Amgen Australia Research Articles

Safety and Activity of the Highly Specific BTK Inhibitor BGB-3111 in Patients with Indolent and Aggressive Non Hodgkin's Lymphoma

Safety and Activity of the Highly Specific BTK Inhibitor BGB-3111 in Patients with Indolent and Aggressive Non Hodgkin's Lymphoma

Effect of Rituximab in Primary Central Nervous System Lymphoma - results of the Randomized Phase III HOVON 105/ALLG NHL 24 Study

Introduction: the effect of rituximab on response rates and survival in Primary Central Nervous System Lymphoma (PCNSL) has not been studied in a phase III randomized clinical trial. Its use in this setting is based on extrapolations of its major impact on survival rates in the systemic B cell lymphoma setting, and on phase II and retrospective PCNSL studies. A major concern is whether the low penetration of the large rituximab molecule through the blood brain barrier can result in therapeutic concentrations within the brain parenchyma. We performed an international intergroup randomized phase III study to investigate the efficacy of rituximab in PCNSL.Methods: newly-diagnosed, non-immunocompromized patients (aged 18-70 years) with PCNSL and ECOG performance status (PS) 0-3 were randomized to induction with 2 cycles of MBVP (high dose methotrexate, BCNU, teniposide, prednisone) chemotherapy with (arm B) or without (arm A) rituximab. Patients were stratified for age (≤60 vs ≥61 years) and PS (0-1 vs 2-3). The rituximab (375 mg/m2) was given weekly during MBVP cycle I (on day 0 and 14) and every other week during cycle II to a total of 6 administrations. Patients with persistently positive CSF after the first (R-)MBVP cycle received intrathecal MTX. Patients with at least a partial response received consolidation with high dose cytarabine. Subsequently, patients ≤ 60 years were treated with 30 Gy whole brain radiotherapy (WBRT) with an additional boost of 10 Gy in case of partial remission. Patients ≥61 yrs were not to be irradiated. MRI evaluation was planned after 2 cycles of (R)-MBVP, after high dose cytarabine and, in case of WBRT, 4 weeks after the WBRT. In follow-up MRI was scheduled every 3 months for the first two years, every six months in years 3-5, and annually thereafter. Primary end-point was event free survival (EFS), where an event was no CR(u) on protocol, relapse or death. Secondary end-points were response rates after induction, consolidation and completion of radiotherapy, as well as progression free and overall survival.Results: between August 2010 and June 2016, 200 patients from 24 centers in the Netherlands, Australia and New Zealand were included and randomized; 100 patients were randomized to arm A and 99 to arm B, 1 was not eligible and excluded from all analyses. 55% were men. The median age was 61 years (range 26-70), 47% were ≤60 years, 72% had an ECOG PS ≤ 1, 29% had elevated LDH and 30% had positive CSF; the two arms were well balanced at baseline. All patients received cycle I according to randomization, 90% received cycle II and 81% received high dose cytarabine. 16 patients, 8 in each arm, received intrathecal treatment. 70 patients (35%) were irradiated, 34% in arm A and 36% in arm B. A boost was given to 15/34 patients in arm A (44%) and 24/36 patients in arm B (67%). CR/CRu rate was 66% in arm A and 68% in arm B. Overall response rate was 87% in both arms. EFS did not differ between the arms: 1 year EFS was 49% in arm A and 52% in arm B; HR 1.00, 95% CI 0.70-1.43, p=0.99 adjusted for age group and WHO. An exploratory multivariate analysis revealed a significant age-arm interaction effect suggesting a possible effect of rituximab in younger patients; within this subgroup, HR = 0.54, 95% CI 0.30-0.98. HR for PFS adjusted for age and WHO was 0.77 (95% CI 0.52-1.13, p=0.18). OS data are not yet mature as median OS has not been reached after a median follow-up of 32.9 months (range 3.6-79.2) in the 120 patients still alive. However, no difference was apparent with an adjusted analysis HR of 0.93 (95% CI 0.59 - 1.44, p=0.74). At database lock 79 patients had died; treatment related mortality was 7% in arm A and 3% in arm B. Grade 3 or 4 adverse events occurred in 59% of patients in arm A, in 63% in arm B, of which infections were the most frequent, occurring in 23% and 21% of patients respectively.Conclusions: in this randomized phase III trial in newly diagnosed PCNSL, the addition of rituximab to HD-MTX-based chemotherapy did not improve response rates, EFS or PFS. Longer follow up is needed to evaluate the effect on overall survival. [Display omitted] DisclosuresMinnema:Janssen: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy; Servier: Consultancy. Cull:Amgen Australia: Other: travel expenses Lugano lymphoma conference 2017; Takeda Australia: Other: travel expenses Highlights of ASH march 2017, Brisbane. Nijland:Novartis Pharmaeuticals Corporation: Honoraria; Kite Pharma: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; MIllennium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria. van den Bent:Roche: Consultancy. Jong:BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Research Funding. Doorduijn:Celgene: Honoraria; Roche: Honoraria.

Prognostic Factors and the Impact of Frontline Therapy in Peripheral T-Cell Lymphoma: A Multicenter Australian Study

BackgroundPeripheral T cell lymphomas (PTCL) are a heterogeneous group of lymphomas that have poor outcomes with current frontline chemotherapeutic strategies. Cyclophosphamide, vincristine, doxorubicin and prednisone, with or without the inclusion of etoposide (CHO(E)P), remains the standard of care, although scarce data exist regarding the benefit of intensive regimens, including hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate/cytarabine (HyperCVAD). This multicenter study aims to characterize presenting features, prognostic factors and the influence of frontline therapy in patients (pts) with PTCL.MethodsWe retrospectively analysed presenting features, frontline therapy and outcomes of all pts diagnosed with PTCL at the 3 tertiary referral centers within Western Australia from 2005-2014. Overall survival (OS) and progression free survival (PFS) were calculated by the Kaplan Meier method. Univariate comparisons were made by log rank test and multivariate analysis (MVA) performed using step-wise Cox regression. Comparisons between categorical variables were made using Fisher's exact tests.ResultsA total of 98 pts were included in the analysis, with a median follow-up of 4.6 years (range 0.1 - 8.6). Median age was 64 years and 78% presented with advanced stage (III-IV) disease. Complete pt characteristics and histological subtypes are presented in Table 1.Most pts were treated with CHO(E)P (47%) or HyperCVAD (21%), with a smaller proportion receiving reduced intensity chemotherapy (9%), other therapy (12%) or supportive care alone (10%).Four year PFS was 21% (95% CI 12.2 - 29.8%) and 4 year OS was 34% (24.2 - 43.8%). Excluding pts treated with palliative intent, the overall response rate (ORR) was 73%, with a complete response rate (CRR) of 59%.OS was strongly predicted by International Prognostic Index score (IPI) (Figure 1). In MVA, age, elevated LDH and >1 extranodal sites were found to be significantly associated with survival, whereas marrow involvement, B symptoms and stage were not (Table 2).We then restricted the analysis to pts treated initially with either CHO(E)P or HyperCVAD to compare outcomes between these two commonly used regimens at our centers. Response rates were similar with an ORR/CRR to CHO(E)P of 78%/67%, and 76%/61% to HyperCVAD (p=0.90). Likewise, 4yr PFS did not differ significantly between the two regimens - CHO(E)P: 20% (6.9 - 33.1%) vs. HyperCVAD: 33% (12.6 - 53.4%), p = 0.30. On univariate analysis (UVA), 4yr OS was 27% (13.3 - 40.7%) for CHO(E)P and 62% (40.4 - 83.6%) for HyperCVAD, p = 0.042. On MVA adjusted for age, LDH and extranodal sites, there was no significant difference between treatment groups (Table 3).Consolidation stem cell transplantation (SCT) following response to first line chemotherapy was performed in only 6 (10%) pts and occurred more frequently in pts initially treated with HyperCVAD (4/16 [25%] vs. 2/36 [6%], p=0.074). In relapsed or refractory disease, pts treated initially with HyperCVAD were more likely than those treated with CHOP to receive salvage chemotherapy (11/12 [92%] vs. 20/33 [61%], p=0.046) and have SCT incorporated into subsequent lines of therapy (7/12 [58%] vs. 4/33 [12%], p=0.003).Pts treated with reduced intensity chemotherapy had poor outcomes, with median OS of 3 months. Those receiving only supportive care had a median OS of 0.8 months.ConclusionWhilst pts with PTCL presenting with low risk (IPI 0-1) disease have favourable outcomes, the majority present with higher risk disease and have poor long-term survival with current frontline therapy. Survival in our cohort was strongly associated with IPI risk factors including age, elevated LDH and multiple extranodal sites.The use of HyperCVAD did not improve response rate or PFS when compared to CHO(E)P in our pts. The superior OS noted on UVA for this group was lost on MVA, and appears to be explained by selection of younger, fitter pts, more of whom underwent salvage therapy, including autologous or allogeneic SCT, at time of progression. Whilst some expert guidelines support SCT as part of initial therapy (Moskowitz, Blood 2014), this was seldom performed at our centers.Our results do not support the frontline use of HyperCVAD over CHO(E)P in PTCL. Given poor outcomes with current chemotherapeutic options, alternative induction regimens incorporating novel agents are urgently required. [Display omitted] DisclosuresCull:Amgen Australia: Other: travel expenses Lugano lymphoma conference 2017; Takeda Australia: Other: travel expenses Highlights of ASH march 2017, Brisbane.

Safety and Activity of the Highly Specific BTK Inhibitor BGB-3111 in Combination with the PD-1 Inhibitor BGB-A317 in Patients with B-Cell Lymphoid Malignancies

IntroductionBGB-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 demonstrates favorable pharmacokinetic and pharmacodynamics properties (Tam et al. ASH 2016). BGB-A317, a humanized IgG4 variant monoclonal antibody with no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor and is being developed for the treatment of solid and hematologic malignancies (Friedlander, ASCO, 2017). The combination of PD-1/PD-L1 inhibitors with B-cell receptor pathway inhibitors is being evaluated in different B-cell malignancies with the expectation of greater benefit for patients. Here, we present early safety data from a Phase 1b trial exploring the combination of BGB-3111 and BGB-A317.MethodsThis is an open-label, multicenter, phase 1b study to evaluate safety, tolerability, and preliminary efficacy of BGB-3111 in combination with BGB-A317 in subjects with B-cell malignancies, including Waldenström's macroglobulinemia (WM), aggressive and indolent non-Hodgkin's lymphoma, and transformed chronic lymphocytic leukemia/follicular lymphoma (FL) amongst other B-cell malignancies. The study includes a standard 3+3 dose escalation phase followed by dose expansion. The dose levels are: Cohort 1, BGB-3111 320 mg once a day (QD) combined with BGB-A317 2.0 mg/kg every 3 weeks (Q3W); Cohort 2, BGB-3111 320 mg QD combined with BGB-A317 5.0 mg/kg Q3W; and Cohort 3, BGB-3111 160 mg BID combined with BGB-A317 200 mg (flat dose) Q3W.ResultsAs of 01 June 2017, 25 pts were enrolled in the dose escalation portion of the trial: 15 pts in Cohort 1 and 10 pts in Cohort 2. Key patient characteristics, safety, and efficacy are shown in the Table.Safety: Median follow - up was 2.8 (range, 0.4-10.7) months. There were no dose-limiting toxicities (DLTs) in Cohort 1. Cohort 2 saw hemolysis in 2 pts, both with WM; one qualified as a DLT. These events were not associated with a positive direct antiglobulin test and resolved with immunosuppressive therapy, but resulted in the decision to exclude further enrollment of WM pts in the trial. No further DLTs were observed after exclusion of WM pts.The most frequent adverse events (AEs) of any cause in Cohort 1 were diarrhea (n=4, 26.7%), fatigue (n=4, 26.7%), and pyrexia (n=3, 20%) and in Cohort 2 were contusion (n=3, 30%), anemia, hemolysis, headache, peripheral edema, thrombocytopenia, and upper respiratory tract infection (n=2, 20% each). Frequent AEs ≥ Grade 3 from both Cohorts included anemia (n=32, 12%), and thrombocytopenia and hemolytic transfusion reaction (n=2, 8% each).Serious AEs related to study treatment were seen in 8 patients: hemolysis (n=2), pneumonitis, infusion-related reaction, abscess limb, pneumonia, anemia, ulcerative keratitis, catheter site hemorrhage, autoimmune encephalitis, dyspnea, and eczema (n=1 each). The encephalitis could not be attributed to other causes and resolved with immunosuppressive therapy. No serious hemorrhages or atrial fibrillation have been reported to date.Discontinuation due to AEs occurred in six patients for the following AEs: hemolysis (n=2), nausea, lymph gland infection, ALT increased and GGT increased (same patient), auto-immune encephalitis, and progression-related complications (n=1 each).Efficacy: Efficacy data is very early with limited follow-up and most pts treated at the lowest dose. So far, 30% of pts have responded, including responses in both WM pts as well as complete responses seen in FL and non-GCB DLBCL pts.ConclusionsThe combination of BGB-3111 and BGB-A317 has a manageable toxicity profile in a wide variety of B-cell malignancies. Autoimmune adverse events, consistent with anti-PD-1 therapy, were observed and managed with supportive care. Notably, hemolysis in 2 WM patients suggestlimitations of this combination in indolent lymphoid diseases such as WM, especially given the risk/ benefit profile of single-agent BGB-3111 in indolent settings .Enrollment is now open for Cohort 3, which will be followed by expansion cohorts to further characterize safety and efficacy of the combination. [Display omitted] DisclosuresCull:Amgen Australia: Other: travel expenses Lugano lymphoma conference 2017; Takeda Australia: Other: travel expenses Highlights of ASH march 2017, Brisbane. Opat:Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Beigene: Research Funding; Mundipharma: Consultancy; Amgen: Research Funding. Trotman:Janssen Cilag: Other: Funding facilitating research paid to third party (BioGrid Australia), Research Funding. Hilger:BeiGene: Employment. Zhang:BeiGene: Employment. Feng:BeiGene: Employment. Ro:BeiGene: Employment. Huang:BeiGene: Employment. Tam:Abbvie: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

Effect of Urate-Lowering Therapy on Cardiovascular and Renal Outcomes: A Systematic Review and Meta-Analysis

Background: Several clinical practice guidelines noted the potential benefits of urate-lowering therapy (ULT) on cardiovascular disease (CVD) and chronic kidney disease (CKD) progression, however effect of this regimen remains much uncertainty. In this systematic review, we aimed to evaluate the efficacy of ULT on major adverse cardiovascular events(MACEs), all-cause mortality and kidney failure events. Methods: We systematically searched MEDLINE, Embase, and the Cochrane databases for trials published through April 2019. We included prospective, randomized, controlled trials assessing the effects of ULT on cardiovascular or renal outcomes. We extracted published data and did a meta-analysis of urate-lowering therapy on relative risks (RRs) of major adverse cardiovascular events, all-cause mortality, kidney failure events, and adverse events. Summary estimates of RR reductions were calculated with a random effects model. Findings: We identified 28 trials including a total of 9194 participants, of which 5070 participants received ULT, 4104 participants received placebo, usual-care or no treatment. Finally, 1279 MACEs, 377 deaths and 87 kidney failure events were recorded. Among all the population with 3103 (34·18%) participants having chronic kidney disease and 5718 (61·14%) having cardiovascular disease or stroke, ULT reduced the risk of MACEs [risk ratio (RR) 0·80, 95% confidence interval (CI) 0·67-0·95; I2 = 42·7%] and all-cause mortality (RR 0·80, 95% CI 0·66-0·97; I2 =0·0%), but had no effect on kidney failure (RR 1·04, 95%CI 0·43-2·42; I2 =64·4%). There was no significant difference (RR=0·99, 95% CI 0·95 to 1·03; I2 =55·7%) in the risk of adverse events between the participants receiving ULT and the control group. Interpretation: ULT has a beneficial effect on reducing the risk of MACEs and all-cause mortality. However, there is insufficient evidence to support an effect of ULT in reducing risk of kidney failure events. Funding Statement: This work was funded by National Key Research and Development Program of China (2018YFC1314004). JL was supported by the grant from the National Natural Science Foundation of China (no. 81270795), JZ was supported by the National Natural Science Foundation of China (81874401). Dr Badve is supported by a John Chalmers Clinical Research Fellowship with the support of Servier from The George Institute for Global Health. Declaration of Interests: Dr Badve reports grants from the National Health and Medical Research Council of Australia, personal fees from Bayer AG and Amgen Australia, and nonfinancial support from Bayer AG. Other authors listed in this paper declare no competing interests. Ethics Approval Statement: This study is registered with PROSPERO, number CRD42018104227.

1130-P: Temporal Trends in Pharmacotherapy for Diabetes

Background: Multiple regimens for the pharmacological management of diabetes exist. In Australia, new agents have become available in recent years. We examined temporal trends in prescribing patterns of pharmacotherapy regimens in Australia. Methods: The EXTEND45 Study links health information on consenting participants of the 45 and Up Study (2006-2009) with administrative health information from the Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) (provided by the Department of Human Services), community pathology providers and other routinely collected health information sources. Linkage was performed by the Centre for Health Record Linkage and the Sax Institute (MBS and PBS). We identified a population-based cohort (2006-2014) of people aged ≥45 years who met a pre-specified definition for diabetes. Treatment episodes amongst our cohort were identified, and defined as the period that a patient adhered to a particular regimen of pharmacotherapy without any changes or treatment breaks of two or more standard coverage days (SCD). Episodes were attributed to the calendar year in which they commenced and were categorized into six patterns of glucose lowering medication use. Results: We identified 24,236 participants with diabetes who experienced 149,532 treatment episodes over a mean follow-up period of 4.97 years. Episodes included: never treated (4.4%), monotherapy (33.1%), dual therapy (17.0%), triple or more therapy (4.0%), insulin-based therapy (21.7%) and treatment break (20.3%). Metformin (a biguanide) accounted for the majority (68.5%) of monotherapy episodes, followed by sulfonlyureas (23.1%). The combination of metformin and a sulfonylurea was the most common dual therapy episode (56.1%) but became less common over the study period (75.5% in 2006 to 41.1% in 2014). Conclusion: Most treatment episodes in our cohort involved a monotherapy regimen. There was a temporal change in the specific drug agents prescribed in dual therapy regimens, likely related to the availability of newer agents. Disclosure T.K. Young: None. C. Hockham: None. L. Sukkar: None. A. Kang: None. M. Jun: Research Support; Self; AstraZeneca. J. Baker: None. K. Rogers: None. A. Cass: None. C.A. Pollock: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma. Board Member; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Novartis AG, Vifor Pharma. Other Relationship; Self; Janssen Pharmaceuticals, Inc. D. Sullivan: None. G. Wong: None. M.J. Jardine: Advisory Panel; Self; Akebia Therapeutics, Baxter, Boehringer Ingelheim International GmbH, CSL Behring, Vifor Pharma. Research Support; Self; Amgen Inc., Baxter, Eli Lilly and Company, Gambro, Merck Sharp & Dohme Corp. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding National Heart Foundation of Australia (100720); Roche Products Pty Ltd. (FR-MIR-0095); Rebecca L. Cooper Grant (REB002); Eli Lilly Australia Pty Ltd. (PO4100294024); Merck Sharp & Dohme Australia Pty Ltd. (MSD_EXTEND45); Amgen Australia Pty Ltd. (Amgen01)

1129-P: Association between the Intensity of Diabetes Therapy, Achieved HbA1c, and Persistence

Background: Comparative, real-world evidence for clinical outcomes of different glucose lowering pharmacotherapy regimens in diabetes is limited. We compared therapy persistence and achieved HbA1c amongst episodes of different pharmacotherapy regimens in a community-based Australian cohort. Methods: The EXTEND45 Study combines baseline questionnaire responses (2006-2009) with data from community pathology providers, the Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) (provided by the Department of Human Services) and other routinely collected health databases for participants of the 45 and Up study for the period 2005 to 2014. Linkage of MBS and PBS data was performed by the Sax Institute and all other data sources by the Centre for Health Record Linkage. We identified 24,236 people aged ≥45 years with diabetes. Using treatment episodes as our unit of analysis, the persistence and achieved glycaemic control of episodes was compared according to therapy regimens using Wilcoxon Sum rank tests. Results: Among 149,532 episodes, mean (median) therapy persistence was 163 (76), 175 (84), 132 (54) and 164 (108) days for mono-, dual, multioral-, and insulin-based therapy episodes, respectively. For monotherapy episodes, mean persistence was greatest for metformin (178 days). For dual therapy, mean persistence was longest for combinations that did not involve metformin or a sulfonylurea (195 days). Mean HbA1c was 6.9%, 7.3%, 7.4% and 7.9% for mono-, dual, multioral-, and insulin-based therapy episodes, respectively. For monotherapy episodes, mean HbA1c was lowest for metformin (6.8%) whilst for dual therapy, mean persistence was highest for sulfonylurea combinations that did not involve metformin (7.5%). Conclusion: Persistence with therapy is heterogeneous across different intensities of therapy and is shortest for multioral-agent regimens. Participants requiring insulin therapy have the highest achieved HbA1c, which is likely to reflect disease severity. Disclosure T.K. Young: None. C. Hockham: None. L. Sukkar: None. A. Kang: None. M. Jun: Research Support; Self; AstraZeneca. J. Baker: None. K. Rogers: None. A. Cass: None. C.A. Pollock: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma. Board Member; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Novartis AG, Vifor Pharma. Other Relationship; Self; Janssen Pharmaceuticals, Inc. D. Sullivan: None. G. Wong: None. M.J. Jardine: Advisory Panel; Self; Akebia Therapeutics, Baxter, Boehringer Ingelheim International GmbH, CSL Behring, Vifor Pharma. Research Support; Self; Amgen Inc., Baxter, Eli Lilly and Company, Gambro, Merck Sharp & Dohme Corp. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding National Heart Foundation of Australia (100720); Roche Products Pty Ltd. (FR-MIR-0095); Rebecca L. Cooper Grant (REB002); Eli Lilly Australia Pty Ltd. (PO4100294024); Merck Sharp & Dohme Australia Pty Ltd. (MSD_EXTEND45); Amgen Australia Pty Ltd. (Amgen01)

Updated Safety and Activity of the Investigational Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Mantle Cell Lymphoma

Updated Safety and Activity of the Investigational Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Mantle Cell Lymphoma

Durable Responses in Fit Elderly Patients with Chronic Lymphocytic Leukemia (CLL) in a Randomised, Fludarabine-Based, Immunochemotherapy Dose De-Escalation Study - Long-Term Follow-up By Treatment Arm and Mutational Status

BACKGROUNDImmunochemotherapy (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. METHODSPreviously 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. RESULTSThe 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. [Display omitted] DisclosuresGill: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.

Randomized Trial in Unfit, Elderly Chronic Lymphocytic Leukemia (CLL) Patients with Comorbidities of Dose-Reduced Oral Fludarabine and Cyclophosphamide Plus Obinutuzumab (FC+G) Versus Chlorambucil Plus Obinutuzumab (Cbl+G) As Front-Line Therapy

BACKGROUNDThe prior Australasian Leukaemia and Lymphoma Group (ALLG) CLL5 Study showed dose-reduced oral fludarabine and cyclophosphamide plus rituximab (FCR3) was safe, tolerable and effective in fit elderly patients for front-line therapy for CLL. The German CLL11 Study showed chlorambucil plus obinutuzumab (Cbl+G) was superior to chlorambucil alone or with rituximab in unfit patients requiring initial therapy. We conducted a randomized study to assess the safety, tolerability, and efficacy of dose-reduced FC + obinutuzumab (G) (FC+G) versus Cbl+G in unfit (i.e. with comorbidity), elderly patients with CLL.METHODSPatients aged ≥65 years and considered “unfit” defined by co-morbidities using the Cumulative Illness Rating Scale [CIRS] ≥6 were eligible for the ALLG CLL7 study. Patients with any single organ system score ≥4 were excluded. Previously untreated patients with progressive CLL aged ≥65 and CIRS ≥6 were randomised to one of 2 therapy arms: (i) Chlorambucil 0.5mg/kg D1+15 p.o. + obinutuzumab (“G”) (i.v. 1000mg/m2 cycle 1, Day 1, 8, 15, and 1000mg/m2 D1 cycles 2-6), or (ii) FC(rd)+G: F-24mg/m2 p.o. and C-150mg/m2 p.o. D1-3 + G (same schedule above) at 4 weekly intervals for planned 6 cycles. Early stopping for toxicity was mandated: treatment could be delayed for 2 weeks for grade 3+ toxicity, but if unresolved by 2 weeks, patients were taken off study. The primary end-point was grade 3+ non-hematological, and grade 4 hematological adverse events. Secondary objectives were overall response rate (ORR), complete remission (CR), partial remission (PR), progression-free survival (PFS) and overall survival (OS) and minimal residual disease (MRD) negativity. Final staging was performed between 2-3 months following final treatment cycle.RESULTSPatient characteristics Patient recruitment was terminated early due to poor recruitment. At the time of study closure, there were 32 patients, with 15 on Cbl+G and 17 on FC(rd)+G. The mean age was 74.2 years (range 66-85 years) with 23 females (71.9%) and 9 males (28.1%). The CIRS score was 6 in 4 patients (12.5%), 6-8 in 14 (43.8%), 8-10 in 11 (34.4%) and >10 in 3 (9.4%). Binet stage at registration was stage A 18.2%, B 27.3% and C 54.5%.Tolerability Both therapies were tolerable with 15/17 (88.2%) completing all 6 cycles of FC(rd)+G and 12/15 (92.3%) completing six cycles of Cbl+G.Toxicity Most toxicity was hematological and manageable. Grade 3/4 hematological toxicity was more common with FC(rd)+G than Cbl+G occurring in 60% with FC(rd)+G and 38.5% with Cbl+G (Table 1). There was one death due to progressive CLL on the FC(rd)+G arm.Response rate A complete remission (CR), confirmed by bone marrow (BM) trephine, was achieved in 86.6% of patients on FC(rd)+G versus (vs) 53.9% on Cbl+G, partial response (PR/nPR) in 1 (6.7%) on FC(rd)+G, and 6 (46.2%) on Cbl+G, and either stable or progressive disease (SD or PD) on 1 on FC(rd)+G, and nil on Cbl+G. BM MRD-negativity rates were 3/17 (20.0%) FC(rd)+G vs 1/15 (7.7%) Cbl+G (Table 2).CONCLUSIONThis randomized trial of dose-reduced FC(rd)+G vs Cbl+G in elderly patients aged ≥65 and with co-morbidities (CIRS ≥6) was terminated early due to poor recruitment. Due to the dose-reduced FC, and early stopping rule, treatment was safe and tolerable and most patients completed all 6 cycles of planned therapy. Grade 3/4 toxicity was mainly hematological and manageable, with higher rates of neutropenia with the FC (60%) vs Cbl (35.7%) backbone. FC(rd)+G compared to Cbl+G resulted a higher CR rate of 86.6%% versus 53.9%, and higher MRD-negativity (20% vs 7.7%). Progression-free and overall survival are being evaluated. [Display omitted] DisclosuresBadoux:Roche: Research Funding. Cull:Takeda Australia: Other: Travel Expenses; Amgen Australia: Other: Travel Expenses; AbbVie (Australia): Membership on an entity's Board of Directors or advisory committees. Tam:Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Identifying priorities for the pharmacy profession: the SHPA 2014 Future Summit

The concept of the Society of Hospital Pharmacists of Australia (SHPA) Future Summit 2014 grew from the SHPA's desire to create a 'think tank' for members to progress ideas about future advances in pharmacy and the role that SHPA and others have in implementing these ideas. The 2014 Future Summit, which was held in Melbourne on 4 and 5 August 2014, was the first of three planned annual summits, held with the financial support of Amgen Australia. The responsibility for all aspects of the planning, organisation and convening the event was held by the SHPA, through the Steering Committee.

Thalidomide and prednisolone versus prednisolone alone as consolidation therapy after autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the ALLG MM6 multicentre, open-label, randomised phase 3 study

We previously showed that consolidation therapy with thalidomide and prednisolone improved progression-free and overall survival in patients with multiple myeloma who had undergone autologous stem-cell transplantation. We aimed to assess whether these survival advantages were durable at 5 years. The ALLG MM6 trial was a multicentre, open-label, randomised phase 3 trial done between Jan 13, 2002, and March 15, 2005, at 29 sites in Australia and New Zealand. Patients with newly diagnosed multiple myeloma were randomly assigned (1:1), via computer-generated randomisation charts, to receive indefinite prednisolone maintenance alone (control group) or in combination with 12 months of thalidomide consolidation (thalidomide group) after autologous stem-cell transplantation. Randomisation was stratified by treating centre and pre-transplantation concentrations of β2 microglobulin. Patients and treating physicians were not masked to treatment allocation. Primary endpoints were progression-free survival and overall survival. Analysis was by intention to treat. Secondary endpoints were overall response to salvage therapy, incidence of second primary malignancy incidence, and cost-effectiveness. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12607000382471. We randomly assigned 269 patients to the thalidomide (n=114) or control group (n=129). After a median follow-up of 5·4 years (IQR 3·1-7·2), estimated 5-year progression-free survival was 27% (95% CI 23-32) in the thalidomide group and 15% (11-18) in the control group (hazard ratio [HR] 0·16, 95% CI 0·044-0·58; p=0·0054) and 5-year overall survival was 66% (95% CI 61-70) and 47% (42-51), respectively (HR 0·12, 95% CI 0·028-0·56; p=0·0072). There was no difference in overall response to salvage therapy, survival post-progression, or incidence of secondary malignancies between the two groups. Incremental cost-effectiveness ratio was AUS$26 996 per mean life-year gained. Consolidation therapy with thalidomide and prednisolone after autologous stem-cell transplantaion is an acceptable therapeutic approach when alternative drugs are not available. Pharmion Corporation, Novartis Pharmaceuticals, Amgen Australia, The Merrin Foundation, and Alfred Health.

A Phase II Study of Risk-Adapted Intravenous Melphalan in Patients with AL Amyloidosis,

Abstract 3973 Aims:High-dose IV melphalan is standard autograft (ASCT) conditioning in patients with AL amyloidosis, but careful patient selection is required to avoid high transplant-related mortality rates. In patients ineligible for ASCT, intermediate-dose IV melphalan (IDM) may provide advantages over oral dosing where the already variable intestinal absorption is complicated by gastrointestinal amyloid deposition. We aimed to assess a risk-adapted strategy to IV melphalan dosing in patients with AL amyloidosis. Methods:The MM8 study was a prospective clinical trial conducted by the Australasian Leukaemia and Lymphoma Group. Transplant candidates (minimal cardiac disease including BNP<300ng/L, age <65, ECOG<2, <2 organs involved) received melphalan at 140 or 200mg/m2 IV. All other patients received IDM (melphalan 20mg/m2 IV d1 and dexamethasone 40mg PO d1-4 every 4 weeks for 3–6 cycles). Treatment was continued until 2 cycles beyond free light chain normalisation or maximal response, or to a maximum of 6 cycles. IDM was discontinued if there was no haematologic response after 3 cycles. Results:21 patients enrolled with median age 61yrs. Organ involvement was cardiac 48%, renal 81%, liver 14%, neurologic 43%. 6, 10 and 5 were low, intermediate and high cardiac biomarker risk, respectively. 7 underwent ASCT and 14 IDM.The trial closed early due to excessive myelotoxicity in the IDM arm. In this cohort, grade 3/4 neutropenia and thrombocytopenia during the 1st cycle occurred in 54% and 23%, with 15% having neutropenic fever. Grade 3/4 neutropenia and thrombocytopenia during any cycle occurred in 85% and 54% of patients, with 38% having neutropenic fever. First cycle severe neutropenia was not predicted by age, cardiac or renal function but was significantly more common with lower body surface area (p=0.01). 8 IDM patients died before the 6 month response assessment, 2 achieved a 50% reduction in baseline involved FLC and 4 failed to respond. All 7 patients receiving ASCT are alive at a median of 33 months. Conclusions:IV melphalan at 20mg/m2 is excessively myelotoxic for patients with AL with no evidence of response benefit to offset this toxicity. BNP<300ng/L may identify patients suitable for ASCT.This study was supported by the Leukaemia Foundation of Queensland and Amgen Australia. Disclosures:Mollee:Amgen Australia: Research Funding; Leukaemia Foundation of Queensland: Research Funding. Cannell:Nereus Pharmaceuticals:.

Antibody-mediated acquired pure red cell aplasia (PRCA) after treatment with darbepoetin

Recombinant erythropoietin (EPO) is used successfully as treatment for anaemia in chronic kidney disease (CKD), to maintain stable haemoglobin levels, avoiding the need for multiple transfusions. From 1998, epoetin formulations, in particular epoetin alfa (Eprex , Ortho Biologics LLC), have been associated with a substantial increase in the incidence of antibody (Ab)-mediated pure red cell aplasia (PRCA) [1]. PRCA is a rare immunopathological disorder characterized by a severe reticulocytopenia, the absence of marrow erythroid precursors, normal granulocytic and megakaryocytic precursors, and the identification of circulating antibodies against EPO [2]. Patients typically develop an abrupt onset of severe transfusiondependent anaemia. Consequently, EPO must be withdrawn and therapy initiated to decrease the production of the anti-EPO antibodies. Darbepoetin alfa (Aranesp , Amgen Inc., CA) is a second generation erythropoiesis stimulating agent with two extra carbohydrate chains and eight extra sialic acid residues as compared with epoetin alfa. It is suggested that the modifications to this molecule may make it more resistant to antibody development. There is only a single published case report of PRCA related to the exclusive use of darbepoetin alfa [3]; however, communication with Amgen Australia Pty Ltd indicate about four cases on their database. In a sole published case of PRCA due to darbepoetin alfa, the patient did not respond to treatment with steroids alone, intravenous immunoglobulin, cyclosporin or combination prednisolone and cyclophosphamide [3]. We report a second case of PRCA related to the exclusive use of darbepoetin alfa, where the patient responded to the first line treatment of oral cyclophosphamide and prednisolone, had non-neutralizing anti-EPO and anti-darbepoetin antibodies on bioassay, and died from severe pulmonary infection.

Renal safety evaluation of zoledronic acid and thalidomide when used as post-stem cell transplant maintenance therapy in multiple myeloma

6655 Background: Anecdotal reports suggest that combination therapy with zoledronic acid (ZA) and thalidomide (T) in multiple myeloma (MM) patients may increase the risk of renal dysfunction compared to ZA alone. As part of a multicentre Phase III trial of post autologous stem cell transplant (ASCT) T maintenance therapy we have compared renal function in MM patients receiving ZA with or without concomitant T. Methods: A multicentre, open label, randomised trial of T 200mg p.o daily for 12 months post-ASCT in patients with non-progressive MM. All patients also received ZA 4mg IV over 15 minutes every 28 days and alternate day prednisolone 50mg. A subset of patients underwent ZA Cmax and AUC (0–48) determinations for the first two ZA doses. Univariate analysis was conducted using student t-tests and chi-square tests for equal proportion. Multivariate analysis was conducted using a repeat measures analysis of variance. Differences in creatinine (Cr) between arms over time were determined by fitting an interaction between dose and arm, with dose and arm treated as linear predictors. Results: To-date 83 patients have commenced maintenance therapy (T=40), received a median of 9 (T) or 8 (no T) ZA doses and 15 patients have completed the PK study (T=8). The arms were well matched for gender, age, pre-ASCT B2microglobulin and baseline Cr. Four patients have had ZA withheld because of a rise in Cr (T = 1, no T=3). No ZA-related serious adverse events have occurred. Multivariate analysis demonstrated that higher Cr levels were associated with male gender and pre-ASCT B2M >4mg/L (both p<0.001). The relationship between Cr and cumulative ZA dose demonstrated no significant difference between the two arms (p =.12, for T vs no T). Peak drug concentrations (Cmax) and overall drug exposure (AUC 0–48) were similar between the two arms, both at day 1 and day 29 (p = ns, student t-test), and there was no suggestion of accumulation or changed PK profile after the second ZA dose. Conclusions: There is no evidence for a PK interaction by T on ZA. ZA was found to be safe in this previously treated MM population irrespective of concomitant T administration. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals; Novartis Pharmaceuticals Australia Pty Ltd. Novartis Pharmaceuticals Novartis Pharmaceuticals Pharmion Pty Ltd. Novartis Pharma; Amgen Australia Pty Ltd.; Pharmion Pty Ltd.

Renal safety evaluation of zoledronic acid and thalidomide when used as post-stem cell transplant maintenance therapy in multiple myeloma

6655 Background: Anecdotal reports suggest that combination therapy with zoledronic acid (ZA) and thalidomide (T) in multiple myeloma (MM) patients may increase the risk of renal dysfunction compared to ZA alone. As part of a multicentre Phase III trial of post autologous stem cell transplant (ASCT) T maintenance therapy we have compared renal function in MM patients receiving ZA with or without concomitant T. Methods: A multicentre, open label, randomised trial of T 200mg p.o daily for 12 months post-ASCT in patients with non-progressive MM. All patients also received ZA 4mg IV over 15 minutes every 28 days and alternate day prednisolone 50mg. A subset of patients underwent ZA Cmax and AUC (0–48) determinations for the first two ZA doses. Univariate analysis was conducted using student t-tests and chi-square tests for equal proportion. Multivariate analysis was conducted using a repeat measures analysis of variance. Differences in creatinine (Cr) between arms over time were determined by fitting an interaction between dose and arm, with dose and arm treated as linear predictors. Results: To-date 83 patients have commenced maintenance therapy (T=40), received a median of 9 (T) or 8 (no T) ZA doses and 15 patients have completed the PK study (T=8). The arms were well matched for gender, age, pre-ASCT B2microglobulin and baseline Cr. Four patients have had ZA withheld because of a rise in Cr (T = 1, no T=3). No ZA-related serious adverse events have occurred. Multivariate analysis demonstrated that higher Cr levels were associated with male gender and pre-ASCT B2M >4mg/L (both p<0.001). The relationship between Cr and cumulative ZA dose demonstrated no significant difference between the two arms (p =.12, for T vs no T). Peak drug concentrations (Cmax) and overall drug exposure (AUC 0–48) were similar between the two arms, both at day 1 and day 29 (p = ns, student t-test), and there was no suggestion of accumulation or changed PK profile after the second ZA dose. Conclusions: There is no evidence for a PK interaction by T on ZA. ZA was found to be safe in this previously treated MM population irrespective of concomitant T administration. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals; Novartis Pharmaceuticals Australia Pty Ltd. Novartis Pharmaceuticals Novartis Pharmaceuticals Pharmion Pty Ltd. Novartis Pharma; Amgen Australia Pty Ltd.; Pharmion Pty Ltd.