ALBERT

Description: Multicentric Castleman’s disease (MCD) is a rare, lymphoproliferative disorder with high morbidity. MCD signs and symptoms are driven by dysregulated interleukin (IL)-6 production. Preliminary data suggest efficacy of siltuximab, a chimeric mAb against human IL-6, in MCD patients (van Rhee et al. J Clin Oncol 2010;28:3701-8). We evaluated the efficacy and safety of siltuximab in patients with symptomatic, measurable, HIV- and HHV-8-negative MCD in a phase 2, randomized, double-blind, controlled, multicenter study. Patients could be newly diagnosed/pre-treated and on stable, low-dose corticosteroids. Patients were randomly assigned 2:1 to siltuximab 11 mg/kg or placebo given by 1-h IV infusion q3w. All patients also received best supportive care to manage MCD symptoms. Patients received study agent until protocol-defined treatment failure, after which patients randomized to placebo could cross over to unblinded siltuximab. Primary analysis occurred after the last treated patient completed assessments at 48 wks. Primary endpoint was durable tumor and symptomatic response defined as PR or CR (Cheson criteria) by independent review and improvement/stabilization in MCD-related symptoms for ≥18 wks. Secondary endpoints included additional predefined efficacy measures and safety. 79 patients were randomized and treated with siltuximab (n=53) or placebo (n=26) from Feb 2010 to Feb 2013. Treatment arms were well balanced. Median age was 48 yrs, 48% were Asian, 39% were white, 66% were male, 30% were on corticosteroids, and 58% had prior systemic therapy. Patients had mixed (44%), hyaline vascular (33%), or plasmacytic (23%) histologic subtypes by pre-randomization central pathology review. Baseline MCD symptoms included fatigue (86%), malaise (61%), night sweats (52%), peripheral sensory neuropathy (38%), anorexia and pruritus (37% each). Median treatment duration was 375 vs. 152 d with siltuximab vs. placebo, with 64% vs. 27% completing 48 wks of treatment. A higher percentage of durable tumor and symptomatic response was observed with siltuximab compared with placebo (34% (1 CR, 17 PR) vs. 0%; p=0.0012). Investigator-reported response provided consistent conclusions. Median duration of tumor and symptomatic response in siltuximab-treated patients of 340 d indicates prolonged disease control. Tumor response rate by central radiology review was 38% vs. 4% (p=0.0022). Median time to treatment failure was not reached vs. 134 d (p=0.0084). Median time to next treatment was not reached vs. 280 d (p=0.0013). Durable symptomatic response rate was 57% vs. 19% (p=0.0018), including complete symptom resolution in 25% vs. 0% (p=0.0037). Hb improvement by ≥15 g/L at wk 13 was seen in 61% vs. 0% anemic patients (p=0.0002). Sustained decreases in CRP (a marker of IL-6 bioactivity), ESR, and fibrinogen, and increase in albumin were seen with siltuximab. 13 of 26 patients on placebo crossed over to siltuximab. The safety profile as defined by frequencies of treatment-emergent AEs was similar between siltuximab and placebo despite the 〉2x longer treatment duration with siltuximab: gr ≥3 AEs 47% vs. 54%, SAEs 23% vs. 19%, AEs leading to discontinuation 23% vs. 38% (mostly due to PD), AEs leading to treatment interruption 28% vs. 19%. Infusion reactions with siltuximab were infrequent (8%) and low grade, except for 1 anaphylactic reaction that led to treatment discontinuation. Gr ≥3 AEs frequently reported with siltuximab were fatigue (9%); night sweats (8%); and hyperkalemia, hyperuricemia, localized edema, hyperhidrosis, neutropenia, thrombocytopenia, hypertension, and weight increased (4% each). Gr ≥3 AEs reasonably related to siltuximab reported in 〉1 patient were neutropenia and thrombocytopenia (4% each). 3 (6%) patients had SAEs reasonably related to siltuximab. 2 (4%) patients in siltuximab died due to PD after treatment discontinuation. 4 (15%) noncrossover patients in placebo died (1 AE, 3 PD). This is the first randomized study in MCD. The efficacy of siltuximab in MCD patients was demonstrated by durable tumor and symptom response, and clinical benefit was confirmed by marked improvement of time to treatment failure, MCD-related symptoms, Hb levels, and sustained reduction in inflammatory markers. In conjunction with the tolerable safety profile in this population, this study provides compelling evidence that siltuximab should be considered a new treatment of choice for MCD patients. Disclosures: Wong: Roche: Research Funding; MSD: Research Funding; Johnson & Johnson: Research Funding; Bayer: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen-Idec: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Baxter: Research Funding; Amgen: Research Funding; Alexion: Honoraria. Casper:St. Jude Children's Hospital and Research Center: Membership on an entity’s Board of Directors or advisory committees; Hutchinson Cancer Research Institute--Uganda: Membership on an entity’s Board of Directors or advisory committees; Up-To-Date: Royalties Patents & Royalties; National Institutes of Health: Research Funding; Janssen Research & Development: Consultancy, Research Funding. Munshi:Janssen Research & Development: Membership on an entity’s Board of Directors or advisory committees. Fosså:Janssen Research & Development: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Simpson:Janssen Research & Development: Honoraria. Goh:Gilead Sciences, Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Janssen Pharmaceuticals Inc: Research Funding; Novartis Pte Ltd: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Hospira, Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cavet:Janssen Research & Development: Research Funding. Bandekar:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Rothman:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Puchalski:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Chaturvedi:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. van Rhee:Janssen Research & Development: Research Funding.

Description: Hodgkin’s Disease (HD) is the most common lymphoma affecting young adults and teenagers. Bone marrow involvement is rare but if present, infers Stage IV disease and an inferior outcome. Adult studies have suggested that bone marrow examination (BME) may not be necessary unless certain risk factors are present. However, some pediatric centers continue to perform BME routinely on all children with HD. BME is invasive and generally performed under conscious sedation in children. We validated and administered an internet-based survey to examine the practice of all Canadian pediatric oncologists regarding BME in children with HD. We also retrospectively evaluated the impact of routine BME on the HD patients treated at our institution over the past 27 years. Forty-three percent of eligible physicians (n=93) completed the survey and 16 of a total of 17 Canadian pediatric oncology centers were represented. BME universally consisted of bilateral bone marrow aspirates and trephine biopsies. Routine BME for Stage III and IV disease was consistently practised nationally (by 92% and 97% of respondents, respectively). By contrast, 54% and 70% of respondents reported performing routine BME in low stage (Stage I and II) disease, respectively. Respondents were more likely to report performing routine BME in low stage patients, if their pediatric hematology/oncology training was entirely outside Canada (p=0.04 for Stage I and p=0.07 for Stage II) and if they practiced at smaller centers (p=0.05 for Stage I and p=0.03 for Stage II). There were no differences in practice regarding BME associated with the number of years in practice or the number of patients seen annually by the respondent. If not part of routine staging for all patients, BME was more likely performed if there were “B” symptoms, cytopenias, and/or bulky disease. Most respondents (95%) would proceed with BME following a positive PET scan. In the review of local institutional practice, 62 patients with HD and BME were eligible for analysis. Only 4 patients (6.5%) had a positive BME. No patient with otherwise low stage disease was found to have bone marrow involvement. Two patients, who would have been assigned as Stage III disease, were upstaged to Stage IV due to their BME. Comparison of staging with and without BME demonstrated no significant difference. Hemoglobin level was found to be the to be the only significant risk factor for marrow involvement based on univariate analysis(put in statisticp=0.006). Age, gender, histologic subtype, presence of “B” symptoms, and other blood parameters (white count, platelets, ESR and transaminases) were not significant factors. Practice regarding BME in children with low stage HD is highly variable across Canada. Bone marrow examination in pediatric patients with low stage HD should be abandoned, unless there is a specific indication to do so (for example positive PET scan or unexplained anemia). Moreover, BME does not appear to add any additional therapeutic direction for higher stage patients.

Description: Background: Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) occurs primarily in older patients (pts) who often have increased comorbidities and cannot tolerate aggressive treatments, which leads to poorer outcomes (Balducci, Cancer Control 2015; Thurmes, Leuk Lymphoma 2008). Alkylating agents, such as chlorambucil (clb), have been commonly used to treat these pts (Eichhorst, Blood 2009). Ibrutinib (ibr), a first-in-class, once-daily, inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. RESONATE-2 (PCYC-1115) is a randomized phase 3 trial designed to compare the efficacy and safety of ibr vs clb in pts with treatment-naïve (TN) CLL/SLL (Tedeschi, ASH 2015). Primary results, as assessed by an independent review committee (IRC), demonstrated with a median follow-up of 18.4 mo that ibr significantly reduced the risk of progression or death by 84% (P

Description: Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs

Description: Background : Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US and EU for patients (pts) with CLL and allows for treatment without chemotherapy. Standard of care for first-line CLL in older pts or those with comorbidities includes single-agent ibr or chemoimmunotherapy (CIT) with chlorambucil (clb) plus anti-CD20 therapy. As no data were available from phase 3 studies directly comparing single-agent ibr with CIT, we performed a cross-trial analysis using data from two phase 3 studies to assess single-agent ibr vs clb plus obinutuzumab (G) in first-line CLL. Methods : In the ongoing PCYC-1115/1116 (RESONATE-2), pts with previously untreated CLL/SLL aged ≥65 years without del(17p) were randomized to receive ibr (420 mg once daily continuously) or clb. In PCYC-1130 (iLLUMINATE), pts with untreated CLL/SLL aged ≥65 years or

Description: Background The diagnosis and treatment of CLL may have a great impact on the quality of life (QoL) due to a variety of reasons including disease-related symptoms, infection, effects of therapy and the emotional, socio-economic, and functional effects of living with an 'incurable' illness. The main aim of any treatment is to maximize QoL by inducing remission with minimal short- and long-term toxicity. Balancing disease and symptom control with QoL in elderly patients receiving CLL therapy regimens can be challenging. There is little published QoL data in elderly CLL patients receiving the FCR (fludarabine, cyclophosphamide, rituximab) immunochemotherapy regimen. Our prior study showed no significant difference in health related QoL for first-line therapy of CLL with monotherapy between chlorambucil, fludarabine and cladribine (Mulligan, SP et al. Leuk Lymphoma, 2014). Aim We report the QoL assessments of CLL patients enrolled in the ALLG clinical trial CLL5, a randomised, 3-arm, dose de-escalation study of the FCR regimen. Methods The treatment schedule has been described with fit elderly patients randomly assigned to one of three treatment regimens: FR5, FCR3, and FCR5 (Mulligan SP et al. iwCLL Abstract, 2015). Treatment was repeated every 28 days for a planned total of 6 cycles. Importantly, an early stopping rule mandating cessation of therapy was included for any patient having grade 3 or 4 toxicity lasting 〉2 weeks. QoL assessments using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were measured at 8 time points: before commencement of therapy, at the end of the 3rd and 6th cycles of treatment, at the final staging and thereafter every 3 months for 12 months. Results Of the 116 evaluable in the study, 2 patients had no QoL data, 6 patients had only baseline QoL data, and 4 patients had no baseline QoL data, therefore the number of patients included in the QoL analysis was 104. There appeared to be a trend towards improved global health (figure 1), physical functioning (figure 2) and role functioning with full dose (FCR5) towards the end of the follow-up period compared to commencement of therapy. Comparison of cognitive functioning (figure 3) between the three arms showed a statistically significant improvement with FCR5. However, on multivariate analysis there was no statistical significant difference. Conclusions Despite a trend favouring full-dose FCR, there were no definitively significant differences in the QoL domains following treatment with FCR-based immunochemotherapy between the three different groups. QoL continues to be a neglected issue, particularly for the typical elderly CLL patient. This study highlights the need for objective QoL assessment as part of all CLL trials, especially those targeted in the typical elderly patient. Figure 1. Mean change from baseline global health status scores with 95% confidence intervals Figure 1. Mean change from baseline global health status scores with 95% confidence intervals Figure 2. Mean change from baseline physical functioning scores with 95% confidence intervals Figure 2. Mean change from baseline physical functioning scores with 95% confidence intervals Figure 3. Mean change from baseline cognitive functioning scores with 95% confidence intervals Figure 3. Mean change from baseline cognitive functioning scores with 95% confidence intervals Disclosures Gill: Roche: Research Funding; Sanofi Aventis: Research Funding; AbbVie: Honoraria; Roche: Honoraria. Turner:Roche: Research Funding; Sanofi Aventis: Research Funding. Renwick:Sanofi Aventis: Research Funding; Roche: Research Funding. Latimer:Sanofi Aventis: Research Funding; Roche: Research Funding. Mackinlay:Sanofi Aventis: Research Funding; Roche: Research Funding. Berkahn:Sanofi Aventis: Research Funding; Roche: Research Funding. Simpson:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Forsyth:Sanofi Aventis: Research Funding; Roche: Research Funding. Cull:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel. Harrup:Roche: Research Funding; Sanofi Aventis: Research Funding. Kuss:Sanofi Aventis: Research Funding; Roche: Research Funding. Mulligan:Sanofi Aventis: Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Abstract 155 Background Bendamustine is a unique alkylating agent, active as monotherapy and in combination with rituximab for relapsed and refractory indolent non-Hodgkin's lymphoma (NHL). This study compared efficacy and safety of bendamustine-rituximab (BR) with standard treatment regimens of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in first-line treatment of patients with indolent NHL or mantle cell lymphoma (MCL). The primary objective was to determine whether the complete response rate for BR was noninferior to R-CHOP/R-CVP (presented separately). The present analysis reports results for quality of life (QOL) as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). Methods Previously untreated patients with indolent NHL or MCL were randomized to receive BR (bendamustine 90 mg/m2/day on days 1 and 2; rituximab 375 mg/m2 on day 1 of each 28-day cycle) or R-CHOP/R-CVP (rituximab 375 mg/m2 and vincristine 1.4 mg/m2 (up to maximum 2 mg) on day 1 and prednisone at 100 mg on days 1–5 (of a 21-day cycle), plus either [1] cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 or [2] cyclophosphamide 750 mg/m2 or 1000 mg/m2(investigator choice) on day 1. QLQ-C30 was administered at screening (baseline); after cycles 1, 3, 6, 8; and at the end-of-treatment visit. Linear transformation to standardize raw scores was performed. The QLQ-C30 is composed of 5 multi-item functional scales, 1 global health status (GHS)/QOL scale, 3 symptom scales, and 6 single-item measures; all scores could range from 0 to 100. Rising scores for functional scales and GHS/QOL indicate improvement. Rising scores for symptom scales/single items indicate worsening. GHS/QOL score change at last QLQ-C30 administration postbaseline was interpreted using analysis of covariance. Data from the last observation (end-of-treatment visit) were analyzed. Results The 447 enrolled patients were randomly assigned to 1 of the 2 treatments; 224 to BR (NHL n=187, MCL n=36, missing n=1) and 223 to R-CHOP/R-CVP (NHL n=184, MCL n=38, missing n=1). Treatment groups were well matched for demographic and clinical characteristics. Among all randomized patients, mean change in GHS/QOL score from baseline to final visit was significantly higher (indicating relative improvement) for patients treated with BR than those treated with R-CHOP/R-CVP (3.6 vs −5.1 respectively, P=0.0005). For patients with indolent NHL, mean change in GHS/QOL score by final visit was significantly higher in patients treated with BR than those receiving R-CHOP/R-CVP (2.1 vs −6.3, respectively, P=0.0021); in patients with MCL, mean change in GHS/QOL score was numerically higher in the BR group, but the difference was not statistically significant (10.9 vs 1.6, P=0.0654). All randomized patients receiving BR showed greater improvement in QLQ-C30 Emotional Functioning (from baseline to final visit), compared with patients receiving R-CHOP/R-CVP. Mean change from baseline scores (± SEM) for QLQ-C30 for Cognitive, Physical, Role, and Social Functioning scales of the QLQ-C30 decreased (signifying deteriorating effect) in both treatment groups, with patients treated with BR deteriorating less than patients treated with R-CHOP/R-CVP (Figure). For symptom scales/item measures, patients treated with BR showed larger reductions in mean scores from elevated baseline levels (signifying greater improvement), compared with R-CHOP/R-CVP for Appetite Loss (−2.9 for BR vs −1.1 for R-CHOP/R-CVP), Pain (−5.6 vs −1.7), and Constipation (−0.7 vs 1.8). For symptom scales/item measures of Dyspnea, Fatigue, and Financial Difficulties, both treatments showed deteriorating effects, with BR showing less than R-CHOP/R-CVP: Dyspnea (0.8 vs 4.8), Fatigue (0.5 vs 7.2), and Financial Difficulties (0.9 vs 1.3). Patients receiving R-CHOP/R-CVP had larger reductions in mean scores for Insomnia (−2.1 for BR vs −6.7 for R-CHOP/R-CVP), Diarrhea (0.5 vs −1.3), and Nausea and Vomiting (1.8 vs 0.9). Conclusions In this study, BR significantly improved GHS/QOL, compared with R-CHOP/R-CVP treatment, in previously untreated patients with indolent NHL or MCL. In addition, BR provided improved patient QOL scores for most aspects of functioning and symptoms, as measured by the QLQ-C30. Support: Teva Pharmaceutical Industries Ltd. Disclosures: Burke: Spectrum Pharmaceuticals: Consultancy. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Van der Jagt:Celgene: Consultancy, Research Funding, Sponsorship Other; Novartis: Consultancy, Research Funding, Sponsorship, Sponsorship Other; Roche: Consultancy, Sponsorship, Sponsorship Other; Teva: Consultancy, Research Funding; Incyte: Research Funding; Xanthus: Research Funding; Bristol-Myers Squibb: Consultancy. Kahl:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. MacDonald:Lundbeck: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Teva Pharmaceutical Industries Ltd.: Employment. Munteanu:Teva Pharmaceutical Industries Ltd.: Employment. Clementi:Teva Pharmaceutical Industries Ltd.: Employment. Chen:Teva Pharmaceutical Industries Ltd.: Employment. Flinn:Teva: Research Funding.

Description: Background: Ponatinib is an approved potent oral tyrosine kinase inhibitor active against native and mutated forms of BCR-ABL, including T315I. The phase 2 PACE study demonstrated that ponatinib is highly active in heavily pretreated Philadelphia chromosome‒positive leukemia patients. Ponatinib efficacy and safety were evaluated in newly diagnosed CP-CML patients in the EPIC trial. Methods: EPIC was a multicenter, international, phase 3, randomized, 2-arm, open-label trial of ponatinib (45 mg once daily) compared with imatinib (400 mg once daily) in newly diagnosed CP-CML; patients were stratified by Sokal risk score (low [1.2]). On 18 October 2013,EPIC was terminated due to the observation of arterial thrombotic events in the ponatinib development program. Consequently, none of the prospectively defined endpoints could be analyzed. Data as of 1 April 2014 are presented for endpoints that could be analyzed: BCR-ABLIS

Description: Introduction AL amyloidosis is a systemic disease where the immunoglobin light chains produced by clonal plasma cells accumulate as insoluble fibrils causing end organ damage. In patients with AL amyloidosis, renal involvement is common, and proteinuria is frequently detected. Current treatment for AL amyloidosis aims at reducing production of these pathological immunoglobulin light chains by eliminating the clonal plasma cell population. Following treatment and normalisation of serum free light chains (SFLCs), improvement in end organ function, as demonstrated by reduction of proteinuria in patients with renal AL amyloidosis, occurs at a much slower rate. Although reduction in proteinuria has been linked to improved outcomes, the rate of this reduction has not been documented in detail in the literature. The purpose of this study is to analyse the tempo of proteinuria resolution in patients with renal AL amyloidosis following bortezomib based chemotherapy. Methods Cases were selected by retrospectively reviewing the hospital electronic database. All patients with biopsy confirmed renal AL amyloidosis were included. Induction chemotherapy was a combination of weekly bortezomib (1.6mg/m2), cyclophosphamide (300mg/m2) and dexamethasone (40mg) given in 4-weekly cycles. During the follow-up period, proteinuria was measured by urinary protein / creatinine ratio (PCR) from random urine samples. The results of the PCR over time were plotted on a scatter plot, and a best fit curve was fitted using IBM SPSS Statistics 20 software to determine the trend of PCR over time. Patients who did not complete bortezomib chemotherapy, or did not have follow-up urinary PCR were excluded. Results After applying the exclusion criteria, seven patients were analysed, and the baseline characteristics are listed in table 1. The median follow-up was 30.9 months (range: 13.2 – 44.1 months). The median age was 68.8 years (range: 52.5 – 80.5 years). Patients received a median of 6 cycles of chemotherapy (range: 2 – 9 cycles), and all patients received full doses of bortezomib based on their body surface area (average dose of 1.6mg/m2, range: 1.53 – 1.64mg/m2). Five of the 7 patients normalised their SFLCs after one cycle of chemotherapy, and the median time to normalisation was 26 days (range: 13 – 185 days). PCR was used to monitor the level of proteinuria following chemotherapy. One patient was excluded in this part of the analysis due to progressive diabetic and hypertensive nephropathy following an initial improvement in PCR after normalisation of SFLCs. Although there was marked fluctuation of PCR (figure 1), the PCRs followed an exponential decay pattern over time (R2 between 0.223 – 0.976). The median half-life of reduction was 6.2 months (range: 3.4 – 18.2 months). Conclusions PCR from random urine samples is a useful and convenient way of assessing proteinuria in everyday outpatient setting. Although PCR fluctuates over time in patients with renal AL amyloidosis, there is a general downward trend following bortezomib based chemotherapy and normalisation of SFLCs. This downward trend appears to follow an exponential decay pattern, and most patients have a protracted delay between normalisation of SFLCs and improvement in proteinuria. In view of such delay, normalisation of SFLCs should be the goal of initial therapy, rather than reduction in proteinuria when treating patients with renal AL amyloidosis. Table 1. Baseline patient characteristics Value (range) Age (median) 68.8 years (52.5 – 80.5 years) Male (%) 55.6% Plasma cell burden (median) 12.5% (6 – 25%) Kappa/Lambda light chain ratio (median) 0.164 (0.011 – 37.333) eGFR 〉 30ml/min (%) 88.9% Protein / creatinine ratio at diagnosis (mean) 698mg/L (243 – 1636mg/L) Figure 1 Figure 1. Disclosures Simpson: Onyx: Honoraria, Research Funding; Celgene: Honoraria; Janssen Cilag: Honoraria.

Description: BACKGROUND: Immunochemotherapy (ICT) with fludarabine (F), cyclophosphamide (C) and rituximab (R) provides prolonged progression free (PFS) and overall survival (OS) in fit younger patients with CLL. The Australasian Leukaemia and Lymphoma Group (ALLG) CLL5 study previously showed FCR based therapy was safe, tolerable and effective in fit older CLL patients. We now assess the PFS and OS status by treatment arm and mutational status after a minimum of 5 years following final recruitment. METHODS: Previously untreated patients with progressive CLL aged ≥65 were randomised to one of three treatment regimens FR5, FCR3 and FCR5 (= full dose) as follows: (i) F 24mg/m2 po D1-5 + R (375mg/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 4 weekly intervals for an intended 6 cycles. Early cessation of therapy was mandated for grade 3+ toxicity that delayed the next cycle 〉2 weeks on 〉2 occasions. RESULTS: The ITT population comprised 119 patients: 40 female and 79 male. Mean age was 71.6 years (range 64-83). The distribution by treatment arm was even with 38 patients on FR5, 41 on FCR3, and 40 on FCR5. As previously presented (ASH 2014), the overall response rate (ORR) was comparable at 95%, 95% and 97%, and the bone marrow confirmed complete remission (CR) rates 27%, 44% and 44% respectively. ORR and CR were not statistically significant. Toxicity was tolerable, and mainly hematological with neutropenia and thrombocytopenia. Early stopping due to toxicity occurred in 5.6%, 2.4% and 34% respectively, mainly hematological toxicity without complications. After a minimum of 5 years follow-up, no significant difference by OS (p=0.48) or PFS (p=0.93) (figure 1) was seen by treatment arm. Overall 51 patients (of 117 - 43.6%) died, hence the survival rate was 56.4%. Causes of death by treatment arm for FR5, FCR3 and FCR5 respectively were disease progression 4, 4, 1; Richter transformation 2, 0, 0; infection 2, 0, 7; and second malignancy 2, 4, 4. Of the 119 patients, 61 (51%) had data on immunoglobulin variable gene (IGHV) mutational status. In 33 (54%), IGHV were mutated (M-CLL) and 28 (46%) had unmutated IGHV (UM-CLL). The distribution by mutation status by treatment arm was even, with 10 each in FR5 and FCR3 and 13 in FCR5. Patients with M-CLL had a 61% lower risk of death and a significantly better PFS (p=0.0079; HR 0.39 [95% CL, 0.19 to 0.80]) than UM-CLL (M-CLL median PFS 110 months vs UM-CLL median PFS 48 months) (figure 2). CONCLUSIONS: Oral F(C)R therapy is generally safe and well tolerated in CLL patients aged ≥65 years requiring first-line treatment, when early stopping is utilized if prolonged toxicity is encountered; one third on full dose FCR5 stopped early with this rule, mainly with neutropenia. Response rates were high with ORR of 96% and CR rate of 56%. After a minimum of 5 years follow-up, OS and PFS outcomes by the treatment arms FR5 (full dose F, no C), FCR3 (40% FC dose reduction) and FCR5 (full-dose FCR) are essentially identical in this randomized dose de-escalation study. The median PFS overall was 53 months. CLL patients with M-CLL had a significantly superior PFS compared to UM-CLL. Disclosures Gill: Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Cull:Takeda Australia: Other: Travel Expenses; Amgen Australia: Other: Travel Expenses; AbbVie (Australia): Membership on an entity's Board of Directors or advisory committees. Simpson:Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Research Funding; BeiGene: Research Funding; Merck: Honoraria, Research Funding; Acerta: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Janssen: Honoraria, Research Funding. Tam:Pharmacyclics: Honoraria, Travel funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria; Beigene: Honoraria, Other: Travel funding; Beigene: Honoraria, Other: Travel funding. Badoux:Roche: Research Funding.