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Introduction Bruton's Tyrosine Kinase (BTK) plays a critical role in B-cell receptor (BCR) signaling, which mediates B-cell proliferation, migration, and adhesion (Rickert, 2013; Aalipour, 2013; Choe, 2016). The BCR pathway is an established therapeutic target in multiple subtypes of non-Hodgkin's lymphoma (NHL). BGB-3111 is a potent, highly specific, and irreversible BTK inhibitor, with greater selectivity for BTK vs other TEC- and EGFR-family kinases and demonstrates favorable pharmacokinetic and pharmacodynamic properties. We have previously shown complete and sustained BTK occupancy in both peripheral blood mononuclear cells (PBMCs) and lymph nodes (LN) in patients (pts) treated at the 160 mg BID dose in a phase 1 trial (Tam et al. ASH 2016). A recent update of clinical data suggests that complete and sustained BTK occupancy is associated with durable responses in pts with CLL/SLL and Waldenstrom's macroglobulinemia (Seymour et al. ICML 2017; Trotman et al. ICML 2017). Here, we present early safety and efficacy data in pts with other NHL subtypes: relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Methods This is an open-label, multicenter, phase 1b study of BGB-3111 in pts with B-cell malignancies. Dose escalation included pts with R/R B-cell malignancies, while the expansion phase enrolled disease-specific cohorts at the recommended phase 2 dose (320 mg/d, given once daily [QD] or split as 160 mg twice-daily [BID]). Response was assessed per ICML criteria (Cheson 2014). Results As of 18 May 2017, 75 pts with NHL were enrolled, including 23 DLBCL, 31 MCL, 14 FL, and 7 MZL pts. Patient characteristics are shown in the Table. With the exception of 1 pt with treatment-naive MCL, all pts had R/R disease. Safety: Median follow - up was 7 months (range, 0.3-31.9). The most frequent adverse events (AEs) of any cause were contusion (22.7%), upper respiratory tract infe

OBJECTIVES: Core-binding factor acute myeloid leukaemia (CBF AML) defined by t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) has a favourable prognosis; however, 30%-40% of patients still relapse after chemotherapy. We sought to evaluate the risk factors for relapse in a de novo CBF AML cohort. PATIENTS/MATERIALS/METHODS: A retrospective review of patients from four Australian tertiary centres from 2001 to 2012, comprising 40 t(8;21) and 30 inv(16) AMLs. RESULTS: Multivariate analysis identified age (P = .032) and white cell count (WCC)>40 (P = .025) as significant predictors for inferior OS and relapse, respectively. Relapse risk was higher in the inv(16) group vs the t(8;21) group (57% vs 18%, HR 4.31, 95% CI: 1.78-10.42, P = .001). Induction therapy had no bearing on OS or relapse-free survival (RFS); however, consolidation treatment with >3 cycles of intermediate-/high-dose cytarabine improved OS (P = .035) and RFS (P = .063). Five patients demonstrated post-treatment stable q PCR positivity without relapse. CONCLUSIONS: >3 consolidation cycles of intermediate-/high-dose cytarabine improves patient outcomes Age and inv(16) CBF AML subtype are predictors of inferior OS and RFS, respectively. Stable low-level MRD by qPCR does not predict relapse Similar OS in the inv(16) cohort compared to the t(8;21) cohort, despite a higher relapse rate, confirms salvageability of relapsed disease.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of T-cell lymphoma that occurs after implantation of breast prostheses. We performed comprehensive next generation sequencing based genomic characterization of 11 cases of BIA-ALCL including sequence variant detection on 180 genes frequently mutated in haematological malignancy, genome-wide copy number assessment, structural variant detection involving the T-cell receptor loci and TRB deep-sequencing. We observed sequence variants leading to JAK/STAT activation in 10 out of 11 patients. We also observed germline TP53 mutations in two cases. In addition we detected a recurrent copy number loss involving RPL5 as well as copy number amplifications involving TNFRSF11A [RANK] (in 2 cases), MYC, P2RX7, TMEM119 and PDGFRA. In summary, our comprehensive genomic characterisation of 11 cases of BIA-ALCL has provided insight into potential pathobiological mechanisms (JAK/STAT, MYC and TP53) as well as identifying targets for future therapeutic intervention (TNFRSF11A, PDGFRA) in this rare entity.

To aid the Office of Evaluation and Dissemination (OED) and the Office of Indian Education in development of a Request for Proposal to conduct an impact evaluation of the Indian Education Act, Part A, investigators used findings of the OED-sponsored evaluation of the Indian Education Act and observations of the principal investigator to establish design implications for such an impact evaluation. The three models tested in the evaluation study were the Glass model, for reading and math scores; the MANOVA model, involving the remedial reading, remedial math, and self-concept objectives; and the ANCOVA models, involving achievement test results. No differences were obtained in ANCOVA tests. The feasibility of impact evaluation in reading and self-concept areas appears generally favorable, but evaluation in math is not favorable. Recommendations for the six major design categories of conceptualization, sampling, testing, data collection, design, and analysis, include the following: (1) obtain near equivalent Indian control groups for impact evaluation model and address the most frequently obtained objectives; (2) study a larger sample and use large subsamples; (3) control testing in five specific ways and expand the definition of impact to focus on primary program emphasis; (4) collect data via site visits; and (5) consider pretest and post-test control group design. (SB)

The purposes of the national evaluation survey of the Indian Education Act (IEA) Title IV, Part A, projects were to evaluate the implementation of Part A objectives, conduct a feasibility study to determine evaluation criteria for future impact studies, and identify non-fiscal obstacles to Part A projects. Exhaustive preliminary research resulted in development of evaluation strategy, sampling framework, survey management, and data analysis plans. The final sample of 223 local education agencies (LEA's) allowed for nationwide estimates for all funded urban LEA's, rural high-density Indian LEA's and rural low-density LEA's. Among the 41 conclusions (reflective of the findings) were that: parents rated programs in areas of overcoming academic difficulties from moderately to very effective; the major areas of need were Native American heritage, remedial reading, and remedial general academic areas; and lack of motivation, deficient early education, adverse home environment, and ethnic discrimination were factors contributing to the educational problems of Indian children. Ten recommendations included: examine the use of a minimum level of funding; align proposal, funding, and project implementation cycles more closely; and continue to require local evaluation. (SB)

Introduction: BTK inhibitors have been shown to be highly active in WM, particularly WM harboring a MYD88 mutation (MYD88MUT). BGB-3111 is a potent, specific, and irreversible BTK inhibitor. In primary patient (pt) samples, BGB-3111 demonstrated profound BTK inhibition with minimal inhibition of off-target kinases such as EGFR, ITK, JAK3, HER2, and TEC. In phase 1 testing, high plasma concentrations were safely achieved, resulting in complete, sustained BTK inhibition in blood and lymph nodes. Method(s): This was an open-label, multicenter, dose-finding phase 1 study of BGB-3111 in pts with B-cell malignancies, with indicationspecific expansion cohorts. Here, updated safety and efficacy in WM are reported. Result(s): As of 31 Dec 2016, 46 pts with WM were enrolled: median 2 prior therapies (range 0-8), median follow-up 8.2 months (1.4-28), 46 evaluable for safety, 41 for efficacy; 5 non-evaluable pts had either baseline IgM <500 mg/dL (n = 3) recent plasmapheresis (n = 1) or <12 weeks' follow-up (n = 1). The most frequent adverse events (>=20%, all grade [Gr] 1 or 2) were upper respiratory infection (33%), contusion (28%), and constipation (22%). There were 3 treatment-related serious adverse events (Gr 2 atrial fibrillation [AF], Gr 2 headache, Gr 3 cryptococcal meningitis); in all 3 cases, BGB-3111 was withheld and safely resumed. 3 pts developed AF (one Gr 1, two Gr 2), and 1 developed Gr 3 diarrhea. No serious hemorrhage was reported. The objective response rate was 93% (38/41), with a major response rate of 78% (32/41): VGPR in 39% (16/41) and PR in 39% (16/41). Median time to response was 28 days. Response by MYD88 and CXCR4 mutational status, in pts with known status (n = 32) is shown in Table 1. In pts with hemoglobin <10 g/dL at baseline, hemoglobin increased from a median of 8.8 g/dL (7.1-9.8) to 13.8 g/dL (10.7-16.1). IgM decreased from a median of 32.5 g/ L (6-88.5) at baseline to 5.4 g/L (0.4-47.8).16 pts with baseline lymphadenopathy had a median reduc

Objectives: To assess the effect of iron chelation therapy with deferasirox on cardiac iron and function in patients with transfusion-dependent thalassemia major, sickle cell disease (SCD), and myelodysplastic syndromes (MDS). Method(s): This phase IV, single-arm, open-label study over 53 wk evaluated the change in cardiac and liver iron load with deferasirox (up to 40 mg/kg/d), measured by magnetic resonance imaging (MRI). Result(s): Cardiac iron load (myocardial T2*) significantly improved (P = 0.002) overall (n = 46; n = 36 thalassemia major, n = 4 SCD, n = 6 MDS). Results were significant for patients with normal and moderate baseline cardiac iron (P = 0.017 and P = 0.015, respectively), but not in the five patients with severe cardiac iron load. Liver iron concentration (LIC) significantly decreased overall [mean LIC 10.4 to 8.2 mg Fe/g dry tissue (dw); P = 0.024], particularly in those with baseline LIC >7 mg Fe/g dw (19.9 to 15.6 mg Fe/g dw; P = 0.002). Furthermore, myocardial T2* significantly increased in patients with LIC <7 mg Fe/g dw, but not in those with a higher LIC. Safety was consistent with previous reports. Conclusion(s): Once-daily deferasirox over 1 yr significantly increased myocardial T2* and reduced LIC. This confirms that single-agent deferasirox is effective in the management of cardiac iron, especially for patients with myocardial T2* >10 ms (Clinicaltrials.gov identifier: NCT00673608).Copyright © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Introduction: BGB-3111 is a potent, highly specific, and irreversible Bruton tyrosine kinase (BTK) inhibitor, with greater selectivity for BTK vs other TEC- and EGFR-family kinases and favorable pharmacokinetic and pharmacodynamic properties. BGB-3111 was shown to achieve complete, continuous BTK occupancy in peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL and Waldenstrom macroglobulinemia. Here, updated preliminary safety and activity data in relapsed/refractory (R/R) and treatment-naive (TN) pts with CLL/ SLL are reported. Method(s): This is an open-label, multicenter, phase 1b study of BGB-3111 in pts with B-cell malignancies. Pts with R/R CLL/SLL were included in dose escalation, and both TN and R/R CLL/SLL pts were included in expansion cohorts at the recommended phase 2 dose (320 mg/d, given once daily [QD] or split as a twice-daily [BID] dose). Adverse events (AEs) are reported per Common Terminology Criteria for AEs version 4.03, and response per the modified iwCLL criteria (Hallek 2008, Cheson 2012 clarification for novel therapies). Result(s): As of 15 Dec 2016, 68 pts with CLL/SLL (50 R/R and 18 TN) were enrolled: 4 pts in dose escalation and 64 in cohort expansion at doses of 160 mg QD (n = 3), 160 mg BID (n = 25), and 320 mg QD (n = 40). Patient characteristics are shown in Table 1. Safety: Median follow-up was 7.2 (range, 0-23.3) months. The most frequent AEs of any cause were bruising (35%) and petechiae (11%), upper respiratory tract infection (28%), fatigue (25%), cough (22%), and diarrhea (21%). Four serious AEs related to BGB-3111 were seen in 3 pts: grade (Gr) 2 cardiac failure, Gr 2 pleural effusion, Gr 3 purpura, and Gr 3 pneumonia. The case of Gr 3 purpura (subcutaneous hemorrhage) was the only major bleeding event reported. Atrial fibrillation (Gr 3) occurred in 1 pt. One pt discontinued BGB-3111 for an AE (pleural effusion). Activity: of the 54 pts evaluable

Patients with chronic lymphocytic leukaemia (CLL) are generally older, with many considered 'unfit' for fludarabine-cyclophosphamide-rituximab therapy. In these patients, the combination of obinutuzumab-chlorambucil may be an appropriate therapeutic choice. Obinutuzumab-chlorambucil has been demonstrated to improve overall survival rates compared to chlorambucil alone and to improve progression-free survival and overall response rates compared to rituximab-chlorambucil. This combination can lead to certain toxicities that need to be addressed through appropriate patient selection, pre-medication and management. In this paper, we discuss evidence-based and author-recommended practical management of first-line CLL patients receiving obinutuzumab-chlorambucil.Copyright © 2017 Royal Australasian College of Physicians

OBJECTIVES: To assess the effect of iron chelation therapy with deferasirox on cardiac iron and function in patients with transfusion-dependent thalassemia major, sickle cell disease (SCD), and myelodysplastic syndromes (MDS). METHODS: This phase IV, single-arm, open-label study over 53 wk evaluated the change in cardiac and liver iron load with deferasirox (up to 40 mg/kg/d), measured by magnetic resonance imaging (MRI). RESULTS: Cardiac iron load (myocardial T2*) significantly improved (P = 0.002) overall (n = 46; n = 36 thalassemia major, n = 4 SCD, n = 6 MDS). Results were significant for patients with normal and moderate baseline cardiac iron (P = 0.017 and P = 0.015, respectively), but not in the five patients with severe cardiac iron load. Liver iron concentration (LIC) significantly decreased overall [mean LIC 10.4 to 8.2 mg Fe/g dry tissue (dw); P = 0.024], particularly in those with baseline LIC >7 mg Fe/g dw (19.9 to 15.6 mg Fe/g dw; P = 0.002). Furthermore, myocardial T2* significantly increased in patients with LIC <7 mg Fe/g dw, but not in those with a higher LIC. Safety was consistent with previous reports. CONCLUSIONS: Once-daily deferasirox over 1 yr significantly increased myocardial T2* and reduced LIC. This confirms that single-agent deferasirox is effective in the management of cardiac iron, especially for patients with myocardial T2* >10 ms (Clinicaltrials.gov identifier: NCT00673608).

Patients with chronic lymphocytic leukaemia (CLL) are generally older, with many considered 'unfit' for fludarabine-cyclophosphamide-rituximab therapy. In these patients, the combination of obinutuzumab-chlorambucil may be an appropriate therapeutic choice. Obinutuzumab-chlorambucil has been demonstrated to improve overall survival rates compared to chlorambucil alone and to improve progression-free survival and overall response rates compared to rituximab-chlorambucil. This combination can lead to certain toxicities that need to be addressed through appropriate patient selection, pre-medication and management. In this paper, we discuss evidence-based and author-recommended practical management of first-line CLL patients receiving obinutuzumab-chlorambucil.

Abstract Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) rece

BACKGROUND: A high level of support for tissue banking has been identified amongst both the general public and patients. However, much debate remains about the regulatory framework of tissue banks. OBJECTIVE: This study explored the views of haematological cancer patients regarding tissue banking and how tissue banks should operate. METHODS: Haematological cancer patients from three outpatient clinics in Australia completed a questionnaire examining their preferences for tissue banking as well as items about their sociodemographic characteristics, disease and treatment history. RESULTS: The majority of participants (95%) reported being willing to allow their leftover tissue to be used for medical research. Three quarters (76%) supported the idea of their medical record being linked to their tissue sample, and 77% preferred a blanket (one-off) consent model for future research use of their tissue sample. Only 57 (27%) participants had been asked to give a tissue sample for research, 98% of whom gave permission. CONCLUSION: The majority of haematological cancer patients are willing to donate their leftover tissue to a tissue bank and have their medical records linked to tissue samples and prefer a one-off consent process. These novel data from potential donors inform the debate about how tissue banks might operate. FUNDING: Strategic Research Partnership Grant from the Cancer Council NSW to the Newcastle Cancer Control Collaborative (New-3C) and infrastructure funding from the Hunter Medical Research Institute (HMRI). A.W. is supported by an Australian Research Council DECRA fellowship (DE150101262). T.C.M. was supported by a Leukaemia Foundation of Queensland Post-Doctoral Fellowship. A.B. is supported by National Health and Medical Research Council (APP1073317) and Cancer Institute NSW (13/ECF/1-37) Early Career Fellowships.

The efficacy of a fixed-dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 x 109/l and <=50 x 109/l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed-up on weeks 1-8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 x 109/l) or partial response (PR; platelet count >50 x 109/l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 x 109/l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m2 four-dose schedule in relapsed/chronic ITP.Copyright © 2014 John Wiley & Sons Ltd.

Background. Cardiac failure is the leading cause of death in patients with thalassemia major. However, the introduction of new monitoring techniques, such as cardiac iron Magnetic Resonance Imaging (MRI) may lead to the improvement of patient care and prolong survival. The examination of the effect of iron chelators such as deferasirox on cardiac iron reduction is crucial in the development of treatment protocols, while the clinical consequences of cardiac iron accumulation in myelodysplastic syndromes (MDS) is still controversial. Aims. The primary objective of this study is to investigate the effect of single agent deferasirox on cardiac iron levels and cardiac function in a cohort of patients receiving regular red blood cell transfusions. Methods. Patients with transfusional siderosis were enrolled in this study and received deferasirox up to 40 mg/kg/day for 53 weeks. The primary endpoint was to investigate the change in cardiac T2* at 53 weeks compared to baseline (power and sample size calculation based on previously published literature). Secondary efficacy endpoints included change in left ventricular ejection fraction (LVEF), liver iron concentration (LIC) by R2-MRI and serum ferritin. All analyses were performed for all subjects in the full analysis population that included patients with hemoglobinopathies and MDS. Informed consent was obtained from all patients. Results. Results were available for 40 patients with hemoglobinopathies (36 thalassemia major, 4 sickle cell disease) and 6 patients with MDS (inferential statistics, all 46 patients with baseline and post-baseline cardiac T2* values). An overall increase in cardiac T2* from 21.9 to 24.1 ms was observed (10% increase, 95% CI=4 to 16%, P=0.002). Further analysis was performed based on T2* baseline values: 5-10 ms, no significant change (n=5; 7.3 to 7.6 ms; P=0.6); 10-20 ms, improvement of 18% (n=9 from 13.2 to 15.5 ms; P=0.015); >20 ms, increase of 9% (n=32; 30 to 32.7 ms; P=0.017). Descriptive sta

Summary: Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B-cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open-label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty-seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression-free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.Copyright © 2014 John Wiley & Sons Ltd.