July 2009. Thirty-seven pts have received treatment for at least 6 cycles and are evaluable for response and toxicity. The median age is 59 yrs (range 44–83), 15 pts (41%) have Rai stage III-IV disease and the median beta-2M level was 3.6 mg/dL (1.5–9). The median number of prior treatments was 2 (1–9), 9 pts (24%) were refractory to fludarabine and all pts had received prior rituximab. Twenty-six pts (70%) had unmutated IgVH, 9 pts (24%) had chromosome 17p deletion and 10 pts (37%) had 11q deletion by FISH analysis. After 6 cycles of treatment, 25 pts achieved a response [6 nodular PR (16%), 19 PR (51%)] for an OR of 68% (according to 1996 NCI-WG criteria). Six pts (16%) attained stable disease or clinical improvement and are continuing on treatment, and 6 pts (16%) failed to respond, including one death that occurred on day 34 owing to infectious complications. Responses according to pts characteristics are summarized in the table: Most common grade 3–4 treatment related adverse events observed were: neutropenia (16 pts, 43%), fatigue (6 pts,16%) and thrombocytopenia (4 pts, 11%). One pt (3%) developed grade 3 tumor lysis syndrome and 1 pt (3%) had grade 3 joint pain. Infectious complications occurred in 9 pts (24%): neutropenic fever (6 pts), pneumonia (2 pts) and urosepsis (1 pt). Lenalidomide-associated tumor flare reaction was limited to grade 1 (8 pts, 22%) and grade 2 (1 pt, 3%). We examined the effect of therapy with lenalidomide and rituximab on the distribution of circulating B, T, and NK cell subsets. When compared to the baseline, there were significant decreases in the percentage of CD19+CD20+ B cells along with significant increases in the percentages of CD4+ T, CD8+ T, CD4+CD25hiCD127− regulatory T, and CD3−CD16+CD56+ NK cells after 3 cycles of therapy (paired sample t test). In conclusion, our results suggest that the combination of lenalidomide and rituximab is superior to single agent lenalidomide, despite all our pts having received prior rituximab. Additionally, there was no increase in toxicity and lenalidomide-associate tumor flare reaction was less frequent and less severe with this combination compared to single agent lenalidomide. Disclosures: Ferrajoli: Celgene: Research Funding; Genentech: Research Funding. Off Label Use: The use of Lenalidomide for the treatment of CLL is considered investigational.. O'Brien:Celgene: Consultancy; Genentech: Research Funding. Wierda:Genentech: Honoraria; Celgene: Speakers Bureau. Keating:Celgene: Data Monitoring Committee, Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees.

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: Abstract 4636 Background: Single agent rituximab has limited activity in chronic lymphocytic at standard doses; however, the addition of rituximab to purine analogues, monoclonal antibodies or steroids has been shown to improve responses and response duration in patients with untreated and relapsed chronic lymphocytic leukemia (CLL). The combination of rituximab and high dose methylprednisone has shown activity in patients with untreated and fludarabine-refractory CLL (Castro 2008, Castro 2009); however, there is limited reported experience with this regimen in elderly patients. These data prompted us to review our center's experience with rituximab in combination with high dose methylprednisone in elderly patients with CLL. Patients and Methods: We retrospectively identified 24 patients 65 years or older with CLL who received rituximab and methylprednisone between July 2002 and April 2010 at MD Anderson Cancer Center. Six patients received this treatment as initial therapy and 18 patients as salvage treatment. Rituximab 375–750 mg/m2 and methylprednisone 500–2000 mg were administered i.v. weekly for 4 weeks. Three patients received further maintenance treatment with rituximab 375–750 mg/m2 and methylprednisone 500 mg/m2 every month or every 3 months until failure of response. Responses were assessed according to 2008 NCI-WG criteria. Estimated progression free survival and OS were analyzed from time of treatment to progression or death using Kaplan-Meier survival curves. Results: The median age was 71 (65 – 87) years and 17 of 24 (71%) had Rai stage III or IV disease. Two patients had concomitant autoimmune hemolytic anemia (AIHA), one patient had immune thrombocytopenic purpura and AIHA was the indication for therapy in one patient. Median β2-microglobulin was 7.7 (2.3 – 21) mg/l and 5 patients had chromosome 17 abnormalities. Previously treated patients had received a median of 3 (1 – 7) prior treatments and 6 (32%) pts were refractory to fludarabine. Responses were observed in 4 of 6 untreated patients (ORR 67%) and included 3 clinical complete responses unconfirmed by bone marrow biopsy (CRu, 50%) and 1 partial response. The estimated median PFS and OS in this group were 13 and 55 months, respectively. Among patients who received rituximab and methylprednisone as salvage therapy, 7 patients achieved a partial response (ORR 39%), 10 (50%) patients failed treatment, 1 patient (6%) received another therapy after 1 cycle for lack of response and 1 patient (6%) was lost to follow-up. In the salvage group, estimated median PFS and OS were 4 and 18 months, respectively. Four deaths occurred 3, 5, 11 and 12 months after rituximab and methylprednisone without further therapy; 3 patients had progressive CLL and the cause of death was unknown in 1 patient. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in 6 (33%), 3 (14%) and 1 (5%) of evaluable patients. Four patients (17%) experienced grade 3 or 4 infections (3 pneumonia and 1 colonic abscess), 5 patients experienced minor infections and 3 patients experienced viral reactivations (1 CMV, 1 HSV, 2 VZV). There were four grade 3 or 4 non-hematological adverse events including grade 4 gastrointestinal and pulmonary hemorrhage (1), colitis (1), steroid myopathy (1) and peripheral edema (1). All grade 3 or 4 complication occurred in salvage patients. Conclusions: Based on our experience, rituximab and methylprednisone therapy can be safely administered to older patients with CLL. As previously reported by Castro et al, higher response rates were seen in untreated patients, whereas responses were less frequent and shorter lasting in patients with relapsed disease, although this group had high risk disease based on β2-microglobulin levels. Additional studies are required to explore the benefit of this regimen in elderly patients with CLL. Disclosures: Off Label Use: Ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia. O'Brien:Celgene: Consultancy; Genentech BioOncology: Consultancy. Wierda:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Advisory Board, Consultancy, Speakers Bureau. Estrov:Celgene: Consultancy. Keating:Celgene: Consultancy; Genentech: Consultancy. Ferrajoli:Celgene: Research Funding; Genentech: Research Funding.

Description: Background/Aims The Haematology Clinical Research Network of New South Wales & the Australian Capital Territory (HCRN NSW/ACT) comprises public hospital clinical trial unit managers committed to collaboration in the clinical research endeavour. In June 2013 we launched the ClinTrial Refer Application (App) on iTunes and Google play. This smart-phone and iPAD/Tablet tool provided clinicians, research staff and patients with instant knowledge of currently recruiting local haematology trials. It was associated with an immediate increase in inter-hospital cross referrals of patients to trials. Following this, the HCRN aimed to sustain and measure this increased referral and trials recruitment and to create a not-for-profit 'template App' that could be transferrable to other clinical trial portfolios. Methods Patient cross-referral patterns, recruitment and staffing data were obtained from each of the 18 contributing hospitals in the HCRN from June 2013 to June 2015 and compared with prior to June 2013. Google analytics for the App were downloaded. We worked with research staff of other cancer networks to create modified versions of the App, establishing search functions unique to each network's geography and/or tumour stream. Newly derived Apps had to conform to the specifications of ClinTrial Refer, namely being publically available and free to download, simple to use and hosting only publically listed data of currently recruiting trials. Results Within the HCRN there has been a sustained increase in cross referrals for clinical trials (median 1/month (range 0-6) to 9/month (0-18)) (Figure 1) and a state-wide 〉50% increase in recruitment from 300 to 460 from 2012 to 2014 and a 20% increase in unit staffing from 2013 to 2014. Google analytics usage metrics identify 3362 App users, over 24,703 sessions lasting an average 56 seconds. 19,907 of these sessions are in NSW where 91% of users are repeat users. Ten other state and national haematology or other tumour stream ClinTrial Refer Apps have been derived from the original App, from Sept 2013 to July 2015 (Figure 2). While maintaining the basic structure of an easy-to-navigate listing of currently recruiting trials, each new App has been re-designed to ensure relevance for the needs of each network. This ranged from a simple re-configuration of the logo, splash screen and recruiting locations for other Australian haematology Apps, to providing mutational status options for melanoma trials or age criteria for paediatric and adolescent- young adult Networks. The back-end database of listed trials, selection criteria and recruiting sites can be rapidly easily updated by local trial unit managers ensuring currency of trial information (est. 30 minutes/month in total). The "early adopters" within other cancer research networks have reported a similar upswing in trials recruitment and Google analytics for these newer Apps are similarly impressive. Recognising ClinTrial Refer as an effective tool for patients to identify recruiting trials close to home, cancer consumer groups have posted the Apps on their websites. Conclusions An instantly accessible, simple smartphone Application has provided better knowledge management of local clinical trials across the spectrum of rare haematologic malignancies. A tool to facilitate collaboration in clinical research, it has significantly enhanced cross-referral and recruitment rates, increasing patient access to emerging therapies and supporting the viability of haematology clinical trial units across Australia. ClinTrial Refer has been rapidly adapted to suit the trials portfolios of other clinical trial networks, both within and beyond cancer. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1248 Poster Board I-270 Background There has recently been substantial work to identify factors that correlate with clinical outcome for patients with CLL. Identifying and validating factors may give understanding and insight into the biology of the disease and may help guide management of patients. TP53 is a gene located on the short arm of chromosome 17 (17p). The protein product of TP53, p53, is a transcription factor that regulates cell cycle and functions as a tumor suppressor. Therefore, p53 is critically important for the survival of CLL cells. In addition, p53 is critical for the therapeutic response to chemotherapy, particularly for alkylating agents and purine analogues. Thus patients with loss (17p del) or mutation of TP53 have inferior response to standard treatments, shorter remission duration, and shorter overall survival. We previously reported outcomes for untreated patients with de novo loss of 17p identified by FISH (Tam et al. Blood 114:957, 2009). In that analysis, there were patients with 17p del who did not require treatment and were observed for a prolonged period, however, it was clear that once treatment was required, outcomes markedly deteriorated. The current analysis summarizes outcomes for previously treated patients with 17p del who went on salvage therapy at MD Anderson Cancer Center. Methods and Results We identified 95 previously treated patients who were evaluated at MDACC, had 17p del by FISH, and went on a salvage therapy from March 2004 to May 2009 (Table). There were 10 patients known to have de novo 17p del prior to frontline therapy and 9 patients with acquired mutations (76 unknown). In addition to 17p del, 18 also had 11q del, 17 had +12, 53 had 13q del; 26 had no additional, 53 had 1 additional, 13 had 2 additional, and 3 had 3 additional chromosome abnormalities by FISH analysis. The median number of prior treatments was 3 (range 1-10); prior treatment regimens in hierarchical order consisted of multi-agent-based chemotherapy (N=18); fludarabine combination-based (N=59); single purine analogue or alkylating agent-based (N=13); and monoclonal antibody- (mAb) or steroid-based (N=4). For this analysis follow-up began from the first salvage therapy after discovery of 17p del by FISH. Salvage therapies included alemtuzumab or alemtuzumab with rituximab (N=15); other mAb-based (N=12); lenalidomide-based (N=8); fludarabine-based combinations (N=24); combined oxaliplatine, fludarabine, cytarabine, rituximab (OFAR) (N=28), and others not fitting any of these categories (N=8). The outcomes for these patients were very poor (Table). The complete remission (CR) rate with salvage therapy was 6% and the overall response rate (ORR) was 36%. The median follow-up was 10 months, time to treatment failure was 4.1 months, and overall survival was 14 months. Sixteen patients proceeded on to allogeneic stem cell transplant with a median OS of 27 months. Conclusion Previously treated patients with 17p del have extremely poor prognosis and outcomes based on low response rate to salvage treatment, short time to treatment failure and overall survival, including with alemtuzumab-containing treatment. This is a population who clearly needs new and active treatment regimens that have a p53-independent mechanism of action. Experience with allogeneic stem cell transplant in this population is limited and requires further investigation. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3448 Poster Board III-336 Introduction Patients (pts) with CLL have more than twice the risk of developing second malignancies [1]. Frontline therapy with FCR was the strongest independent determinant of survival when compared to FC in patients with CLL in retrospective analysis [2]. This study aims to identify pretreatment factors that may be associated with the development of 2nd malignancies in patients with CLL treated with FCR as initial therapy. Methods Our analysis includes pts with CLL treated between July 1999 and November 2003, on a Phase II trial of FCR as initial therapy. Patients who had developed a 2nd malignancy prior to initiation of therapy were excluded. Patients were divided in 2 groups according to whether they developed a 2nd malignancy during the follow up period. Time to 2nd malignancy was defined as the time from treatment to the first occurrence of 2nd malignancy. Chromosomal abnormalities were detected by metaphase karyotype of bone marrow leukemia cells. Patient characteristics, response to FCR, and overall survival were compared between the two groups using: Wilcoxon rank for continuous variables or Chi-square tests for categorical variables; Kaplan-Meier method was used to generate survival curves and log-rank test was used to assess differences in survival between subgroups. Responses were assessed by 1996 NCI-WG criteria after completion of treatment. Univariate and multivariate Cox proportional hazards model were fitted to assess the association between pts' characteristics and the second malignancy-free survival. Results Among 300 pts with CLL treated with frontline FCR, 46 had a 2nd cancer diagnosed prior to FCR were therefore excluded from this analysis, resulting in a total of 254 pts (85%). With a median follow-up of 76 months, 58 pts (23%) have developed a 2nd malignancy. These included hematological malignancies n=20, non-melanoma skin cancer n=18, solid tumors n=15 and 5 patients have more than 1 type of malignancy. Pts who developed a 2nd malignancy had significantly higher pretreatment percent of lymphocyte in the bone marrow (p=0.04), were less likely to have enlarged spleen size (p=0.024), and were more likely to have deletion of or abnormal chromosome 17 (p=0.008). The overall survival or the responses to treatment were not different between the 2 groups of pts. In the Cox proportional hazards model, abnormalities of chromosome 17 and 13 were statistically significantly associated with shorter time to 2nd malignancy: HR, 9.79 (95% CI, 2.84 - 33.82), p=0.0003 and HR, 4.019 (95% CI, 1.41 - 11.42), p=0.009, respectively. Conclusion Chromosome 17 and 13 abnormalities identified by standard metaphase karyotype analysis were more common in patients with CLL who develop 2nd malignancy after FCR therapy. The response rates and overall survival were not different between patients with CLL with or without 2nd malignancy after frontline therapy with FCR. Univariate Cox proportional hazards model in estimating the associations between covariates and 2nd malignancy free survival. Disclosures No relevant conflicts of interest to declare.

Description: Background Readily accessible, smart-phone applications (Apps) have the potential to revolutionise and improve the delivery of patient care. Significant challenges associated with recruiting patients to haematology clinical trials include the rarity of diseases, complexity of trials, limited site locations, and maintaining knowledge of current trials in the context of rapid therapeutic developments. The Haematology Clinical Research Network, of New South Wales and the Australian Capital Territory (NSW/ACT) aimed to develop an App to facilitate clinician and patient access to current information on local clinical trials and improve trial participation by increasing referrals. Methods Key objectives were to develop an App that was free to download, simple to use and effective. Only publically listed data was to be included. Endpoints were rates of App usage, and cross-site and internal clinical trial referrals. Through liaison between the end-users (clinicians, trial managers and patients), and the contracted software developer, App specifications were refined through successive iterations. With the key search filters of Disease, Location, Sponsor and Study Status, the App has an easy to navigate listing of currently recruiting haematology trials. Useful features include: listing of inclusion and exclusion criteria; direct links to ClinTrials.gov; a lay summary; and direct contacts from the mobile device to participating study sites. Real-time data entry into the database app manager ensures currency of trial information. Results ClinTrial Refer went live in May 2013, on both iOS and Android platforms. As at 10th August, ClinTrial Refer has 654 users, over 4358 sessions and 13924 screen views.91% of current users are repeat users. Despite its local application the App has been accessed in 46 countries. Among the target audience in NSW 290 repeat users returned for an average 11 sessions each indicating a high user acceptance. It is being endorsed on the websites of Australian blood cancer consumer groups. A survey has confirmed that since its launch, through having readily accessible data on their smart-phones, ClinTrial Refer has increased clinician awareness of the NSW trial portfolio. In just twelve weeks it has resulted in the cross-referral of an additional 30+ patients for clinical trials, representing a 〉300% increase over previous referral patterns. This improvement in trials knowledge management has also increased within-site recruitment; however it is harder to quantify the exact short-term impact of ClinTrial Refer within hospitals. The App has already been duplicated for other Australian state-wide haematology networks and the Adolescent & Young Adult Research Network, NSW. Conclusion ClinTrial Refer is an innovative but simple, readily accessible mobile Application. Its widespread adoption across 18 Haematology Clinical Research sites in NSW Australia is facilitating increased patient recruitment to trials. Only recently available on iTunes and Google Play, it has attracted national and international attention as a template for any clinical trial network portfolio. Disclosures: Trotman: Celgene: Grant for App development Other. Huseincehajic:Celgene: Grant for App development Other.

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: Background Rituximab plus FC is standard treatment for pts with CLL (NCCN Clinical Practice Guidelines, v2.2014). Rituximab is currently administered by the IV route, which may take several hours. SC administration of rituximab is associated with significant administration time savings and is preferred by pts receiving rituximab for B-cell malignancies, compared with IV administration. Rituximab binds CD20 on the surface of systemic B-cells, and the SC formulation was developed to attain serum Ctrough levels at least as high as with IV infusion, to achieve at least the same degree of target-site saturation and hence similar efficacy to IV administration. Methods SAWYER is a two-part, randomized, open-label Phase Ib study of rituximab SC or IV plus FC (oral or IV) for up to 6 cycles in previously untreated CLL pts. Part 1 of the study predicted that a rituximab SC fixed dose of 1600 mg would achieve Ctrough levels non-inferior to those with rituximab IV 500 mg/m2 (manuscript submitted: Assouline S, 2014). We report data from part 2 of the study, which aimed to confirm the non-inferiority of Ctrough levels for fixed-dose rituximab SC 1600 mg compared with IV 500 mg/m2 given 4-weekly. Pts were randomized 1:1 to receive rituximab IV (n=88) or SC (n=88) in combination with FC, stratified by Binet stage and route of FC administration (oral vs IV); all pts received rituximab IV 375 mg/m2 in the first cycle. For cycles 2–6, pts received either rituximab IV 500 mg/m2 or rituximab SC 1600 mg fixed dose. The primary endpoint of part 2 was non-inferiority in observed rituximab Ctrough levels at cycle 5 (pre-dose cycle 6). The pre-specified margin for non-inferiority for the geometric mean Ctrough,SC:Ctrough,IV ratio was a lower limit of the 90% confidence interval [CI] of ≥0.8. Secondary endpoints included comparisons of area under the serum concentration–time curve (AUC), safety, end of treatment response, overall response rate (ORR) and complete response rate (CRR; including CR and CRi). Results Untreated pts with CD20+ B-CLL requiring treatment per iwCLL criteria received rituximab SC or IV. The median age was 60 years (range 25–78) and pt characteristics were well balanced, excepting more male pts in the SC arm (71%) than the IV arm (60%). Most pts had Binet stage B (62%), followed by stage C and A (24% and 14%, respectively). At enrollment, 69% of pts received IV FC. The primary endpoint was met: the geometric mean Ctrough,SC:Ctrough,IV ratio was 1.53 at cycle 5 (pre-dose cycle 6), with the lower limit of the 90% CI of 1.27, above the pre-specified non-inferiority margin. The geometric mean Ctrough was 97.5 μg/mL in the rituximab SC arm and 61.5 μg/mL in the rituximab IV arm. The cycle 6 geometric mean ratio of AUCSC:AUCIV was 1.10 [90% CI: 0.98, 1.24]) indicating that AUC after SC was also at least as high as after IV administration. The investigator-assessed ORRs and CRRs at 3 months were 85% (95% CI: 76, 92) and 81% (95% CI: 71, 88); and 26% (95% CI: 17, 37) and 33% (95% CI: 23, 44) in the SC and IV arms, respectively. For both arms, these rates were within the expected range for a comparable CLL population treated with rituximab plus FC. At a median follow-up of approximately 14 months (range 4–20), the overall safety profile for SC was similar to IV administration, with no unexpected adverse events (AEs). AEs were experienced by 96% (n=82) and 91% of pts (n=81) in the SC and IV arms, respectively. Severe (grade ≥3) AEs were observed in 69% of pts in the SC arm and 71% in the IV arm. Of individual grade ≥3 AEs, only neutropenia (56% SC, 52% IV) and leukopenia (14% SC, 12% IV) occurred in 〉10% of pts. Grade ≥3 infections (13% SC [n=11], 10% IV [n=9]) were similar between the two arms. The rate of administration-related reactions (ARRs; AEs occurring during/within 24 hours of drug administration considered treatment-related by the study investigator) was similar in the SC (44%) and IV (45%) arms; the majority being grade 1/2; 10 pts (n=6 SC, n=4 IV) experienced grade 3/4 ARRs. ARRs (all grades) occurring in ≥5% of pts in the SC vs IV arms were: chills (11% vs 7%), pyrexia (8% vs 9%), injection site erythema (12% vs 0%), nausea (2% vs 12%), vomiting (4% vs 7%), hypotension (1% vs 7%), and headache (2% vs 6%). Conclusions These data demonstrate non-inferiority of Ctrough and AUC for rituximab SC 1600 mg compared with rituximab IV 500 mg/m2 when given every 4 weeks in combination with FC in pts with CLL. Both administration routes were associated with comparable safety and response rates. Disclosures Assouline: Roche: Honoraria, Research Funding. Off Label Use: This abstract reports on the use of subcutaneous rituximab in combination with oral or IV chemotherapy (fludarabine plus cyclophosphamide) in patients with untreated CLL. Subcutaneous administration of rituximab for NHL indications (but not CLL), is currently licensed in Europe but not in the US.. Buccheri:Janssen-Cilag Farmaceutica Ltd: Membership on an entity's Board of Directors or advisory committees. Delmer:Roche: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria. Gaidano:Roche: Consultancy; GSK: Consultancy; Onyx: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Brewster:Roche Products Ltd.: Employment. Catalani:Roche: Employment. Li:F. Hoffmann–La Roche Ltd.: Employment. McIntyre:Roche Products Ltd.: Employment. Sayyed:F. Hoffmann–La Roche Ltd.: Employment. Badoux:Roche: Honoraria.