Key Points Proteasome inhibition has pleiotropic immunomodulatory properties and is cytotoxic to antibody-producing B lymphocytes and plasma cells. Bortezomib yields high response rates in antibody-mediated autoimmune hematological diseases refractory to conventional immunosuppression.

Key Points• Prescribing appropriately for age and cardiovascular risk is likely to result in minimal permanent toxicity-related dasatinib cessation.• CML patients on dasatinib with pleural effusion are more likely to have achieved MR4.5 after 6-month therapy than those without effusion.Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation.Age and dose were risk factors for pleural effusion (P , .01 and .047, respectively).Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced (P 5 .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions (P 5 .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.

Introduction : BGB-3111 is a potent, highly specific and irreversible Bruton tyrosine kinase (BTK) inhibitor, with greater selectivity than ibrutinib (IB) for BTK vs. other TEC- and HER-family kinases. We previously reported that BGB-3111 320mg daily (the RP2D, given as a single or split dose) achieved plasma concentrations 6- to10-fold higher than that of IB 560mg QD. Complete BTK occupancy in peripheral blood mononuclear cells (PBMCs) was observed in all pts treated in the dose-escalation (DEsc) component of the Phase 1 trial, and preliminary data suggested that >90% blockade was achievable in lymph nodes (LN). We now report the results of BTK occupancy analyses in LN specimens from a dedicated pharmacodynamics (PD) cohort and update safety and efficacy in patients with CLL/SLL. Aims: (1)To determine BTK occupancy in LN samples from pts receiving either a daily or twice-daily regimen; and (2) to define the safety profile and activity of BGB-3111 in pts with relapsed/refractory (R/R) or previously untreated CLL/SLL. Methods: This Phase 1 trial included a DEsc component in pts with R/R B-cell malignancies, and disease-specific expansion cohorts (ECs), including CLL/SLL, at the RP2D (320mg daily, given either QD or as a split BID dose). Additionally, in a PD cohort, pts with R/R B-cell malignancies were assigned to BGB-3111 160mg BID vs 320mg QD, with paired LN biopsies at baseline and at day 3 (pre-dose), in order to determine BTK occupancy in LN at the time of trough drug exposure. Adverse events (AEs) are reported per CTCAE v4.03, and response according to the 2012 clarification of the International Workshop on CLL criteria (for CLL pts) or the 2014 Lugano Classification (for SLL pts). BTK occupancy was determined by competitive fluorescent probe assay. The data cut-off for this report was 10 June 2016. Results: BTK Occupancy: 30 pts were evaluated for LN BTK occupancy (CLL, n=9; DLBCL, n=3; FL, n=5; MCL, n=6; MZL, n=3; WM, n=4), 23 pts were enrolled in the PD cohort; 7 patients in other ECs (160mg BID) consented to optional paired LN biopsies. BTK occupancy in LN by dose/schedule is shown in Figure 1. Median occupancy was 99.5% (160mg BID, n=18) vs 94.4% (320mg QD, n=12) (p=0.002, Wilcoxon). The proportion of pts with >90% occupancy was 94% (160mg BID) vs 58% (320mg QD) (p=0.027, Fisher exact). Occupancy did not appear to differ amongst histologic subtypes. CLL/SLL Safety and Activity: As of 10 Jun 2016, 45 pts with CLL (n=42) or SLL (n=3) have been enrolled: 8 pts in DEsc (80mg QD [n=1], 160mg QD [n=2], 160mg BID [n=2], and 320mg QD [n=3]), and 37 in either the PD cohort or CLL/SLL EC (160mg BID, n=19; 320mg QD, n=18). 29 CLL/SLL pts are included in this analysis; 11 pts were excluded because of short (<12 weeks) follow-up, and 5 pts accrued at a single study site were excluded because of insufficient study documentation at baseline. Demographic and disease characteristics are shown in Table 1. BGB-3111 was well tolerated with 69% subjects reporting no drug related AE >Gr 1 severity within the first 12 weeks of therapy. The most frequent AEs of any attribution were petechiae/ bruising (38%), upper respiratory tract infection (31%, all Gr 1/2), diarrhea (28%, all Gr 1/2), fatigue (24%, all Gr 1/2), and cough (21%, all Gr 1/2). Three SAEs were assessed as possibly related to BGB-3111 (Gr 2 cardiac failure, Gr 2 pleural effusion and Gr 3 purpura, all n=1). The case of Gr 3 purpura was the only major bleeding event reported. Atrial fibrillation (Gr 2) occurred in one pt. Three pts had temporary dose interruption for AE, and one pt discontinued BGB-3111 for AE. After a median follow-up of 7.5 months (2.9-17.3 months), the response rate is 90% (26/29), with PR in 79% (23/29) and, PR-L in 10% (3/29), SD in 7% (2/29), and non-evaluable response in one pt who discontinued treatment prior to week 12. No instances of disease progression or Richter transformation have occurred. Conclusions: BGB-3111 is well-tolerated and highly active in R/R CLL/SLL. While trough BTK occupancy in lymph nodes was robust with either 320mg QD or 160mg BID dosing, complete and continuous occupancy (median 99.5%) was more frequently achieved with the 160mg PO BID regimen. Late stage clinical trials will determine if the optimized BTK occupancy with this regimen translates into improvements in disease control and reduced drug resistance. Figure. Figure. Disclosures Tam: janssen: Honoraria, Research Funding; 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. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Gottlieb:Indee: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Simpson:Celgene, Roche, Janssen: Honoraria; Amgen Pharmaceuticals: Research Funding. 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:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roberts:Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; Servier: Research Funding.

Key Points• In contrast to other AEs, there is a high risk of recurrent vascular AEs with continuing nilotinib therapy for CML.Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinibassociated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%).VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years.Multivariate analysis identified age (P 5 .022) and dyslipidemia (P 5 .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P 5 .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.Nilotinib has a unique adverse effect (AE) profile, including both hematological and nonhematological AEs. 2 Five-year follow-up of phase 3 data documented grade 3 to 4 AEs of any kind in 61% and 72% of

The role of cytarabine-based induction and autologous stem cell transplantation (ASCT) in front-line treatment of younger patients with mantle cell lymphoma (MCL) is well established, however the utility of intensive approaches in older patients remains unclear. This retrospective study compared first line treatment outcomes in patients aged 60 years or more, treated at six tertiary centres between 2000–2015. 70 patients included had a median age of 69 (60–91) and most (94%) demonstrated advanced stage disease. Treatment regimens included: R-CHOP-like (n = 39), alternating R-CHOP/R-DHAC (n = 10), R-HyperCVAD/R-MA (n = 7), R-CHOP/Cytarabine (Nordic Protocol) (n = 10) and other (n = 4). 16 patients underwent an ASCT. The median follow-up for surviving patients was 37 months. Compared to R-CHOP-like therapies, cytarabine-based regimens were associated with an improved overall response rate (ORR) of 70% vs 33% (p < 0.001) and overall survival (OS) (HR 0.541, [0.292–1.001], p = 0.05). No difference in efficacy between different cytarabine-based regimens was detected, but R-HyperCVAD/R-MA was associated with increased hospitalisation and transfusion requirements. Patients undergoing ASCT demonstrated an improved median OS (HR 0.108 [0.015–0.796], p = 0.029) but were significantly younger. These results reaffirm the use of cytarabine in MCL for selected patients aged over 60. Such regimens should be strongly considered for this population in frontline therapy.