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Promising reports of combination immunosuppression with high-dose dexamethasone and rituximab for the treatment of primary immune thrombocytopenia (ITP) have recently emerged. They suggest a potential to further optimize the efficacy of therapy. We investigate the use of a novel combination of conventional therapies in ITP given over 4 weeks. From 2011 to 2014, 20 patients were prospectively enrolled onto a single-arm phase 2b study to describe the safety, efficacy, and tolerability of oral dexamethasone 40 mg for days 1 to 4, oral cyclosporine 2.5 to 3 mg/kg daily for day 1 to 28, and intravenous low-dose rituximab 100 mg for days 7, 14, 21, and 28. There were no therapy-related serious adverse side effects, 6-month response rate was 60%, and treatment was well tolerated. Responders enjoyed relapse-free survivals of 92% and 76%, respectively, at 12 and 24 months. This study highlights the possibility of achieving an enduring remission from 4 weeks of therapy. This study is registered at www.anzctr.org.au (#ANZCTRN12611000015943).

Introduction: Temsr (Torisel®) administered at 175 mg IV once weekly for first 3 weeks, followed by 75mg IV once weekly (Temsr 175/75 mg) is approved in the European Union for the treatment of adult patients with relapsed and/or refractory MCL based on an overall positive benefit-risk relationship demonstrated for this treatment regimen in the pivotal phase III study (Hess et al. J Clin Oncol. 2009;27:3822-9). This ongoing phase 4, multicenter, randomized, open-label study was conducted to explore whether similar efficacy can be achieved for the treatment of patients with relapsed/refractory MCL with a Temsr regimen that is expected to yield fewer side effects than the Temsr 175/75 mg dose regimen, by skipping the first 3 doses of Temsr 175 (Clinicatrials.gov: NCT01180049). Methods: In this study, previously treated (2-7 lines of prior therapy) patients with relapsed/refractory mantle cell lymphoma were stratified by the histologic subtype (blastoid vs. non blastoid vs unknown histology) and randomized (1:1) to receive Temsr 175/75 mg, or 75mg IV once weekly (Temsr 75 mg). Treatment continued until disease progression, provided that patients were tolerating treatment and achieving clinical benefit. The primary endpoint was progression-free survival (PFS) based on independent assessment. Secondary endpoints included objective response rate (ORR), overall survival (OS) and safety with a particular focus on bleeding- and infection-related adverse events (AEs). Results: Of the 90 patients (77.8% males; 93.3% white, mean age 66.6 years) randomized, 47 were treated with Temsr 175/75 mg, 42 were treated with Temsr 75 mg, and 1 patient was randomized but not treated. At the cutoff date for analysis (November 12, 2015), 39 (83.0%) patients in Temsr 175/75 mg arm and 41 (95.3%) patients in Temsr 75 mg arm discontinued treatment with the primary reason being objective disease progression (53.8% in Temsr 175/75 mg and 56.1% in Temsr 75 mg). Median duration of treatment was comparable in the Temsr 175/75 mg arm and Temsr 75 mg arm (3.2 vs. 3.1 months). Median PFS (80% CI) was 4.3 (3.3-6.4) months in Temsr 175/75 mg arm versus 4.5 (2.7-4.9) months in Temsr 75 mg arm (hazard ratio [HR] 0.731; 80% CI 0.520-1.027). ORR (80% CI) was 27.7% (19.1%-37.7%) in Temsr 175/75 mg arm versus 20.9% (13.0%-31.0%) in Temsr 75 mg arm. Median OS (80% CI) was 18.7 (7.5-48.2) months in Temsr 175/75 mg arm versus 11.0 (6.3-16.2) months in Temsr 75 mg arm (HR 0.681, 80% CI 0.472-0.982). Median duration of response was comparable in both treatment arms (9.0 vs. 8.7 months in Temsr 175/75 mg and Temsr 75 mg arms, respectively). Overall, the safety profile was comparable in both treatment arms, although the number of patients with serious AEs, dose reduction and deaths was lower in the 175/75mg arm compared with 75 mg arm (57.4%, 48.9% and 48.9% vs. 73.8%, 64.3% and 65.1%, respectively), and the number of treatment discontinuations due to AEs was higher in the Temsr 175/75mg arm compared with 75mg arm (19.1% vs. 14.3%). Common (>10%) grade ≥3, all-causality, treatment-emergent AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, were thrombocytopenia (46.8% vs. 38.1%), neutropenia (25.5% vs. 21.4%), and pneumonia (10.6% vs. 19.0%). Treatment-emergent bleeding-related grade ≥2 AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, included epistaxis (10.6% vs. 2.4%) and ecchymosis (2.1% vs. 0). Only 1 grade 3 AE of epistaxis which was not related to Temsr was reported in the Temsr 175/75 arm, and no grade 3 events were reported in Temsr 75 arm. Pneumonia was the most commonly occurring treatment-emergent infection-related grade ≥2 AEs 12.8% in Temsr 175/75 mg arm and 19.0% in Temsr 75 mg arm. Of the 51 deaths reported during the study, none were treatment-related and most were due to disease progression. Conclusions: Overall, PFS, ORR and OS favored the Temsr 175/75 arm, although no formal statistical conclusions were made as the study was not powered for differences. The safety profile in both study arms was comparable, but there was a lower incidence of serious AEs, dose reductions and deaths in the 175/75 mg arm. Temsr 175/75 mg remains the preferred dose regimen for patients with relapsed/refractory MCL. Disclosures Jurczak: Sandoz - Novartis, Morphosys, Roche: Speakers Bureau; Acerta, Novartis, Pfizer, Celgene, Gillead, Janssen, Celtrion, Bayer, Morphosys, Takeda, Servier, Teva, and Roche: Research Funding; Morphosys: Consultancy. Clancy:Pfizer Inc: Consultancy. Lechuga:Pfizer Inc: Employment, Equity Ownership. Casey:Pfizer Inc: Employment, Equity Ownership. Boni:Pfizer Inc: Employment, Equity Ownership. Hess:Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria.

Introduction and aims: High-dose melphalan (HDM) is the commonest conditioning regimen used in autologous transplantation for multiple myeloma (MM), with >10,000 transplants performed annually. The standard dosing algorithm of 200mg/m2, with reduction to 140mg/m2 for renal impairment, has been based upon empiric dose selection, rather than pharmacokinetic (PK) and pharmacodynamic (PD) studies. We have previously examined PK and clinical outcome in 114 patients receiving HDM and shown that exposure (area under the concentration versus time curve: AUC) above the median (12.8 mg/L.h) was associated with increases in ≥ grade 3 mucositis (HR 1.2, p< 0.005), and a median overall survival of 8.5 years vs. 5.4 years for AUC below the median (HR 0.40, p < 0.001) [1]. The aims of this pilot study were to (1) test the feasibility of real-time PK in patients with MM and (2) evaluate whether a test dose reliably predicted exposure to a full dose. Methods: Thirty three patients (age range: 35 to 71 years) scheduled to receive HDM followed by ASCT were recruited from six Australian hospitals situated within 16-860km from the PK laboratory. A test dose (20 mg/m2) was administered one to three days prior to the remaining 180 mg/m2, n=29, or another dose (n = 4, 186- 200mg/m2) chosen by the treating physician. Melphalan infusion duration ranged from 9 to 36 min for the test dose and from 15 to 45 min for the remaining dose. Blood samples were collected after both doses at: 5 min, 15 min, 30 min, 40 min, 1.25 h and 2.5 h after completion of the infusion, stored immediately on ice and centrifuged within 40 minutes at 3000 rpm for 10 minutes at 4o C to collect plasma, then stored at -40°C until transported on dry ice. Melphalan concentrations were determined by HPLC with UV detection. Test dose AUC was calculated using the trapezoidal rule (Kinetica software) and used to predict what the AUC would be for the 180mg/m2 (or modified) dose, assuming linear PK. Percent deviation of actual-from-predicted AUC was calculated as % deviation = (actual AUC - predicted AUC) / predicted AUC*100. Comparison of % deviation between the first patient recruited at each institution and the remaining patients was performed using the Mann-Whitney test. Results: The predicted and actual melphalan AUC values for all 33 patients are charted (Figure 1). AUC values following the test dose were median (range): 1.34 (0.83-1.88 mg/L.h). Predicted AUC values (adjusted for subsequent dose) were median (range): 11.8 (8.3-15.8) mg/L.h, whilst actual values were 10.5 (6.3-16.0) mg/L.h. Median % deviation of actual from predicted values was -8%, (range -43 to 11%), with predictions for 23 patients (70%), being within ± 15%. The median % deviation for the first patient in each centre was -22.1%, and for subsequent patients was -7%, (p=0.046), for whom 21/27 (78%) had full dose AUC values within ± 15%. Conclusions: Test-dose PK predictions of melphalan exposure were accurate to within ± 15% for 70% of patients in this pilot study. The significantly improved AUC predictions with subsequent dosing suggest that meticulous care is required in dose administration and blood sampling. Other factors such as duration of infusion, concomitant medications and renal function are being examined in a larger cohort to identify any impact on melphalan exposure and subsequently whether PK directed dosing of HDM to achieve a desirable AUC is sufficiently reliable to implement for patients undergoing ASCT. [1] Shaw PJ et al. Biol Blood Marrow Transplant (2012): 18 (2), S207 Abs13. Figure 1. Figure 1. Disclosures Grigg: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background ITP is an autoimmune disorder characterized by isolated thrombocytopenia in the absence of other causes. Although the pathogenetic mechanisms may vary between cases, in common is the accelerated peripheral destruction of platelets due to a failure of self-tolerance and a complex interplay between autoantibodies, autoreactive T cells, antigen-presenting cells and the reticuloendothelial system. Conventional therapies such as glucocorticoids and rituximab target only one or some of these players in autoimmunity. Aims To demonstrate the safety and efficacy of a triple therapy approach to targeting all three major agents for autoimmunity in ITP: B-cells, T-cells and antigen-presenting cells. Simultaneous suppression of these three cell lines may benefit responders with prolonged relapse free survival without the burden of significant additional toxicity. Methods A total of 26 patients with ITP were enrolled into two separate sites with three separate triple therapy protocols (TT4, R1 and R2). Eligibility criteria, definitions and toxicity are as per IWG criteria and CTCAE 4.02. Results 25/26 patients completed treatment as planned. Three required salvage glucocorticoids/IVIG during the first four weeks of therapy. One patient additionally required splenectomy and completed triple therapy. There was only one therapy-related Grade III-IV ASE in all of the treatment protocols: hypertension in a patient with a prior history. All therapy-related Grade I-II ASE listed with numbers of patients affected: hirsuitism and dyspepsia 4; headache, insomnia, nausea and tremor 2; hypertension, blurred vision, diarrhea, peripheral oedema, myalgia, parasthesiae, gum hypertrophy, cramps, chills and mood swings 1. There were no therapy-related SAE although five patients required hospital admission: three during treatment phase (social 1, bleeding due to thrombocytopenia 2) and two over 12 months following therapy (atrial fibrillation with prior history and acute renal failure due to non-steroidal anti-inflammatory drugs). One male patient aged 85 was diagnosed with prostate cancer 18 months following treatment with TT4 and has been successfully treated. Other therapy-unrelated AE included renal colic, gum bleeding, easy bruising, back pain and menorrhagia. Conclusions We report on the efficacy, safety and tolerability of a triple therapy approach to treating adult ITP. Notwithstanding the bias of non-random patient selection, we targeted B-cells, T-cells and antigen-presenting cells without the introduction of serious adverse events over the median follow-up period of 15.8 months across all arms. Overall, the 6 month response rate of 75% appears to be maintained beyond 12 months. Ongoing studies are required to confirm the safety of triple therapy approach to ITP. Although the median 7 days time to response seen in triple therapy compares favourably with other regimens, three patients required salvage therapy while awaiting their final doses of rituximab highlighting the need to further optimise sequential dosing strategies in future studies. Disclosures: No relevant conflicts of interest to declare.

Abstract 4928 Background VRE are nosocomial pathogens with resistance to most commonly used antimicrobial agents. VRE BSI occurs in as few as 4% of patients colonised with VRE[i]. A review of factors contributing to the development of VRE BSI was performed to improve patient safety at St George Hospital. Alarmingly, there were 9 new cases of VRE BSI detected amongst haematology inpatients in early 2010, as compared with only 2 in the previous 6 months. In high risk populations, the rate of VRE BSI amongst patients colonised with VRE can be as high as 29%[ii]. VRE BSI is associated with an increased length of hospital stay from 10.5 to 46 days[iii][iv]and an estimated increased cost of $27,190 per patient[v]. Annual net savings of $100,000-150,000 can be achieved by hospitals detecting 6–9 cases of VRE BSI per year by utilising enhanced infection control strategies[vi]. Methods Admission details for haematology in-patients and their microbiology results between 1/6/2009-30/11/2010 were reviewed. A subsequent case-controlled analysis was performed matching for patient age, disease and disease stage. Interventions to reduce the rate of VRE transmission were introduced in July 2010: improved hand hygiene education, additional staffing allocations, additional cleaning services, antimicrobial stewardship, improved patient education, increased staff awareness, monthly census screening of all patients on the 4 East Oncology/Haematology ward for VRE and contact tracing measures. Results 471 patients were admitted a total of 943 times. VRE was isolated in 61 patients. Average length of stay was significantly longer in patients with VRE than for patients without VRE [16.3±3.0 vs 8.4±1.0 days, p=0.01]. 16 patients had VRE BSI. After a median follow-up of 9.8 months, eight of these patients have died (50% mortality), mostly due to progressive disease. 45 patients had non-BSI VRE and were followed up for a median 8.4 months: 24 died (53% mortality), also mostly due to progressive disease. Case-controlled Analysis An age, case and stage of disease matched analysis compared 14 patients with VRE and 14 with no evidence of VRE. Median follow-up from presentation with disease was 16.3 months and from VRE detection was 8 months. Mortality rate was 64% vs 29%. Seven out of nine deaths in the VRE cohort were due to progressive disease. Conclusions The clinical significance of VRE BSI over other modes of detection remains uncertain for individual patients, however high rates may reflect uncontrolled VRE transmission. Case controlled analysis demonstrates an associated additional mortality risk for VRE positive patients. Disclosures: No relevant conflicts of interest to declare.

Advanced age is a poor prognostic factor in acute myeloid leukaemia (AML). There is evidence that continuous low-dose chemotherapy with oral agents can achieve partial remission in AML and may be suitable as palliative therapy in elderly patients. Such low-dose treatment is usually complicated by drug-related neutropenia and thrombocytopenia. Granulocyte colony stimulating factor (G-CSF) may lessen the associated neutropenia and some anecdotal reports suggest G-CSF alone may be able to induce remission in AML. The study aim was to assess the benefits of combining an oral chemotherapeutic agent with continuous G-CSF. We describe a retrospective audit of 12 elderly patients with AML, diagnosed between 2000 and 2002, who were deemed to be either unfit for induction chemotherapy or who had failed to respond to intravenous chemotherapy. Patients were treated with continuous oral mercaptopurine, thioguanine, or hydroxyurea with concomitant G-CSF on three to seven days/week. The median age at diagnosis was 80 years (range 70–89 years). Eight (67%) had a preceding myelodysplastic syndrome. Eleven of the twelve patients died within the study period described, with a median survival of 9 months (95%CI 4.32–13.75). Eleven patients (92%) had a response to treatment, with blast disappearance obtained within 14 days of starting treatment. All patients achieved an increase in neutrophil count >0.5x109/L. Neutrophil recovery was attained within a mean of 13 days of treatment. From the onset of treatment, patients had neutrophils greater than 0.5 x109/L for 71% of the time, despite being on continuous cytotoxic treatment. Five patients (42%) had a platelet response with a rise in count above 100x109/L. A total of nine (75%) patients experienced a period of platelet transfusion independence and four (33%) patients became red cell transfusion independent for a mean of 4.6 and 4.8 months respectively. The analysis of this small cohort suggests that G-CSF administered in combination with one of the above oral chemotherapeutic agents, may be a novel way of providing treatment to elderly patients with AML which is both tolerable and of potential survival benefit.