Abstract: Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL. Updated results on safety and efficacy of the CLL8 trial.

Abstract: Introduction: The management of patients with treatment resistant AML (failure to achieve complete remission, CR; or CR with incomplete blood count recovery; CRi) after intensive chemotherapy is an important clinical consideration. Anticipating the benefit of intensive salvage therapy facilitates patient management decisions and counseling. The UK Medical Research Council (MRC) has associated morphologic partial remission (PRm; defined as 5-15% bone marrow blasts) after course 1 of standard-dose cytarabine (SDAC) based induction, with 5yr overall survival (OS) outcomes comparable to achieving CR (42 vs 51%). In contrast, failure to achieve PRm was linked to 5-year OS of 20% (Wheatley, et al 1999). In an MD Anderson study, patients failing initial high-dose cytarabine (HiDAC) based induction had a 6-month OS expectation of only 7% (Ravandi, et al 2010). Less than 1% of patients in this study achieved PR using International Working Group (IWG) criteria (treatment related decrease in marrow blasts to 5-25% with a 〉 50% reduction from baseline and blood count recovery. We therefore sought to verify the prognostic relevance of PRm in patients with treatment resistant AML (no CR/CRi). Patients and treatment: A retrospective cohort of 104 patients failing intensive chemotherapy at 3 Australian hospitals (Alfred Hospital, Melbourne, Princess Alexandra and Royal Brisbane and Women's Hospitals, Brisbane) was identified. Prior therapy was standard-dose ara-C (SDAC) 100mg/m2 d1-7 in 73% or high-dose ara-C (HiDAC)(³1g/m2 cytarabine per dose for 5-8 doses) in 28% combined with idarubicin 9-12mg/m2 D1-3 as part of induction. For salvage after SDAC failure, the commonest regimens were HiDAC based, fludarabine and cytarabine (FLAG) variants or a second cycle of 7 + 3, the HiDAC group received further HiDAC based therapy, or FLAG based regimens. Outcomes were compared to a contemporaneously treated AML population (n=128) achieving CR/CRi. Results: OS was stratified according to the level of residual bone marrow blasts after induction. Patients with 5-15% residual blasts (PRm) had a median OS of 20.6 mo, compared to only 5.0 mo for patients with a residual blast count 〉 15% (p 〈 0.0001). Outcome was superior in patients achieving a marrow blast reduction of ³50% or greater after induction (median OS 18.7m, vs 5.5m if blast reduction was 〈 50%; p 〉 0.0001). The proportion of patients with treatment resistant AML (no CR/CRi) achieving PRm was 41%. CR/CRi rates from salvage chemotherapy were 64% for those failing SDAC and 52% for those failing prior HiDAC-based induction (p=0.37). The likelihood of attaining subsequent remission SDAC-based induction failure was not related to PRm status after cycle 1 of therapy (CR/CRi 73%, compared to 66% without prior mPR; p=0.85). In contrast, the response to subsequent salvage chemotherapy was more common after attainment of prior PRm in cycle 1 for those receiving HiDAC-based induction (CR/CRi 83%, compared to 14% without prior PRm; p=0.01). For patients receiving prior SDAC-based induction, median OS was not reached for patients with PRm, compared to only 8 mo for those not achieving PRm (p=0.0006) (Fig 1A). For patients receiving prior HiDAC-based induction, median OS was 45.5 mo for patients with PRm, compared to only 3.3 mo for those not achieving PRm (p 〈 0.0001) (Fig 1). If PRm was achieved after cycle 1 of induction, outcomes were not improved by subsequent HSCT (median OS 45.5 mo with HSCT, compared to 48.8 mo without HSCT [p=0.2]) (Fig 1B). In contrast, the benefit of HSCT was greater for resistant patients failing to achieve PRm (median OS 10.5 mo with HSCT, compared to 3.2 mo without [p=0.006] ) (Fig 1B). Conclusion: in patients with AML failing initial chemotherapy, good long-term outcomes are still achievable, especially if a PRm was achieved after the first course of induction chemotherapy, regardless of whether SDAC or HiDAC induction was delivered. In contrast, patients refractory (no CR or PRm) to induction chemotherapy have a very poor prognosis and should be considered candidates for experimental therapies or allogeneic stem cell transplantation. Assessment for PRm may be a useful prognostic factor when clinical decisions regarding adults with AML failing to achieve CR/CRi after induction therapy are being considered. Figure 1. Ð Survival by response, by induction intensity Figure 1. Ð Survival by response, by induction intensity Figure 2. Ð Survival after induction failure and by prior PRm status and subsequent allograft Figure 2. Ð Survival after induction failure and by prior PRm status and subsequent allograft Disclosures Mollee: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees. Wei:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

Abstract: The Hyper-CVAD chemotherapy regimen (JCO2000;18:547) is being increasingly applied to a number of haematological malignancies. We have previously demonstrated Hyper-CVAD to be a highly stem cell toxic regimen which adversely affects peripheral blood stem cell (PBSC) mobilisation and that mobilising efficiency can be significantly improved by collecting PBSC earlier in the treatment course. We now examine the optimal timing of PBSC collection when using this regimen. A retrospective analysis was performed at two centres of consecutive patients (pts) treated with Hyper-CVAD in whom an attempt was made to collect PBSC. The regimen consists of alternating cycles of: (A) cyclophosphamide 300mg/m2 q12hrs for 6 doses d1-3, vincristine 2mg d4 & 11, doxorubicin 50mg/m2 d4 and dexamethasone 40mg daily d1-4 and d11-14; and (B) methotrexate 1g/m2 over 24 hours d1 and ara-C 1–3g/m2 q12hrs for 4 doses d2 & 3. PBSCs were collected on recovery from chemotherapy using G-CSF in a daily dose of 10mcg/kg. Target cell number for optimum engraftment was defined as CD34 ≥5 x106/kg, while the minimum threshold for proceeding to ASCT was CD34 ≥2 x106/kg. Pts were analysed according to the timing of mobilisation. 74 pts were identified: median age 44yrs; 69% male; 53% with initial marrow involvement; diagnoses (ALL n=14, lymphoblastic lymphoma n=7, Burkitt’s/Burkitt-like lymphoma n=8, aggressive NHL n=34, mantle cell lymphoma n=11). 28 pts were mobilized off the back of cycle A, 32 pts off the back of cycle B, and 14pts after other mobilising regimens. Overall 66% and 42% of pts obtained a minimum and optimal PBSC collection, respectively. Only 3 of 17 patients (18%) collected beyond cycle 3B successfully mobilised. Two patients mobilised prior to 3B but receiving alternate mobilising chemotherapy were not analysed. The results of stem cell collection on the 55 remaining patients are shown below. Stem cell collection results following hyper-CVAD chemotherapy Timing of stem cell mobilisation Cycle 1B 2A 2B 3A N 13 21 14 7 Total CD34+ (range) 21.36 (4.2–69.1) 3.41 (0–11.18) 5.1 (0–22.3) 4.6 (1.9–8.6) Day of 1st apheresis 12 (11–13) 13.5 (11–16) 13.5 (12–19) 15 (13–19) % with CD34+≥2 x106/kg All patients 100% 81% 64% 86% Obtained in 1 apheresis 92% 19% 36% 14% % with CD34+≥5 x106/kg All patients 92% 38% 50% 39% Obtained in 1 apheresis 77% 0% 21% 0% Cycle 1B compared to 2A was not significantly better in obtaining a minimum graft (100% vs. 81%, p=0.14), but was superior in terms of total CD34+ yield (21.4 vs. 3.4x106/kg, p 〈 0.001) and in achieving both a minimum (92% vs. 19%, p 〈 0.001) and optimal (77% vs. 0%, p 〈 0.001) PBSC collection with a single apheresis. There were no significant differences in PBSC yields following cycles 2A, 2B and 3A. The dose of ara-C used in cycle B had no effect on the subsequent stem cell yield. Hyper-CVAD is a highly stem cell toxic regimen. The mobilizing efficiency can be significantly improved by collecting PBSC earlier in the treatment course with cycle B appearing to be the superior mobilising arm. Mobilisation following cycle 1B allows the most predictable timing of PBSC collection and provides a significantly better PBSC graft and should be considered in those in whom marrow involvement has cleared.

Abstract: Background: Ocrelizumab is a new humanised anti-CD20 antibody with the potential for enhanced efficacy in non-Hodgkin’s lymphoma (NHL) compared with rituximab due to increased binding affinity for the low-affinity variants of the FcγRIIIa receptor. An open-label, multicentre, dose-escalation study was conducted to evaluate the safety, efficacy, pharmacokinetics and pharmacogenetics of ocrelizumab in patients (pts) with relapsed/refractory follicular NHL following prior rituximab-containing therapy. Methods: A total of 47 pts with a response (complete response [CR], unconfirmed CR [CRu] , partial response [PR]) or stable disease (SD) of ≥6 months’ duration following prior rituximab-containing treatment were enrolled into 3 sequential dose cohorts. Pts received infusions of ocrelizumab q3w at 200 mg/m2 (cohort A), 375 mg/m2 (cohort B) and 750 mg/m2 (cohort C) for up to 8 doses. Response was assessed after 4 doses and after the end of treatment. Results: Fifteen pts were enrolled in cohort A, 16 in cohort B and 16 in cohort C; 60% were male; mean age was 57 years; 78% had stage III/IV disease. At study entry 30%, 50% and 67% had intermediate or high FLIPI score in cohorts A, B and C, respectively. Median number of prior therapies was 2 (range 1–7); time to progression after last rituximab-containing therapy of 〈 12 months: 47% (cohort A), 31% (cohort B) and 62% (cohort C) of pts. The majority of pts reported ≥1 adverse event (AE) [80–100%, cohorts A-C]; most of these were grade 1/2, with only 6 pts experiencing a grade 3 AE and no grade 4 AEs observed. The most common AEs were infusion-related reactions (IRR; 73%, 75% and 69% in cohorts A, B and C, respectively); only one was grade 3. Two pts discontinued treatment due to toxicity (dyspnoea, IRR). A total of 17 pts responded to ocrelizumab for a response rate (RR) of 36% (13% CR/CRu) across all cohorts. RR by cohort was 27% (13% CR/CRu) for A, 50% (25% CR/CRu) for B and 31% (no CR/CRu) for C. In pts relapsing after prior response (CR/PR) to rituximab-containing therapy (n=40), RRs were 23% (15% CR/CRu), 62% (31% CR/CRu) and 33% (no CR/CRu) in cohorts A, B and C, respectively. Of 6 pts with SD after prior rituximab-containing therapy, 1 pt had a PR, 4 pts had SD and 1 pt progressed. Conclusion: Ocrelizumab is well tolerated at doses up to 750 mg/m2 given q3w; AEs consist mainly of grade 1/2 IRRs. Severe IRRs (grade 3/4) following ocrelizumab occur less frequently than with rituximab. In this heavily and rituximab-pretreated pt population, the RR of 36% is encouraging.

Abstract: Abstract 3686 GA101 is a glycoengineered, humanized type II anti-CD20 monoclonal antibody (mAb) anticipated to have superior B-cell-depleting activity to rituximab in vivo on the basis of its enhanced FcR binding and because of the direct cell death induced by type II CD20 mAbs. GA101 has shown significant single-agent activity in Phase I and II studies in patients with FL, and activity in combination with CHOP and fludarabine plus cyclophosphamide in patients with resistant/refractory FL in the first part of this Phase I trial (Radford et al. ASH 2011; abstract 270). This report describes the safety, toxicity, and efficacy of remission induction of GA101 in combination with CHOP or bendamustine in 81 patients aged 〉 18 years with treatment-naïve CD20+ grade 1–3b FL with at least one measurable lesion (longest diameter 〉 1.5 cm by CT scan). All patients received a flat dose of GA101 (1,000 mg on Days 1 and 8 of Cycle 1 and Day 1 of subsequent cycles) combined with either 6–8 cycles of CHOP (every 3 weeks) or 4–6 cycles of bendamustine (90 mg/m2Days 1 and 2 every 4 weeks) on a per center choice basis. Patients achieving complete response (CR) or partial response (PR) were eligible to receive GA101 maintenance therapy (1,000 mg) every 3 months for 2 years or until progression. The primary objective was safety, and secondary objectives included overall response rate (ORR), CR rate, and pharmacokinetics. Response was assessed at the end of induction using International Working Group response criteria; unconfirmed CRs were classified as PRs. 40 patients received G-CHOP and 41 G-bendamustine. Baseline characteristics were similar for both groups: median age 53.5 and 57 years; bone marrow involvement 53% and 49%; bulky disease (≥ 7 cm) 45% and 41%; Median time from diagnosis was only 1.20 months for both groups, high-risk FLIPI status (3–5) 45% and 46%, and intermediate risk (FLIPI 2) 38% and 34%. 38 G-CHOP and 37 G-bendamustine patients completed all cycles of planned induction therapy. Three patients withdrew without any response assessment. In the G-CHOP arm, one withdrawal was due to a GA101-associated infusion-related reaction [IRR] after Cycle 1 and another patient was found to be ineligible and withdrawn after Cycle 1. In the G-bendamustine arm one patient withdrew consent after Cycle 2. Three other patients were withdrawn after interim response assessment, none for safety reasons (insufficient response in the G-bendamustine arm and administrative reasons for two in the G-CHOP arm). The most frequent adverse events were IRRs (all grades: 58% G-CHOP; 59% G-bendamustine; grade 3/4: 5% G-CHOP; 10% G-bendamustine). No Grade 3/4 IRRs occurred after cycle 3. Grade 3/4 neutropenia was reported in 43% of patients in the G-CHOP arm and 29% of patients in the G-bendamustine arm during induction, resulting in delayed delivery of 7.0% and 4.8% of chemotherapy cycles. All delays but one were no longer than 2 weeks. Grade 3/4 infections occurred in 23% of patients receiving G-CHOP and 10% of patients receiving G-bendamustine. Approximately half of these were neutropenic infections or sepsis and all resolved with appropriate management. ORR at the end of the induction period was 95% (38/40) in the G-CHOP arm (CR rate 35%) and 92.7% (38/41) in the G-bendamustine arm (CR rate 39%) (Table). Serum GA101 concentrations increased during the induction period and were similar for both regimens. Mean Cmax was 300–600 μg/mL and Cmin100–300 μg/mL. Following the final administration, a decline in GA101 serum concentration was seen that was similar for the two treatment combinations. In conclusion, efficacy and safety data for GA101 combined with CHOP and bendamustine are encouraging for first-line treatment of patients with FL. Based on these promising results GA101 is now being studied in combination with various chemotherapy regimens in a randomized Phase III study against the standard of care, rituximab-based immunochemotherapy. Patients, n (%) G-CHOP (n = 40) G-bendamustine (n = 41) Efficacy     Overall response 38 (95.0) 38 (92.7)     Complete response* 14 (35.0) 16 (39.0)     Partial response 24 (60.0) 22 (53.7)     Stable disease 0 1 (2.4)     Progressive disease 0 1 (2.4)     Not assessed 2 (5.0) 1 (2.4) Safety     Grade 3/4 IRRs 2 (5.0) 4 (9.8)     Grade 3/4 neutropenia 17 (43) 12 (29)     Grade 3/4 infections 9 (23) 4 (10) * CRu were classified as PR Disclosures: Dyer: Roche: Consultancy, Research Funding. Off Label Use: Obinutuzumab (GA101) in Combination with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) or Bendamustine in Patients with Previously Untreated Follicular Lymphoma (FL). Grigg:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Support of (other) clinical trials and Scientific Advisory Boards Other. Rule:Roche: Consultancy, Research Funding. Lei:Roche: Employment. Wassner-Fritsch:Roche: Employment. Wenger:Roche: Employment. Marlton:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction Midostaurin is the only approved FLT3 inhibitor for combination with intensive induction and consolidation chemotherapy in newly diagnosed patients with FLT3 mutant AML. The FLT3 inhibitor, sorafenib, was investigated in the randomized SORAML trial (Röllig, Lancet Onc 2015), in combination with intensive chemotherapy (IC) for newly diagnosed adults with AML & lt;60 years. A sub-group analysis of 46 patients with FLT3-ITD, indicated a trend for improved overall survival (OS) in the sorafenib (SOR) arm compared to placebo (PBO). Methods The Australasian Leukaemia and Lymphoma Group (ALLG) conducted a randomized phase 2 study [ACTRN12611001112954] in 99 adults aged 18-65 years with newly diagnosed FLT3-ITD positive (allelic ratio (AR) ≥0.05) AML to determine whether addition of SOR to IC would improve event-free survival (EFS). The study was powered to identify a 25% increase in 2-year EFS with SOR. Patients 18-55 yrs received induction with IDAC-3 (idarubicin [IDA] 12 mg/m2 D1-3 and ara-C 1.5 g/m2 BD D1,3,5,7); patients 56-65 received 7+3 (IDA 12 mg/m2 D1-3 and ara-C 100 mg/m2 D1-7 IVI). Patients were randomized 2:1 to SOR or PBO 400 mg BD on days 4-10 of induction and each consolidation cycle. Due to the pharmacokinetic interaction between SOR and azoles, antifungal prophylaxis during induction was with AmBisome 5 mg/kg IV twice weekly. For consolidation, patients 18-55 yrs received 2 cycles of IcE (IDA 9 mg/m2 D1-2, ara-C 100 mg/m2 D1-5 IVI and etoposide 75 mg/m2 D1-5), those 56-65 yrs received 2 cycles of IDAC-2 (IDA 12 mg/m2 D1-2 and ara-C 1g/m2 BD D1,3,5). Maintenance was with SOR/PBO 400 mg bd days 1-28 for 12 cycles. Allogeneic HCT (allo-HCT) was at investigator discretion. SOR/PBO was not continued post allo-HCT. The primary endpoint was EFS without censoring for allo-HCT with events defined as failure to achieve complete remission (CR) or CR with incomplete hematologic recovery (CRi), relapse or death. Pre-specified secondary endpoints included overall response rate (ORR) defined as CR and CRi, tolerability, EFS according to FLT3-ITD AR & lt; or ≥ 0.7 and impact of randomization on allograft outcome. Results Between Jan 2013-May 2018, 18 centers randomized 99 patients to induction with either SOR (n=65) or PBO (n=33); one patient later found to be FLT3-ITD negative was excluded. Patient characteristics are shown in Table 1. Treatment arms were balanced apart from fewer patients in the SOR arm with NPM1 mutant AML. Deliverability of therapy was comparable, with commencement of consolidation in 78% and 79% and maintenance therapy in 32% and 27% in the SOR and PBO arms, respectively. The overall response rate (ORR) was high in both arms; 91% in the SOR (CR 80%, CRi 11%) and 94% in the PBO (CR 70%, CRi 24%) arm. In the SOR arm, 5% achieved partial remission, went off study and were deemed treatment failures. With a median overall follow-up of 25 mo, there was no significant difference in EFS (HR 0.87 95% CI 0.50-1.49; P=0.61)(Fig A) or OS (HR 0.70 95% CI 0.38-1.29; P=0.26)(Fig. B), nor in a sensitivity analysis with censoring at HCT. 2 yr EFS was 47.9% (SOR) vs 45.4% (PBO) and 2-year OS 66.8% (SOR) vs 56.4% (PBO). Hematopoietic cell transplant (HCT) in CR1 was performed in 62% and 58% in the SOR and PBO arms, respectively. For patients in CR1, 2 yr OS post-HCT was 78.5% (SOR) vs 54.2% (PBO)(Fig C). Suggestive of an on-target effect against FLT3-ITD, the impact of SOR on OS appeared greater for patients with higher FLT3-ITD AR ≥0.7 (Fig. D) (Table 2). Only one early death (within 30 days) was recorded in each treatment arm. The frequency of grade 3-4 adverse events (AEs) were similar between the two arms, apart from palmar-plantar rash, reported as drug-related in 15.4% and 6.1% pts in the SOR and PBO arms, respectively. Correlative studies will be reported in a companion abstract. Conclusions SOR did not improve EFS when combined with intensive chemotherapy in adults with newly diagnosed FLT3-ITD AML. Although not powered for significance, SOR showed a trend for improved OS among patients with higher FLT3-ITD AR or receiving HCT in CR1. Further exploration of more potent FLT3 inhibitors in the pre- and post-allograft setting are warranted for patients with newly diagnosed FLT3 mutant AML. Acknowledgements: The ALLG AMLM16 trial was funded through an Australian Government NHMRC grant and a research grant from the Leukaemia Foundation of Australia. Bayer supplied sorafenib and Gilead AmBisome. Disclosures Wei: Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria. Enjeti:Novartis: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; Bayer: Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. D'Rozario:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS/ Celgene: Membership on an entity's Board of Directors or advisory committees. Marlton:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Verner:Janssen Cilag Pty Ltd.: Research Funding. Hahn:Roche: Honoraria; Astra Zeneca: Honoraria. Hiwase:Novartis Australia: Research Funding. Anstee:Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Levis:FujiFilm: Honoraria, Research Funding; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; Menarini: Honoraria; Astellas: Honoraria, Research Funding. Bajel:Abbvie: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Roberts:Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties; Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Sorafenib for FLT3-ITD AML

Abstract: CD123 (IL-3Rα) is a phenotypic marker of putative leukemic stem cells (LSC) in AML (Jordan, Leukemia2000;14:1777). We and others have found that CD34+38− cells from AML patients (pts) express high levels of CD123, in contrast to absence of expression on CD34+38− cells in normal individuals. Binding of CD123 by monoclonal antibody (mAb) 7G3 inhibits IL-3-dependent signalling and proliferation in vitro. In a NOD-SCID xenograft model 7G3 inhibits human AML engraftment, but not normal human hematopoiesis (Lock ASH2007; Abs161). CSL360, a recombinant chimeric IgG1 mAb derived from 7G3, binds the same epitope. CSL360 concentrations ≥ 0.1μg/mL in vitro inhibited 90% AML cell growth in the presence of supraphysiological IL-3 levels. Preclinical toxicology studies with doses up to 100 mg/kg weekly × 4 in cynomolgus monkeys showed no CSL360-related effects in clinical signs, hematology, chemistry, urinalysis, gross pathology or histopathology. A Phase 1 study of safety, pharmacokinetics (PK) and bioactivity of CSL360 in relapsed, refractory or high risk AML began in March 2007. Pts receive 12 weekly iv infusions if not withdrawn early due to treatment-related toxicity or disease progression. Additional treatments may be given to pts who achieve a response. Bone marrow aspirates/trephine samples are obtained at screening, after dose 3 and before doses 5 and 11. More than 180 infusions have been administered to 26 AML pts (21 M, 5 F; 17 de novo, 8 MDS-related, 1 treatment-related AML) in 5 dose level cohorts: 0.1, 0.3, 1.0, 3.0 and 10 mg/kg. There is no intra-patient dose escalation. PK parameters over the dose range, estimated in 19 pts over 7 days after doses 1 and 4, were linear with dose-proportional increases in the AUC and Cmax; dose 1 Cmax ranged from 0.62 – 287.33 μg/mL and dose 4 Cmax from 1.02 – 178.22 μg/mL. CSL360 mean plasma half-life (dose 1, 83 ± 33 h; dose 4, 117 ± 59 h) appears to be independent of dose and treatment number. Dose 1 systemic clearance (0.21 ± 0.16 L/h) and volume of distribution (0.39 ± 0.22 L/kg) were relatively low, consistent with this size IgG. In all pre-treatment samples anti-CSL360 antibody titers were negative, determined by enzyme immunoassay. Anti-CSL360 antibodies were detected post-treatment in 8/12 pts; these antibodies have not been fully quantified or characterised. CSL360 has been well tolerated; a MTD has not been defined. Seven pts received all 12 doses, 13 pts were withdrawn due to progressive disease or investigator’s decision, 3 pts were withdrawn in association with infections, 2 pts withdrew consent, and 1 pt is ongoing. Three serious adverse events have been considered possibly related or related to CSL360: 1 invasive fungal infection (Gr 5), and 2 infusion reactions (Gr 2; hospitalised). Other adverse events are consistent with expectations for the disease population. Of 8 pts in the 3 mg/kg and 10 mg/kg cohorts who are evaluable for response after ≥ 4 doses, 1 complete response (CR) has been observed. A 22 yr old male, de novo FAB M1 cytogenetically normal AML, who had relapsed post-2 allogeneic SCT, achieved a morphologic leukemia free state after 3 doses (3.0 mg/kg) and CR after 12 doses, sustained for & gt; 9 weeks. The pt received 17 doses before withdrawal to treat co-morbidities. Flow cytometry studies with anti-CD123 antibodies demonstrated dose-dependent CSL360 coating of both AML blasts and LSC. Saturation of target antigen on marrow and blood cells was observed 1 day after dosing at 0.3mg/kg, associated with decreased expression of CD123 detected by an antibody to a different epitope. At higher dose levels saturation of CD123 was maintained 7 days post dosing, associated with ongoing reduction in surface CD123 expression. In a representative sample, plasma from a pt treated at 10 mg/kg specifically inhibited IL-3-induced proliferation of AML blasts ex vivo, indicating sufficient circulating concentration of CSL360 to inhibit IL-3 mediated effects in vivo. Effects of CSL360 on proliferation and apoptosis of AML cells in treated patients are being investigated. These preliminary results show anti-CD123 mAb therapy with CSL360 is safe and tolerable; biological effects have been demonstrated; a sustained CR was achieved in 1 advanced, refractory AML pt. The study is continuing, with 20 evaluable patients to be accrued and treated at 10 mg/kg weekly; at this dose level the PK and correlative assays predict that complete blockade of IL-3 signalling through CD123 can be achieved in vivo.

Abstract: Introduction: The BTK inhibitor ibrutinib (IB) is highly active in WM, achieving major responses (CR+VGPR+PR) in approximately 70% of pts. However, VGPR is infrequent, with rates ≤15% in reported series (Treon NEJM 2015, Dimopoulos EHA 2016). BGB-3111 is a potent, highly-specific and irreversible BTK inhibitor, with greater selectivity than IB for BTK vs. other TEC- and HER-family kinases, and superior bioavailability. We previously reported that the recommended phase 2 dose of BGB-3111 is 320mg daily (in single or split dose) in pts with advanced B cell malignancies. This achieves plasma levels equivalent to 6-10 fold that of IB, and 〉 90% continuous inhibition of BTK in lymph node biopsies. We specifically investigated the safety and efficacy of BGB-3111 in pts with WM in an expansion cohort of the initial Phase 1 trial. Reported here are updated results of this study, including data from WM specific expansion cohorts. Aims: To define the safety profile, and clinical activity of BGB-3111 in pts with WM. Methods: These results are from a pre-specified a component of a Phase 1 study (Part 1: dose escalation [DEsc] in pts with R/R B cell malignancies, Part 2: disease-specific dose expansion cohorts [EC] at the recommended Phase 2 dose that included patients with relapsed / refractory or previously untreated WM). Adverse events (AEs) were reported per CTCAE v4.03. Responses were determined according to the modified Sixth International Workshop on WM (IWWM) criteria. The data cut-off is 10 June 2016. Results: As of 10 June 2016, 31 pts with WM have been enrolled; 6 pts in DEsc (40mg [n=2], 80mg [n=2] , 160mg QD [n=1], and 320mg QD [n=1] ), and 25 in the WM EC (160mg BID [n=18], 320mg QD [n=7] ). Three pts in DEsc were increased to 160mg QD after analysis of DEsc data, as allowed by protocol. Twenty-four pts are included in this analysis; 5 pts were excluded because of short ( 〈 60 day) follow-up for safety and efficacy, and 2 pts accrued at a single site were excluded because of insufficient documentation at baseline. Patient demographics, disease characteristics, and prior treatment history are summarized in Table 1. BGB-3111 was well tolerated with 71% reporting no drug related AE 〉 Gr 1 severity within the first 12 weeks of therapy. The most frequent AEs ( 〉 20%) of any attribution (all Gr 1/2) were upper respiratory infection (25%), diarrhea (25%), and nausea (21%). There were 2 SAEs assessed as possibly related to BGB-3111 (Gr 2 atrial fibrillation, Gr 3 cryptococcal meningitis); in both cases, BGB-3111 was temporarily held but safely resumed. In total, 2 pts developed AF (one Gr 1, one Gr 2). No serious hemorrhage (≥Gr 3 or CNS hemorrhage of any grade) was reported. After a median follow-up of 7.6 months (2-21 months), the response rate was 92% (22/24). The major response rate was 83% (20/24), with VGPR ( 〉 90% reduction in IgM and reduction in extramedullary disease) in 33% (8/24) and PR (50-90% reduction in IgM and reduction in extramedullary disease) in 50% (12/24) pts. Pts with WM refractory to their last therapy were equally responsive: major response 77% [10/13], VGPR 31% [4/13] , PR 46% [6/13]. Median time to initial response and major response were 29 days and 34 days, respectively. IgM decreased from a median of 29.9g/l at baseline to 3.0g/l; hemoglobin increased from a median of 10.1 g/dl at baseline to 13.5g/l. Two of 3 pts who had a dose increase after reaching a stable IgM plateau had further falls in IgM levels after dose escalation. Kinetics of IgM and hemoglobin response are presented in Figure 1. Lymphadenopathy was present in 8 pts at baseline; serial CT demonstrated reduction or resolution in all 8 pts (27%-100% reduction in SPD). Only one patient discontinued BGB-3111, due to exacerbation of pre-existing bronchiectasis while in VGPR. There have been no cases of disease progression. Analysis of response by genomic characteristics (including MYD88 and CXCR4 mutational status) is ongoing. Conclusions: BGB-3111 is well-tolerated and highly active in WM. The depth and quality of responses, as reflected by the VGPR rate of 33%, warrant a randomized comparison against ibrutinib in pts with WM. Table 1. Table 1. Figure 1. Figure 1. Disclosures Tam: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Honoraria, Research Funding. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Simpson:Amgen Pharmaceuticals: Research Funding; Celgene, Roche, Janssen: Honoraria. Anderson:Walter and Eliza Hall Institute of Medical Research: Other: Walter and Eliza Hall Institute of Medical Research receives milestone payments for the development of venetoclax. Kirschbaum:Beigene: Employment. Wang:Beigene: Employment. Xue:Beigene: Employment. Yang:BeiGene: Employment. Hedrick:Beigene: Employment. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roberts:AbbVie: Research Funding; Servier: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax.

Abstract: Abstract 5119 Introduction Diffuse Large B cell Lymphoma (DLBCL) is a clinically and biologically heterogeneous lymphoid malignancy, where complete response is achieved in up to 60% of patients, though over half of all patients relapse (Hunt and Reichard, 2007). The prognostic significance of the expression of FOXP1 transcription factor in DLBCL has been highly controversial with some studies describing immunohistochemical FOXP1 expression as a poor prognostic marker (Banham et. all. 2005). Recent transcript analysis has identified over 10 FOXP1 isoforms where some exhibit COOH- or NH3- truncations and also the absence of regulatory domains. These truncated isoforms are highly expressed in ABC-DLBCL (Brown et. al. 2008) and it is suggested that truncated isoforms may aberrantly regulate FOXP1 target genes. Although there have been many studies debating the prognostic significance of FOXP1 overexpression in DLBCL, there has been little examination of the function of FOXP1 in DLBCL, specifically the genes targeted by FOXP1, and how the function of FOXP1 isoforms may contribute to a more aggressive phenotype. Methods Expression constructs for 4 FOXP1 isoforms (isoforms 1, 2, 3 and 8) were kindly provided by Dr. Philip Brown and Dr. Alison Banham. Stable cell lines were established by transfecting the BJAB cell line with either FOXP1 isoform 1 or the empty pBKCMV construct, and selection with G418 antibiotic. Total RNA was extracted from both cell lines and 4 DLBCL tumours (with low to high FOXP1 expression), and gene expression was analysed using Illumina HT12v4 microarray. Genes with 〉 2-fold changes in expression between pBKCMV and Isoform 1 stable cell line were investigated. VisANT analysis and Gene set enrichment was performed on differentially expressed genes and candidates were validated by qRT-PCR. Promoter analysis using MatInspector revealed forkhead-binding sites in the promoter region of candidate genes, and dual luciferase reporter gene assays were performed to ascertain promoter regulation by FOXP1 isoforms. Western blot was also performed to validate translational changes in expression. Results In the gene expression microarray analysis of FOXP1 isoform 1 expression compared to baseline levels, 271 genes were identified with 〉 2-fold differential expression. High versus low FOXP1 expressing DLBCL patients were also compared, where it was found that 2472 genes were differentially expressed over the 2-fold level. Significantly, comparison of differentially expressed genes in both the cell line and patient samples revealed all 271 genes differentially expressed in the cell line overlapped with the patient genes, indicating these results are translatable to FOXP1 function in DLBCL tumours. Pathway analysis was performed on the differentially expressed genes, and unexpectedly there were no significant enrichment of curated pathways. Alternatively visANT was used to examine interactive networks of the 271 candidate genes, and an integrative analysis using the FOXP1 microarray expression data was used to enrich the interactions. This analysis revealed critical interactions that could not be revealed by pathway analysis, and also identified genes that are likely FOXP1 targets. The promoter regions of 5 genes were investigated using reporter gene assays, and FOXP1 isoforms 3 and 8 were found to be significantly stronger transcriptional repressors compared to isoforms 1 and 2. For example, one of the genes identified, heterogeneous nuclear ribonucleoprotein U (HNRNPU) was highly expressed in the presence of isoform 1, however in the presence of isoform 3 was greatly downregulated. Although this gene has not previously been associated with DLBCL, HNRNPU is a potent regulator of snRNP's thereby having global effects on mRNA production and protein synthesis (Xiao et. al. 2012 Cell Vol. 45(5) 656–668). We are currently investigating the biological significance of other novel FOXP1 target genes, and how the truncated isoforms are involved in the differential regulation of these genes. Conclusion We have identified 271 genes that are differentially expressed in both a cell line model and DLBCL patient tissues with high versus low FOXP1 expression. These are novel genes in DLBCL pathogenesis that also show differential expression in the presence of truncated isoforms, indicating truncated isoforms may have aberrant functions and may contribute to a more pathogenic phenotype. Disclosures: No relevant conflicts of interest to declare.

Abstract: The optimal reduction of IST in renal transplant patients with PTLD is uncertain. As chemotherapy used to treat PTLD is inherently immunosuppressive, IST may be able to be stopped during this time without compromising graft function. Subsequent long-term reduction of IST is important to reduce PTLD relapse, but may increase long-term risk of graft rejection. Methods We performed a retrospective matched cohort study of adult renal transplant patients where IST was ceased during chemotherapy and then resumed at lower dose (calcineurin inhibitor at 50%, prednisolone 〈 6mg daily, no third agent). Outcomes were compared to renal transplant patients without PTLD, matched for creatinine at the equivalent time post-transplant that PTLD was diagnosed in the cases, as well as age, gender, year of transplant and age at transplant. The primary endpoint of time to renal deterioration, defined as the time from PTLD diagnosis (cases) or study entry (controls) to a 25% increase in creatinine, was analysed using competing risk survival analyses. Additional endpoints were time to renal allograft failure requiring dialysis or re-transplant and overall survival. Results 24 cases were identified: median age at PTLD diagnosis 45yrs; 75% male; median time to onset of PTLD post-transplant was 9 years. 22 cases received CHOP-like chemotherapy and 2 received primary CNS lymphoma protocols, 7 received concurrent rituximab and 4 had consolidation radiation therapy. 88% attained complete remission. Five patients have relapsed. The 5 yr overall survival for the cases was 71% with a median follow-up of survivors of 11.9 years. The 24 PTLD cases were compared to 84 well matched controls. There were 11 deaths in the cases and 5 in the controls. Three cases recommenced dialysis, compared to 3 controls (HR 2.5, p=0.27). The 5 yr rate of 25% increase in creatinine was 36% in cases and 20% in controls (HR 1.8, p=0.098). Of the 11 cases with ≥25% increase in creatinine, only 1 of these occurred within 6 months of IST cessation in the setting of rapidly progressive PTLD and early death. Only 2 of these 11 cases received rituximab. In contrast 5 of the 7 patients given rituximab did not develop a ≥25% deterioration in renal function. Conclusions IST can be safely ceased during chemotherapy for PTLD in renal transplant patients. Whilst long-term reduction in IST is necessary to reduce PTLD relapse, this is associated with a trend to increased risk of chronic allograft nephropathy. Prospective trials are needed to address the ideal reduction of IST in PTLD. Disclosures: No relevant conflicts of interest to declare.