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Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared to aggressive B-cell lymphomas. However, such outcomes are heavily dependent upon subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remain the standard first-line treatment for most aggressive PTCLs, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to better understand the pathogenesis of PTCLs to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice. This article is protected by copyright. All rights reserved.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30-40% of lymphoma diagnoses. Though aggressive, cure is achievable in approximately 60% of cases with primary chemo-immunotherapy, and in a further substantial minority by salvage therapy and autologous stem cell transplantation. Despite promising activity in early phase clinical trials, no intensified or novel treatment regimen has improved outcomes over R-CHOP21 in randomised studies. However, there remain several areas of controversy including the most appropriate prognostic markers, CNS prophylaxis and the optimal treatment for patients with high-risk disease. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice. This article is protected by copyright. All rights reserved.

BACKGROUND: Elotuzumab plus lenalidomide and dexamethasone has shown improved progression-free and overall survival versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. We aimed to assess these regimens in patients with newly diagnosed multiple myeloma who are ineligible for haematopoietic stem-cell transplantation (HSCT). METHODS: ELOQUENT-1 is an open-label, multicentre, randomised, phase 3 trial conducted at 185 hospitals, oncology practices, and research centres in 19 countries. Eligible patients were aged 18 years or older with newly diagnosed, untreated, symptomatic myeloma and not candidates for high-dose therapy plus HSCT, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Patients were randomly assigned (1:1) to receive elotuzumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone using an interactive voice response system, stratified by the International Staging System (ISS; stage I-II vs III), age (

The management of Hodgkin Lymphoma (HL) has undergone significant changes in recent years. Due to the predilection of HL to affect younger patients, balancing cure and treatment related morbidity is a constant source of concern, for physicians and patients alike. PET adapted therapy has been developed for both early and advanced stage HL to try and improve the outcome of treatment, whilst minimising toxicities. The aim of this review is to digest the plethora of studies recently conducted and provide some clear, evidence-based practice statements to simplify the management HL. This article is protected by copyright. All rights reserved.

Patients post haematopoietic stem cell transplant or CAR-T cell therapy face significant risk of morbidity and mortality from SARS-CoV19, due to their immunosuppressed state. As case numbers in Australia and New Zealand continue to rise, guidance on management in this high-risk population is needed. Whilst we have learnt much from international colleagues who faced high infection rates early in the pandemic, guidance relevant to local health system structures, medication availability and emerging therapies is essential to equip physicians to optimally manage our patients. This article is protected by copyright. All rights reserved.

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

Australia and New Zealand have achieved excellent community control of COVID-19 infection. In light of the imminent COVID-19 vaccination roll out in both countries, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 vaccination in patients with haematological disorders. It is our recommendation that patients with haematological malignancies, and some benign haematological disorders, should have expedited access to high-efficacy COVID-19 vaccines, given that these patients are at high risk of morbidity and mortality from COVID-19 infection. Vaccination should not replace other public health measures in these patients, given that the effectiveness of COVID-19 vaccination, specifically in patients with haematological malignancies, is not known. Given the limited available data, prospective collection of safety and efficacy data of COVID-19 vaccination in this patient group is a priority. Refereed/Peer-reviewed

Myeloproliferative neoplasms are characterised by somatic mutations in pathways that regulate cell proliferation, epigenetic modifications, RNA splicing or DNA repair. Assessment of the mutational profile assists diagnosis and classification, but also aids assessment of prognosis, and may guide the use of emerging targeted therapies. The most practical way to provide information on numerous genetic variants is by using massively parallel sequencing, commonly in the form of disease specific next generation sequencing (NGS) panels. This review summarises the diagnostic and prognostic value of somatic mutation testing in Philadelphia-negative myeloproliferative neoplasms: polycythaemia vera, essential thrombocythaemia, primary myelofibrosis, chronic neutrophilic leukaemia, systemic mastocytosis, and chronic eosinophilic leukaemia. NGS panel testing is increasing in routine practice and promises to improve the accuracy and efficiency of pathological diagnosis and prognosis. Refereed/Peer-reviewed

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.

Background Modern antiretroviral therapy (ART) has reduced HIV associated morbidity and mortality, and allowed a similar treatment approach of aggressive lymphomas in PLWH to that of their HIV negative counterparts. Australia is an ethnically diverse country with a low HIV prevalence and an excellent population-wide ART coverage and adherence in PLWH. We aimed to describe the real-world Australian experience in managing PLWH diagnosed with diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL), and compare our treatment approach and outcomes against international data. Methods This was a retrospective, multicenter study conducted by the Australasian Lymphoma Alliance across 6 centers in 5 states. HIV positive patients with biopsy proven BL and DLBCL, diagnosed between 1st January 2009 and 31st December 2019 were identified through each institution's database. Baseline patient and disease characteristics, treatment exposure and outcomes were extracted from hospital medical records. Descriptive statistics, and survival analyses were performed as appropriate. Results 44 patients (24 DLBCL, 20 BL) were included in the analysis. The median age was 52 years (range 32-78). The median follow-up was 1.8 years (range 0.1-13.1). 36 (82%) patients presented with advanced stage (III-IV) disease. 28 (64%) were defined as high-risk based on disease specific IPI scoring systems. The mean CD4 count was 334 cells/μL at diagnosis and 10 (23%) patients had a CD4 count of 350 cells/μL and >200 cells/μL respectively. Conclusions A significant proportion of PLWH still present with aggressive lymphoma as an AIDS-defining event prior to HIV diagnosis, despite high levels of health education and healthcare availability. Our results appear equivalent to those for non-HIV patients with acceptable toxicity. Current Australian practice favors treating aggressive lymphomas in PLWH similarly to the HIV negative population, with the addition of concurrent ART. CD4+ T-cell-related immune reconstitution appears to recover within 6 months post-therapy. The OS of this cohort appears similar to the HIV negative population and published cohort studies (Coutinho AIDS 2013, Evens Blood 2019, Alderuccio Blood Adv 2021). Figure 1 Figure 1. Disclosures Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cheah: Beigene: Consultancy, Honoraria, Other: advisory; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory. Ku: Genor Biopharma: Consultancy; Antegene: Consultancy; Roche: Consultancy.

Aim: Primary Central Nervous System Lymphoma (PCNSL) [i.e. diffuse large B-cell lymphoma of the CNS] is a rare and poor-prognosis disease occurring predominantly in older patients (median age >60 years old). Prospective studies of two commonly used chemoimmunotherapy (CIT) protocols, MATRix and MPV/Ara-C (± rituximab), have reported 2-year PFS and OS of 57-61% and 69-81% respectively. Our aim was to evaluate registry-reported outcomes of frontline CIT strategies employed at Australasian sites. Method: A retrospective study of consecutive, immunocompetent, adult PCNSL patients (WHO criteria: 2017) treated with curative-intent CIT, from 10 sites (9 Australian, 1 Singaporean) between 1 st January 2009 and 31 st December 2018 (i.e. ten-year period). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier (log-rank) method. Univariate associations were derived using a Cox model with variables p Results: Data was collected on 207 patients, 189 of whom met WHO diagnostic criteria for PCNSL (i.e. diffuse large B-cell lymphoma of the CNS). We excluded patients with insufficient data (6), non-DLBCL histology (6), secondary PCNSL (3) and post-transplant lymphoproliferative disorder (3). Of these, 176 (93%) received curative-intent CIT. The majority (66%) were over 65 years of age (median: 65, range: 25-87); ECOG performance status was ≥ 2 in 31% (data not available for 14% of patients). The majority were male (55%) and had deep structure involvement (64%). International Extranodal Lymphoma Study Group (IELSG) risk criteria could not be calculated in many patients due to missing data (predominantly LDH and CSF protein). CSF involvement was rare (n=23, 13%) but data was only available for 60% of patients. Of the 159 with documented renal function, 26% had renal impairment (defined as Cockroft-Gault creatinine clearance Five CIT regimens were used: MATRix (n=16), MPV/Ara-C + rituximab (Rtx) (n=94), MBVP+- Rtx (n=11), MTX +-Rtx (n=31) and MTX/Ara-C +- Rtx (n=24). Intrathecal chemotherapy was used in only 29 patients (16%), and almost exclusively in combination with R-MPV. Median cumulative MTX dose was 17,500mg/m 2 (range: 1,000-64,000mg/m 2) and 69% received Ara-C (median dose: 12,000mg/m 2 [range: 1,000-44,000mg/m 2]). Eighty percent of patients achieved an overall response at the end of MTX therapy, with 52% achieving a complete response [data unavailable in n=29, 16%]. Estimated 2-year PFS and OS for the entire cohort were 54% (95%CI: 0.46-0.62) and 77% (95%CI: 0.70-0.83) respectively at a median follow-up of 2 years. Older patients (>60yo) had shorter PFS but similar OS compared to their younger counterparts (2-year PFS: 47% vs 68%, p: 0.015, HR: 1.73, 95%CI: 1.11-2.70; 2-year OS: 74% vs 80%, p: 0.145, HR: 1.38, 95%CI: 0.81-2.33). R-MPV achieved superior PFS compared to MATRix although comparison was limited by low numbers in the MATRix cohort (n=16 vs n=94), likely reflective of the census period [2-year PFS: 74% vs 44% p: 0.025, HR 0.41, 95%CI 0.13-1.28]. Neither WBRT (n=57, 32%) nor ASCT (n=13, 7%) conferred a survival advantage but addition of rituximab (n=153, 87%) was associated with improved PFS (p: 0.007, HR: 0.47, 95%CI: 0.19-0.75). On multivariate analysis, type of induction CIT (p: 0.004, HR: 1.42, 95%CI: 1.23-1.42), cumulative MTX dose (p: 0.022, HR: 0.88, 95%CI: 0.83-0.94) and cumulative Ara-C dose (p: 0.016, HR: 0.76, 95%CI: 0.64-0.87) were associated with improved PFS. Cumulative MTX dose (p: 0.02, HR: 0.85, 95%CI: 0.78-0.92) and cumulative Ara-C dose (p: 0.007, HR: 0.67, 95%CI: 0.51-082) were also associated with improved OS. Conclusion: Registry-reported outcomes of contemporary CIT induction for PCNSL are favourable when compared to published trials and historical regimens. PCNSL with contemporary treatment should no longer be considered an invariably poor-prognostic disease. Data supports recent literature highlighting prognostic significance associated with maintenance of chemotherapy dose intensity (Martinez-Calle et al., Br J Haematol. 2020 Aug; 190(3):394-404. doi. 10.1111/bjh.16592). Figure 1 Figure 1. Disclosures Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties: Conference attendance; Novartis: Patents & Royalties: Conference attendance; Roche: Consultancy, Honoraria. Gunjur: Myers Squibb: Honoraria. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Shortt: Amgen: Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Talaulikar: Roche: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Hawkes: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Regeneron: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck KgA: Research Funding; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Specialised Therapeutics: Consultancy; Antigene: Membership on an entity's Board of Directors or advisory committees. Cheah: MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; AstraZeneca: Consultancy, Honoraria, Other: advisory; Celgene: Research Funding; AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Gilead: Consultancy, Honoraria, Other: advisory. Opat: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment. Gregory: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy.

MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (dohle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if dohle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.

The setting of chronic immunosuppression in inflammatory bowel disease (IBD) may promote the proliferation of Epstein-Barr virus-positive neoplastic clones. We report two rare cases of Epstein-Barr virus-associated lymphoproliferative disorder in IBD patients: one resembled lymphomatoid granulomatosis, and the other was a lymphoma resembling Hodgkin lymphoma. There are currently no guidelines for the prevention of lymphoproliferative disorder in IBD patients on immunosuppressive therapy.

FISH analysis of cultured fixed cell suspensions from marrow aspirate is routinely used to diagnose and risk stratify haematological neoplasms. Occasionally, the aspirate is hypoparticulate due to fibrosis, extensive infiltration or operator error. Accordingly, the utility of FISH is reduced due to an absence of neoplastic cells. Although FISH can be performed on formalin fixed, paraffin embedded tissue, e.g., trephines, the success of this technique is variable, subject to certain technical limitations and not available in all laboratories. FISH has been successfully applied to other tissue imprints but its specific application to trephine imprints is not yet widely reported. We aimed to assess the feasibility of FISH analysis on imprints obtained from diagnostic marrow trephines. From our database, five samples positive by FISH for abnormalities with diagnostic, therapeutic or prognostic implications were identified [one each of Ph + ALL, AML t(8;21), APL, CMML inv3 and mantle cell lymphoma]. FISH was performed on stored air-dried imprints of the trephines: in all cases, yielding adequate/comparable signals to that of the cell suspension. These findings suggest FISH on trephine imprints is feasible, may be helpful if the aspirate is hypoparticulate, and that prospective study of its yield in that situation is warranted.

Background The diagnosis and treatment of CLL may have a great impact on the quality of life (QoL) due to a variety of reasons including disease-related symptoms, infection, effects of therapy and the emotional, socio-economic, and functional effects of living with an 'incurable' illness. The main aim of any treatment is to maximize QoL by inducing remission with minimal short- and long-term toxicity. Balancing disease and symptom control with QoL in elderly patients receiving CLL therapy regimens can be challenging. There is little published QoL data in elderly CLL patients receiving the FCR (fludarabine, cyclophosphamide, rituximab) immunochemotherapy regimen. Our prior study showed no significant difference in health related QoL for first-line therapy of CLL with monotherapy between chlorambucil, fludarabine and cladribine (Mulligan, SP et al. Leuk Lymphoma, 2014). Aim We report the QoL assessments of CLL patients enrolled in the ALLG clinical trial CLL5, a randomised, 3-arm, dose de-escalation study of the FCR regimen. Methods The treatment schedule has been described with fit elderly patients randomly assigned to one of three treatment regimens: FR5, FCR3, and FCR5 (Mulligan SP et al. iwCLL Abstract, 2015). Treatment was repeated every 28 days for a planned total of 6 cycles. Importantly, an early stopping rule mandating cessation of therapy was included for any patient having grade 3 or 4 toxicity lasting >2 weeks. QoL assessments using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were measured at 8 time points: before commencement of therapy, at the end of the 3rd and 6th cycles of treatment, at the final staging and thereafter every 3 months for 12 months. Results Of the 116 evaluable in the study, 2 patients had no QoL data, 6 patients had only baseline QoL data, and 4 patients had no baseline QoL data, therefore the number of patients included in the QoL analysis was 104. There appeared to be a trend towards improved global health (figure 1), physical functioning (figure 2) and role functioning with full dose (FCR5) towards the end of the follow-up period compared to commencement of therapy. Comparison of cognitive functioning (figure 3) between the three arms showed a statistically significant improvement with FCR5. However, on multivariate analysis there was no statistical significant difference. Conclusions Despite a trend favouring full-dose FCR, there were no definitively significant differences in the QoL domains following treatment with FCR-based immunochemotherapy between the three different groups. QoL continues to be a neglected issue, particularly for the typical elderly CLL patient. This study highlights the need for objective QoL assessment as part of all CLL trials, especially those targeted in the typical elderly patient. Figure 1. Mean change from baseline global health status scores with 95% confidence intervals Figure 1. Mean change from baseline global health status scores with 95% confidence intervals Figure 2. Mean change from baseline physical functioning scores with 95% confidence intervals Figure 2. Mean change from baseline physical functioning scores with 95% confidence intervals Figure 3. Mean change from baseline cognitive functioning scores with 95% confidence intervals Figure 3. Mean change from baseline cognitive functioning scores with 95% confidence intervals Disclosures Gill: Roche: Research Funding; Sanofi Aventis: Research Funding; AbbVie: Honoraria; Roche: Honoraria. Turner:Roche: Research Funding; Sanofi Aventis: Research Funding. Renwick:Sanofi Aventis: Research Funding; Roche: Research Funding. Latimer:Sanofi Aventis: Research Funding; Roche: Research Funding. Mackinlay:Sanofi Aventis: Research Funding; Roche: Research Funding. Berkahn:Sanofi Aventis: Research Funding; Roche: Research Funding. Simpson:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Forsyth:Sanofi Aventis: Research Funding; Roche: Research Funding. Cull:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel. Harrup:Roche: Research Funding; Sanofi Aventis: Research Funding. Kuss:Sanofi Aventis: Research Funding; Roche: Research Funding. Mulligan:Sanofi Aventis: Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Aims To describe a case of 2 copies of inv (3) in CMML-2. Method Describe cytogenetic and clinical findings in a patient with CMML-2. Results A 59-year-old female presented to hospital in March 2014 with renal colic. An incidental finding of macrocytic anaemia, monocytosis and 4% blasts on peripheral blood was noted. She was subsequently diagnosed with CMML-2 (14% blasts). Cytogenetic analysis from the marrow aspirate of GTL banded metaphases detected an inversion of chromosome 3 involving bands 3q21 and 3q26 in both chromosome 3 homologues in 58/60 cells. In the remaining 2 cells detected, only one homologue with inv(3)(q21q26) was noted. Subsequent fluorescent in situ hybridisation (FISH) investigation with a MECOM break apart probe detected signals consistent with 2 copies of inv(3) in 85/200 (42%) cells. Azacitidine treatment had an unsatisfactory response. Allogeneic stem cell transplant is planned for December 2014. Discussion 2 copies of inv(3) observed in this case of CMML-2 has not been previously reported. SNP microarray studies are in progress to determine loss of heterozygosity or if both chromosome 3 s have independently undergone the same inversion. Impact of this abnormality on clinical course and prognosis is yet unknown.

BACKGROUND: Fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free (PFS) and overall survival (OS) versus (vs) FC in the CLL8 Study. The median age in CLL8 was 61 years compared to 72 years for CLL overall. We aimed to assess the safety, tolerability and efficacy of FCR based therapy in elderly patients (pts). METHODS: Previously untreated pts with progressive CLL aged ≥65 were randomised to one of 3 therapy arms: (i) FR5: F 24mg/m2 po D1-5 + R (375mg/m2 cycle 1, 500mg/m2 cycles 2-6) iv D1, (ii) FCR3: F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 or (iii) FCR5: F 24mg/m2 po+ C 150mg/m2 po D1-5 + R iv D1 all at 4 weekly intervals for an intended 6 cycles. Cycles could be delayed up to 2 weeks for grade 3+ toxicity, and if unresolved by 2 weeks, pts were taken off study. All analyses were by intention to treat (ITT) and adjusted for pre-treatment Binet stage. RESULTS: Recruitment of 120 pts was completed in July 2012. 117 fulfilled eligibility and 1 had no treatment or follow-up reducing the cohort to 116. Median age was 71 (range 65-82) years; 78 males (67%) and 39 females (33%). Binet stage was progressive A - 19 (16.2%), B – 55 (47.0%), C – 43 (36.8%). Response data are shown in table 1 and grade 3+ toxicity in table 2. All 6 protocol cycles were completed in 69% but less on FCR5 44% vs FR5 89% and FCR3 76% (p ORR was high in all 3 arms but CR rates were higher with FCR5 (p Toxicity was lower with FR5 compared to FCR3 and FCR5 (p=0.004) (FCR3 vs FCR5 NSS). Dose delay occurred in 43 pts (37%): FR5 12 (32%), FCR3 14 (34%), FCR5 17 (44%) (p=0.653), but early cessation due to toxicity was more common with FCR5 (p CONCLUSIONS: Final analysis shows oral FCR therapy is generally safe and well tolerated in CLL pts aged ≥65 years requiring first-line treatment, when early stopping is utilised if prolonged toxicity occurs. Toxicity was mostly hematological and manageable. Response rates were very high with ORR of 96% and CR rate of 56% (39% not including CRu). Full dose FCR is highly effective and while cessation due to toxicity appears important, a dose intensity effect may exist. Dose reduced FCR provides a balance of effectiveness, safety and tolerability as first-line therapy for fit elderly pts. Disclosures Mulligan: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria. Gill:Roche: Research Funding; Sanofi Aventis: Research Funding. Turner:Roche: Research Funding; Sanofi Aventis: Research Funding. Renwick:Roche: Research Funding; Sanofi: Research Funding. Latimer:Roche: Research Funding; Sanofi: Research Funding. Mackinlay:Roche: Research Funding; Sanofi: Research Funding. Berkahn:Roche: Research Funding; Sanofi: Research Funding. Simpson:Onyx: Honoraria, Research Funding; Celgene: Honoraria; Janssen Cilag: Honoraria. Forsyth:Roche: Research Funding; Sanofi: Research Funding. Harrup:Roche: Research Funding; Sanofi: Research Funding. Kuss:Roche: Research Funding; Sanofi: Research Funding.

BACKGROUND Fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free (PFS) and overall survival (OS) versus (vs) FC in the CLL8 Study. The median age in CLL8 was 61 years compared to 72 years for CLL overall. There has been considerable debate regarding the tolerability and toxicity of FCR based therapy in older patients (pts) and those with comorbidities. METHODS Previously untreated fit pts with progressive CLL aged ≥65 were randomised to one of 3 therapy arms: (i) FR5: F 24mg/m2 po D1-5 + R iv D1 (375mg/m2 cycle 1, 500mg/m2 cycles 2-6), (ii) FCR3: F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 or (iii) FCR5: F 24mg/m2 po+ C 150mg/m2 po D1-5 + R iv D1 all at 4 weekly intervals for an intended 6 cycles. Cycles could be delayed up to 2 weeks for grade 3+ toxicity, and if unresolved by 2 weeks, pts were taken off study. Fitness was assessed using the Cumulative Illness Rating Scale (CIRS) score with eligibility restricted to CIRS ≤6. RESULTS Recruitment of 120 pts was completed in July 2012. 117 fulfilled eligibility and 1 had no treatment or follow-up reducing the cohort to 116. Median age was 71 (range 65-82) years (yrs) with 78 males (67%) and 39 females (33%). Patient registration by age was 65-69 yrs – 44, 70-74 yrs – 44, 75-79 yrs – 20 and 80-84 yrs – 8 pts, and by CIRS score was 0-2 – 61, 3-4 – 38, 5-6 – 17 pts. Toxicity data by age and CIRS score are shown in tables 1 and 2 respectively. All 6 protocol cycles were completed in 69% but less on FCR5 44% vs FR5 89% and FCR3 76% (p There was no statistically significant difference by age (p=0.429). Table 2:Grade 3+ Adverse Events by CIRS scoreCIRS scoreTotal0-23-45-6(n=116)(N=61)(N=38)(N=17)Hematological38 (62%)21 (55%)11 (65%)70 (60%)Neutropenia31 (51%)16 (42%)11 (65%)58 (50%)Thrombocytopenia11 (18%)6 (16%)2 (12%)19 (16%)Anaemia7 (11%)5 (13%)3 (18%)15 (13%)Haemolytic Anaemia1 (2%)4 (11%)0 (0%)5 (4%)Febrile Neutropenia / Infection11 (18%)9 (24%)4 (24%)24 (21%)Skin/Allergy/Fatigue/hypersensitivity6 (10%)4 (11%)1 (6%)11 (9%)Other (Card / resp / neuro / metabolic)12 (20%)9 (24%)6 (35%)27 (23%)At least 1 grade 3+ AE78 (79%)27 (71%)15 (88%)90 (78%) There was no statistically significant difference by CIRS score (p=0.355). Table 3:Abbreviated Grade 3+ Adverse Events by Treatment ArmTreatment armTotal (n=116)FR5 (N=37)FCR3 (N=41)FCR5 (N=38)Hematological15 (41% )26 (63% )29 (76% )70 (60%)At least 1 grade 3+ AE21 (57%)34 (83%)35 (92%)90 (78%)Early cessation due to toxicity2 (5.6%)1 (2.4%)13 (34%)16 (14%) Early cessation due to toxicity was significantly more common with FCR5 (p CONCLUSIONS Final analysis in this randomised dose de-escalation study shows oral FCR therapy is generally safe and well tolerated in CLL pts aged ≥65 years requiring first-line treatment, when early stopping is utilised if prolonged toxicity occurs. Early cessation due to toxicity was more common with full dose FCR5, but not associated with age or CIRS score within this arm. Overall in this relatively fit elderly CLL cohort, neither age nor CIRS score were associated with toxicity, or early cessation of therapy due to toxicity. The results highlight the difficulty of predicting toxicity based on age and comorbidity in elderly CLL pts. Disclosures Mulligan: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria. Gill:Roche: Research Funding; Sanofi Aventis: Research Funding. Turner:Roche: Research Funding; Sanofi Aventis: Research Funding. Renwick:Roche: Research Funding; Sanofi: Research Funding. Latimer:Roche: Research Funding; Sanofi: Research Funding. Mackinlay:Roche: Research Funding; Sanofi: Research Funding. Berkahn:Roche: Research Funding; Sanofi: Research Funding. Simpson:Roche: Research Funding; Sanofi: Research Funding. Forsyth:Roche: Research Funding; Sanofi: Research Funding. Harrup:Roche: Research Funding; Sanofi: Research Funding. Kuss:Roche: Research Funding; Sanofi: Research Funding.

Abstract 436 Background: Combination immunochemotherapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free and overall survival compared to FC in the CLL8 Study. The median age in CLL8 was 61 years compared to a median age for overall CLL patients of 72 years. There is ongoing debate regarding the tolerability and safety of FCR in elderly patients, and what are the most appropriate criteria for selection of therapy. Methods: Previously untreated patients with progressive CLL aged ≥65 were randomised to one of three treatment regimens FR5, FCR3 and FCR5 as follows: (i) F 24mg/m2 po D1-5 + R (375 mg/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/m2po D1-5 + R iv D1 (FCR5), all given at 4 weekly intervals for an intended 6 cycles. The dosage of FCR5 is equivalent to standard 3 day IV FCR in the CLL8 Study. Patients were administered their therapy arm with no dose reduction but fludarabine dose was reduced if the eGFR was 50–69ml/min. Therapy was delayed up to 2 weeks if there was grade 3 or 4 toxicity, and if unresolved after 2 weeks, patients were taken off study. If toxicity resolved to grade 2 or less, therapy proceeded. Results: Recruitment of all 120 randomised patients was completed in July 2012. An analysis was performed with a cut-off date of 5 May, 2012 at which time there were 117 of 120 recruited from 29 centres in Australia and New Zealand. Median age was 71.7 (range 65–83) years. Binet stage at registration was progressive A – 20 (17.1%), B – 55 (47.0%) and C – 42 (35.9%). Response data are shown in table 1 for the total patient cohort - no analysis has been performed to date by treatment arm. Analysis of grade 3 and 4 toxicity events by Cumulative Illness Rating Scale (CIRS) score and age are shown in Tables 2 and 3 with data available at the cut-off date. Conclusions: Oral F(C)R therapy appears generally safe and well tolerated in CLL patients aged ≥65 years requiring first-line treatment according to data available at end of recruitment. Using stringent stopping criteria with delay of 2 weeks for recovery of grade 3 or 4 toxicity but no dose reduction, ∼40% of patients stop early due to toxicity, intercurrent illness or patient choice. Based on the 66 patients with completed Final Pathological Staging 2 months after end of therapy, response rates appear high with an overall response rate (ORR) of 92.3%. For this relatively fit elderly patient cohort, neither a CIRS score of 0 to 6, nor age predicted for grade 3 and 4 toxicity. Disclosures: Mulligan: Roche: Consultancy, Research Funding, Speakers Bureau; Genzyme: Consultancy, Research Funding, Speakers Bureau.