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Obinutuzumab (G)-chemoimmunotherapy demonstrated improved progression-free survival (PFS) versus rituximab-based chemoimmunotherapy in patients with previously untreated follicular lymphoma (FL) in the GALLIUM trial. Atezolizumab (atezo) is a programmed death-ligand 1 inhibitor with a complementary mechanism of action to G, by restoring cytotoxic T-cell function. We evaluated the safety and efficacy of atezo-G-bendamustine in patients with previously untreated FL in a phase Ib/II trial (NCT02596971). A safety run-in phase was followed by an expansion phase with atezo-G-bendamustine induction, and atezo-G maintenance for <= 24 months. Forty patients with previously untreated FL were enrolled and treated with atezo-G-bendamustine. The primary endpoint, complete response (CR) rate, assessed by an independent review committee (IRC; modified Lugano 2014 criteria) was 75.0% (95% confidence interval [CI], 61.3-85.8). Three-year investigator-assessed PFS and overall survival rates were 80.9% (95% CI, 63.9-90.5) and 89.3% (95% CI, 73.9-95.9), respectively. At baseline, 21/40 patients had circulating lymphoma-specific clonotypes and underwent repeat testing at end of induction; all these were minimal residual disease negative (10-5 sensitivity), with 16 (76.2%) CRs, 3 (14.3%) partial responses, and 2 (9.5%) with stable disease (IRC-assessed). Grade 5 (fatal) adverse events (AEs) were reported in five patients. The efficacy of atezo-G-bendamustine in previously untreated FL did not appear superior to G-bendamustine efficacy as seen in the GALLIUM trial, and the addition of atezo to G-bendamustine was associated with an increased risk of AEs. Particularly due to the unfavorable safety profile, this regimen cannot be recommended in patients with previously untreated FL. This trial is registered at www.clinicaltrials.gov as NCT02596971.Copyright © 2022 American Society of Hematology.

Background: Histologic transformation (HT) is an important event with adverse prognosis in the natural history of indolent lymphomas. There are minimal data on HT in the Australian setting. Aim(s): To characterise patients with biopsy-proven HT and their outcomes identified at a tertiary Australian Hospital. Method(s): All patients with biopsy-proven HT during a 15-year period (2002-2017) were included. Clinico-pathological data were systematically collected from review of patient records. Survival estimates were assessed using the Kaplan-Meier method and compared using the log-rank test. Associations between variables and clinical outcomes were evaluated using Cox's proportional hazards model. Result(s): A cohort of 45 patients was identified with a median age of 66 years and the majority (59%) having high-risk disease (Revised-International Prognostic Index score >=3). R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) induction was used in 69%, with an overall response rate of 82% (complete response (CR), 75%). Sixty-one percent of these induction responders received consolidation, with autologous stem cell transplant (ASCT) performed in only 17% and rituximab maintenance given to 31%. With a median follow up of 47 months (range: 4-136), the 5-year overall survival (OS) was 69% (95% CI: 52%, 81%). Chemotherapy-naivety at HT was associated with a superior rate of CR (84% vs 54%, P = 0.057) and 5-year OS (82% vs 46%, P = 0.012). Rituximab maintenance was associated with a durable progression-free survival in induction responders. Conclusion(s): Excellent OS was observed in this modern cohort of patients treated with rituximab-containing induction and low rate of consolidation by ASCT, particularly in those who were chemotherapy-naive at HT.Copyright © 2020 Royal Australasian College of Physicians

[Formula presented] Background: Langerhans Cell Histiocytosis (LCH) is a rare inflammatory neoplasm originating from bone marrow-derived CD207+/CD1+ clonal dendritic cells, with cells expressing BRAF V600E in around 50% of cases. Although more common in the paediatric setting, LCH is rare in adults, with an incidence of 1 to 2 cases per million. This combination of disease heterogeneity and infrequency means that data on treatment strategies and outcomes is limited, and a consensus on management is lacking. Data has historically been extrapolated from the larger paediatric cohort, with emerging phase II data on the efficacy and safety of upfront methotrexate and cytosine arabinoside (AraC) in adult LCH. Other agents used include cladribine (CdA), hydroxyurea, vinblastine, and prednisolone-based regimens, and more recently MEK/BRAF inhibitors, but none of these have been trialled prospectively. LCH can be an aggressive disease with a poor prognosis. Methods : We included patients aged >=18 years diagnosed with LCH on histopathology between January 1, 2000 and August 1, 2021 from ten sites across Australia and New Zealand. Variables included demographic data, system and organ involvement, central nervous system (CNS) involvement, bone marrow involvement and BRAF V600E mutation status. Outcomes measured included overall survival (OS), progression-free survival (PFS) and total lines of therapy. Response to therapy was modified from the Scoring System of the HS LCH III trial: Complete response (CR) was defined by resolution of all signs of disease activity, including neuroendocrine dysfunction, skin and radiological lesions; and a partial response (PR) was defined as patients with "active disease better" and those with "mixed response". Stable or worsening symptoms/radiology were classified as progressive disease (PD). Patients who were alive or lost to follow-up were censored on the date of last follow-up. Results : We identified 46 patients with a median age at diagnos

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. Positron emission tomography adapted therapy has been developed for both early and advanced stage HL to try and improve the outcome of treatment, while 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 of HL.Copyright © 2021 Royal Australasian College of Physicians.

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(s): 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<0.10 entered stepwise into a multivariate model. Result(s): 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 <60ml/min or eGFR <90ml/min). Five CIT regimens were used: MATRi

Background: In primary central nervous system lymphoma (PCNSL), venous thromboembolism (VTE) can cause significant morbidity and hinder chemotherapy delivery. Objective(s): To assess VTE incidence, timing and adequacy of inpatient and outpatient VTE prophylaxis in patients with PCNSL receiving chemoimmunotherapy with curative intent. Patients/Methods: We reviewed patients diagnosed with PCNSL between 1997 and 2018 who received methotrexate, procarbazine, and vincristine +/- Rituximab. Patient demographics, VTE prophylaxis and incidence, adverse events of anticoagulation, and survival outcomes were collected. Result(s): Fifty-one PCNSL patients were included (median 67 years [range, 32-87], 30 males [59%]). Thirteen patients (25%, 95% confidence interval [CI], 14-40) developed VTE at a median of 1.6 months from diagnosis (range, 0-4). Patients with Khorana Risk Score >=2 were more likely to have VTE than those with a KRS < 2 (60% vs 15%; P =.01). Eighty-five percent had deviations from inpatient VTE prophylaxis guidelines, and outpatient prophylaxis was not routinely administered. Three patients required inferior vena cava filters. Hemorrhagic complications of anticoagulation included an intracranial hemorrhage from therapeutic anticoagulation and three cases of major bleeding from prophylactic anticoagulation. No patients died from VTE or its treatment. Conclusion(s): Patients with newly diagnosed PCNSL are at high risk of VTE. Further research is required into optimal VTE prophylaxis in PCNSL.Copyright © 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH)

[Formula presented] Introduction Central nervous system relapse (secondary central nervous system lymphoma -SCNS) is an uncommon but devastating complication of aggressive B-cell lymphoma. Patients (Pts) with CNS-IPI 4-6 are at greatest risk (10.2% at 2 years). Intravenous high-dose methotrexate (HD-MTX) is widely used to mitigate SCNS risk but data supporting this practice are limited. Methods We performed a multicentre, retrospective study at 21 sites in Australia, Asia, North America and Europe. Chart or registry review was performed for consecutively diagnosed pts with diffuse large B-cell lymphoma (DLBCL) and CNS-IPI 4-6, high grade B-cell lymphoma (HGBL) with rearrangements of MYC+BCL2 and/or BCL6 and primary breast/testicular DLBCL irrespective of CNS-IPI. Pts were diagnosed between 2000-2020, 18-80 years at diagnosis, and treated with curative intent anti-CD20 based chemo-immunotherapy. Pts with CNS involvement at diagnosis were excluded. HD-MTX was defined as at least one cycle of intravenous MTX at any dose. Time to SCNS was calculated from date of diagnosis (all-pts), and from the end of frontline systemic lymphoma therapy, defined as 6x21 days from diagnosis (complete response (CR-pts)), until SCNS, systemic relapse, death, or censoring, whichever came first. Cumulative risk of SCNS was computed using the Aalen-Johansen estimator treating death and systemic relapses as competing events. Adjusted cumulative risks were obtained by using an inverse probability of treatment weighting approach. The average treatment effect was computed as the difference in adjusted 5-year risk of SCNS. Results - 2300 and 1455 pts were included in the all-pts and CR-pts analyses, respectively. Baseline demographics and details of therapy are summarised in Table 1. Except for a predominance of males, pts <=60 years and pts with ECOG 0-1 in the HD-MTX vs no HD-MTX groups, the demographics and treatments were well balanced. At a median follow up of 5.9 years (range 0.0-19.1) and

BACKGROUND: Ferric carboxymaltose is increasingly utilised to treat iron deficiency and is usually diluted in saline and administered as an intravenous infusion over 15 minutes. Whilst this is highly convenient compared with older formulations, we hypothesised the drug could be administered safely given as a rapid bolus injection. AIMS: To define the risk of serious adverse events following administration of an undiluted, rapid, high dose ferric carboxymaltose injection. Secondary aims included all other adverse events, as well as longitudinal effects on haemoglobin, iron stores, phosphate, and hepcidin. METHOD(S): In a single arm, Phase II study in 121 patients with iron deficiency anaemia, we administered up to 1000mg of ferric carboxymaltose as a rapid undiluted bolus injection, and recorded adverse events and collected blood samples over the first hour, and again at two and four weeks post-treatment. RESULT(S): No patient experienced a serious adverse event. Flushing during the injection was common, as was a transient headache in the subsequent weeks. A single patient experienced Grade 3 chest tightness necessitating emergency department assessment but not admission or treatment. Treatment produced an average 12.3g/L improvement in haemoglobin within two weeks, but commonly caused reductions in serum phosphate (although none of these were clinically symptomatic). Parenteral iron caused elevations in hepcidin sustained to four weeks post injection. Patients stated they would be prepared to receive the treatment again. CONCLUSION(S): Rapid injection of undiluted ferric carboxymaltose is well tolerated and could provide an approach to treat patients in the ambulatory setting. This article is protected by copyright. All rights reserved.

Background: Prophylactic immunoglobulin (Ig) replacement and prophylactic oral antibiotics (PA) are used to prevent infections in patients with haematological malignancies and acquired hypogammaglobulinemia. Ig has been shown to reduce infection risk, but is costly and in limited supply. PA have been shown to reduce infection risk in other patient populations and are less expensive, but have side-effects and can increase antimicrobial resistance rates. Guidelines and clinical practice vary internationally, with some recommending a trial of PA prior to commencing Ig replacement, and others omitting PA. The efficacy, safety and cost-effectiveness of Ig and PA have not been directly compared in a randomised controlled trial (RCT) in patients with acquired hypogammaglobulinemia secondary to haematological malignancies. Aim(s): To determine the feasibility of delivering PA as an alternative to Ig replacement in patients with haematological malignancies and acquired hypogammaglobulinemia. Method(s): Phase II, multicentre, feasibility RCT (ACTRN12616001723471). Eligible patients had acquired hypogammaglobulinemia due to a haematological malignancy, a history of recurrent or severe bacterial infections or an IgG level <4g/L (excluding paraprotein), and had a life expectancy more than 12 months. Exclusion criteria included prior allogeneic haematopoietic stem cell transplant and prior Ig replacement in the preceding 3 months. Patients were randomised to receive Ig (0.4g/kg IV every 4 weeks, modified to achieve an IgG trough level >= lower limit of reference range; or 0.1g/kg/week SC, modified to achieve an IgG trough level of >= lower limit of reference rage) or daily oral prophylactic antibiotics (trimethoprim-sulfamethoxazole 160mg/800mg, with 100mg doxycycline as an alternative for hypersensitivity) for 12 months at a 1:2 ratio. Randomisation was stratified by site. Patients allocated to PA were allowed to cross over to Ig if they experienced a CTCAE >= Grade 3 infection.

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/muL at diagnosis and 10 (23%) patients had a CD4 count of <100 cells/muL. 23 (52%) had a HIV viral load <50 copies/ml. 12 (27%) were diagnosed with HIV at the time of lymphoma diagnosis (Mean CD4 count 191 cells/muL, mean viral load 665,612 copies/ml). 41 (93%) patients received chemotherapy with curative intent and 39 (88%) received Rituximab. 37 (84%) were given concurrent ART and chemo(immuno)therapy. 11 (55%) of BL patients were treated with CODOX-M/IVAC or HyperCVAD followed by 6 (30%) with Da-EPOCH. 14 (58%) of DLBCL patients received CHOP-based therapy with 1

Background: Ferric carboxymaltose is increasingly utilised to treat iron deficiency and is usually diluted in saline and administered as an intravenous infusion over 15 min. Although this is highly convenient compared with older formulations, we hypothesised the drug could be administered, safely given as a rapid bolus injection. Aim(s): To define the risk of serious adverse events following administration of an undiluted, rapid, high-dose ferric carboxymaltose injection. Secondary aims included all other adverse events, as well as longitudinal effects on haemoglobin, iron stores, phosphate and hepcidin. Method(s): In a single-arm, Phase II study in 121 patients with iron-deficiency anaemia, we administered up to 1000 mg of ferric carboxymaltose as a rapid undiluted bolus injection, and recorded adverse events and collected blood samples over the first hour, and again at 2 and 4 weeks post-treatment. Result(s): No patient experienced a serious adverse event. Flushing during the injection was common, as was a transient headache in the subsequent weeks. One patient experienced Grade 3 chest tightness, necessitating emergency department assessment but not admission or treatment. Treatment produced an average 12.3 g/L improvement in haemoglobin within 2 weeks, but commonly caused reductions in serum phosphate (although none of these was clinically symptomatic). Parenteral iron caused elevations in hepcidin sustained to 4 weeks post-injection. Patients stated they would be prepared to receive the treatment again. Conclusion(s): Rapid injection of undiluted ferric carboxymaltose is well tolerated and could provide an approach to treat patients in the ambulatory setting.Copyright © 2021 Royal Australasian College of Physicians

BACKGROUND: Histologic transformation (HT) is an important event with adverse prognosis in the natural history of indolent lymphomas. There are minimal data on HT in the Australian setting. AIMS: To characterise patients with biopsy-proven HT and their outcomes identified at a tertiary Australian Hospital. METHODS: All patients with biopsy-proven HT during a 15-year period (2002-2017) were included. Clinico-pathological data were systematically collected from review of patient records. Survival estimates were assessed using the Kaplan-Meier method and compared using the log-rank test. Associations between variables and clinical outcomes were evaluated using Cox's proportional hazards model. RESULTS: A cohort of 45 patients was identified with a median age of 66 years and the majority (59%) having high-risk disease (Revised-International Prognostic Index score ≥3). R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) induction was used in 69%, with an overall response rate of 82% (complete response (CR), 75%). Sixty-one percent of these induction responders received consolidation, with autologous stem cell transplant (ASCT) performed in only 17% and rituximab maintenance given to 31%. With a median follow up of 47 months (range: 4-136), the 5-year overall survival (OS) was 69% (95% CI: 52%, 81%). Chemotherapy-naivety at HT was associated with a superior rate of CR (84% vs 54%, P = 0.057) and 5-year OS (82% vs 46%, P = 0.012). Rituximab maintenance was associated with a durable progression-free survival in induction responders. CONCLUSIONS: Excellent OS was observed in this modern cohort of patients treated with rituximab-containing induction and low rate of consolidation by ASCT, particularly in those who were chemotherapy-naïve at HT.

BACKGROUND: Ferric carboxymaltose is increasingly utilised to treat iron deficiency and is usually diluted in saline and administered as an intravenous infusion over 15 min. Although this is highly convenient compared with older formulations, we hypothesised the drug could be administered, safely given as a rapid bolus injection. AIMS: To define the risk of serious adverse events following administration of an undiluted, rapid, high-dose ferric carboxymaltose injection. Secondary aims included all other adverse events, as well as longitudinal effects on haemoglobin, iron stores, phosphate and hepcidin. METHODS: In a single-arm, Phase II study in 121 patients with iron-deficiency anaemia, we administered up to 1000 mg of ferric carboxymaltose as a rapid undiluted bolus injection, and recorded adverse events and collected blood samples over the first hour, and again at 2 and 4 weeks post-treatment. RESULTS: No patient experienced a serious adverse event. Flushing during the injection was common, as was a transient headache in the subsequent weeks. One patient experienced Grade 3 chest tightness, necessitating emergency department assessment but not admission or treatment. Treatment produced an average 12.3 g/L improvement in haemoglobin within 2 weeks, but commonly caused reductions in serum phosphate (although none of these was clinically symptomatic). Parenteral iron caused elevations in hepcidin sustained to 4 weeks post-injection. Patients stated they would be prepared to receive the treatment again. CONCLUSION: Rapid injection of undiluted ferric carboxymaltose is well tolerated and could provide an approach to treat patients in the ambulatory setting.

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. Positron emission tomography adapted therapy has been developed for both early and advanced stage HL to try and improve the outcome of treatment, while 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 of HL.

Children with intellectual disabilities are more likely to experience sleep disorders of insomnia, excessive daytime sleepiness and sleep breathing disorders than typically developing children. The present study examined risk factors for these sleep disorders in 447 children (aged 5–18 years), diagnosed with an intellectual disability and comorbid autism spectrum disorder, cerebral palsy, Down syndrome or Rett syndrome. Primary caregivers reported on their child’s sleep using the Sleep Disturbance Scale for Children (SDSC), as well as medical comorbidities and functional abilities. Multivariate linear and logistic regressions were used to examine the effects of these factors on SDSC t scores and a binary indicator, respectively for the relevant subscales. Receiving operating characteristic curves were generated for each logistic regression model to determine their ability to discriminate between poor and good sleep. Comorbidities rather than functional abilities were associated with poorer sleep. In particular, recurrent pain, frequent seizures, frequent coughing, constipation and prescription of sleep medications were associated with abnormal sleep across the entire sample, but predictors differed between diagnostic groups. The present study suggests that comorbidities are more strongly associated with quality of sleep than functional impairments. The present study provides new information on potential associations between frequent coughing, prescription sleep medications and sleep quality that should be further investigated.

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

BACKGROUND: Histologic transformation (HT) is an important event with adverse prognosis in the natural history of indolent lymphomas. There is minimal data on HT in the Australian setting. AIM: To characterise patients with biopsy-proven HT and their outcomes identified at a tertiary Australian Hospital. METHOD(S): All patients with biopsy-proven HT during a 15-year period (2002-2017) were included. Clinico-pathological data were systematically collected from review of patient records. Survival estimates were assessed by the Kaplan-Meier method and compared using the log-rank test. Associations between variables and clinical outcomes were evaluated using Cox's proportional hazards model. RESULT(S): A cohort of 45 patients was identified with a median age of 66years and the majority (59%) having high-risk disease (Revised-International Prognostic Index score >=3). R-CHOP induction was used in 69% with an overall response rate of 82% (complete response (CR), 75%). 61% of these induction-responders received consolidation, with autologous stem cell transplant (ASCT) performed in only 17% and rituximab maintenance given to 31%. With a median follow-up of 47 months (range: 4-136), the 5-year overall survival (OS) was 69% (95% CI: 52%, 81%). Chemotherapy-naivety at HT was associated with a superior rate of CR (84% vs. 54%, p = 0.057) and 5-year OS (82% vs. 46%, p = 0.012). Rituximab maintenance was associated with a durable progression-free survival in induction-responders. CONCLUSION(S): Excellent OS was observed in this modern cohort of patients treated with rituximab-containing induction and low rate of consolidation by ASCT, particularly in those who were chemotherapy-naive at HT. This article is protected by copyright. All rights reserved.

Background: Grade 3B Follicular lymphoma (G3BFL) comprises approximately 15% of FL and controversy exists over whether it follows the relapsing/remitting course of low-grade FL, or more closely resembles diffuse large B cell lymphoma (DLBCL), which is potentially curable. Thus it is largely excluded from clinical trials for either group, hence robust data and management consensus are lacking. Aim(s): To establish survival outcomes of G3BFL. Method(s): We performed an international retrospective study of patients aged > / = 18 years, with G3BFL from tertiary institutions in Australia, Canada and England. Pure G3B, composite Grade 3A/G3BFL and G3BFL/ DLBCL treated with rituximab (R) or obinutuzumab (O) + chemotherapy +/- radiotherapy (RT) or RT alone between 2002-2019 were included. FL grading was according to WHO criteria. A comparator DLBCL group, treated with R-CHOP +/- radiotherapy from 2012-2018 was identified using the same criteria from 2 Australian sites. OS was defined as the time from the date of diagnosis until death from any cause; PFS was defined from diagnosis until relapse/progression (to any B cell lymphoma subtype) or death; both were calculated according to the Kaplan-Meier method. Associations between prognostic factors and outcomes were analysed with log-rank tests and Cox proportional hazards models. Result(s): 161 G3BFL cases were evaluable. Histology was G3BFL in 84, G3A/G3B FL in 25, and G3B/DLBCL in 52 ("G3B" group). Median age was 62 (18-86) and 55% were male. 71% of patients had stage III/ IV disease. 58% had a high FLIPI score. Treatment was R or O-CHOPlike chemotherapy +/- RT in 96% of cases with RT alone or BR in the remainder (2% each). 90% received anthracyclines. 171 DLBCL comparator cases were included with a median age of 68 years (25-91) and a high R-IPI in 54%. Compared to the G3B group, there was a statistically significant difference in age > 60 years (G3B: 53%, DLBCL 71%; P = 0.001), ECOG performance status > 2 (G3B 5%, DLBCL 23

BACKGROUND: In primary central nervous system lymphoma (PCNSL), venous thromboembolism (VTE) can cause significant morbidity and hinder chemotherapy delivery. OBJECTIVES: To assess VTE incidence, timing and adequacy of inpatient and outpatient VTE prophylaxis in patients with PCNSL receiving chemoimmunotherapy with curative intent. PATIENTS/METHODS: We reviewed patients diagnosed with PCNSL between 1997 and 2018 who received methotrexate, procarbazine, and vincristine ± Rituximab. Patient demographics, VTE prophylaxis and incidence, adverse events of anticoagulation, and survival outcomes were collected. RESULTS: Fifty-one PCNSL patients were included (median 67 years [range, 32-87], 30 males [59%]). Thirteen patients (25%, 95% confidence interval [CI], 14-40) developed VTE at a median of 1.6 months from diagnosis (range, 0-4). Patients with Khorana Risk Score ≥2 were more likely to have VTE than those with a KRS < 2 (60% vs 15%; P = .01). Eighty-five percent had deviations from inpatient VTE prophylaxis guidelines, and outpatient prophylaxis was not routinely administered. Three patients required inferior vena cava filters. Hemorrhagic complications of anticoagulation included an intracranial hemorrhage from therapeutic anticoagulation and three cases of major bleeding from prophylactic anticoagulation. No patients died from VTE or its treatment. CONCLUSIONS: Patients with newly diagnosed PCNSL are at high risk of VTE. Further research is required into optimal VTE prophylaxis in PCNSL.

Background : Venous thromboembolism is common in patients with brain tumours with rates of symptomatic VTE in up to 30% of patients. Important factors in pathogenesis may include release of procoagulant substances such as tissue factor and physical immobility due to disability associated with CNS lesions. While combined modality therapy is highly effective, the occurrence of VTE can cause significant morbidity and impact chemotherapy delivery and rehabilitation. Aims : To determine the incidence of as well as risk factors and treatment practices for VTE in patients with Primary Central Nervous System Lymphoma (PCNSL) treated with HD-MTX. Methods : Retrospectively we reviewed patients diagnosed with PCNSL between 1997 and 2018 and treated at Monash Health with Methotrexate, Procarbazine, Vincristine +/-Rituximab. VTE events from 14 days prior to PCNSL diagnosis were recorded. Primary endpoints of the study were VTE incidence and adequacy of prophylaxis. Secondary outcomes included VTE treatment, adverse events, impact on overall survival and whether Khorana score could predict VTE. Results : 51 PCNSL patients were included (Table 1, median age at diagnosis 67 years, 30 males [59%]). 13 patients developed VTE (median 1.5 months from diagnosis, range 0-4, Figure 1). Only 15% of these patients had adequate VTE prophylaxis despite all being admitted prior to VTE diagnosis. Therapeutic anticoagulation was started promptly, within 4 hours of diagnosis. Two patients required IVC filters, one prophylactically in the perioperative setting and another due to intracranial haemorrhage post anticoagulation. The only other major bleeding complication was gastrointestinal. No patients died from VTE or its treatment and there was no impact on OS. The Khorana score did not predict for VTE. Conclusions : The VTE incidence in PCNSL was 25% and was greatest during the diagnostic and initial chemotherapy period. Possible contributors include patients' underlying physical immobility, the

Management practices in early-stage (I/II) follicular lymphoma (FL) are variable and include radiation (RT), systemic therapy, or combined modality therapy (CMT). There is a paucity of data regarding maintenance rituximab in this cohort. We conducted an international retrospective study of patients with newly diagnosed early-stage FL staged with positron emission tomography (PET)-computed tomography and bone marrow biopsy. Three hundred sixty-five patients (stage I, n 5 221), median age 63 years, treated from 2005-2017 were included, with a median follow-up of 45 months. Management included watchful waiting (WW; n 5 85) and active treatment (n 5 280). The latter consisted of RT alone (n 5 171) or systemic therapy (immunochemotherapy [n 5 63] or CMT [n 5 46]). Forty-nine systemically treated patients received maintenance rituximab; 72.7% of stage I patients received RT alone, compared to 42.6% with stage II (P, .001). Active therapies yielded comparable overall response rates (P 5 .87). RT alone and systemic therapy without maintenance rituximab yielded similar progression-free survival (PFS) (hazard ratio [HR], 1.32; 95% confidence interval [CI], 0.77-2.34; P 5 .96). Maintenance rituximab improved PFS (HR, 0.24; 95% CI, 0.095-0.64; P 5 .017). The incidence of transformation was lower with systemic therapy compared to RT or WW (HR, 0.20; 95% CI, 0.070-0.61; P 5 .034). Overall survival was similar among all practices, including WW (P 5 .40). In the largest comparative assessment of management practices in the modern era, variable practices each resulted in similar excellent outcomes. Randomized studies are required to determine the optimal treatment in early-stage FL.Copyright © 2019 by The American Society of Hematology

Introduction: Despite advances in novel therapy for diffuse large Bcell lymphoma (DLBCL), salvage chemotherapy prior to autologous stem cell transplant (HSCT) remains the standard approach at relapse. However, there is no consensus salvage regimen and practice varies considerably. Refractory DLBCL or short remission duration cases have particularly poor outcomes (Gisselbrecht, 2010). R-IVAC is an infusional protocol incorporating etoposide (60mg/m2 Day 1-5), ifosfamide (1.5g/m2 Day 1-5), cytarabine (2g/m2 BD Day 1-2) in addition to Rituximab (375mg/m2). Method(s): We retrospectively analysed 27 patients treated at two teaching hospitals to determine the safety and efficacy of R-IVAC for relapsed DLBCL. Disease response was assessed by PET (Lugano 2014 criteria). Result(s): Patient characteristics are summarised in Table 1. 13 patients (48%) were refractory to their previous therapy and 9 patients (33%) had relapsed in <12 months. 70% of patients received 2 cycles of treatment (range 1-3) and 92.5% received rituximab with IVAC. In 26 evaluable patients, the overall response rate (ORR) was 54% (42% complete response, 12% partial response). In patients with disease relapsing after >12 months, the ORR was 100%, versus 43% in relapses <12months or refractory disease. 21 patients were referred for HSCT, and 10 (37%) patients proceeded (9 autograft, 1 allograft). Stem cell mobilisation succeeded in 90% of patients. 2 patients declined HSCT, 8 did not proceed due to inadequate disease control. With a median duration of follow-up in surviving patients of 30 months, 2-year progression-free survival (PFS) of the whole cohort was 25% and 2-year overall survival (OS) was 32%. Patients who responded achieved 2-year PFS of 53% and OS of 62%. In HSCT recipients, 2-year PFS and OS were 44% and 66%. Hematologic toxicity was considerable with grade 3/4 neutropenia and thrombocytopenia in 92.5% and 100% patients respectively. 25 patients experienced febrile neutropenia, but only 1 pati

Introduction: Recent evidence has demonstrated associations between adverse risk characteristics and survival outcomes in diffuse large B-cell lymphoma (DLBCL) patients with a shorter diagnosis-to-treatment interval (DTI) (Maurer et al, 2018). The imperative for exigent therapy in aggressive DLBCL presentations may select against the recruitment of such patients to clinical trials and introduce significant bias. We sought to confirm the relationship between DTI and risk status and to compare cohorts of patients receiving standard therapy versus a clinical trial as initial treatment. Method(s): Treatment and outcome data were collected for patients with newly diagnosed DLBCL (as per WHO criteria) treated at our institution either with standard therapy or an upfront clinical trial. Associations between DTI and clinical characteristics and outcomes were investigated. Overall survival (OS) and progression free survival (PFS) were modelled using Cox regression. Differences in patient and disease characteristics were analysed with the Mann-Whitney U test or Chi-square test. Result(s): 455 patients receiving non-trial therapy with reliably determined DTI were identified. An additional 21 patients received upfront treatment on a clinical trial. The median DTI of the non-trial treatment group was 14 days, compared to 20 days for the clinical trial group (p=0.031). 1 patient was treated on a clinical trial within 7 days of diagnosis (5%) vs 122 (26.8%) patients receiving non-trial treatment. Patients with a DTI of >7 days demonstrated superior OS, HR 1.555 [95%CI: 1.085-2.227], p=0.016, and PFS, HR 1.564 [95%CI: 1.15-2.129], p=0.004. DTI of <7 days was significantly associated with several established markers of poor prognosis in DLBCL, including elevated lactate dehydrogenase (p<0.001), and advanced Ann Arbor stage (III or IV) p=0.034. Other poor prognostic markers such as the revised international prognostic (RIPI) score, cell of origin, Eastern Cooperative Group (ECOG) sco

Mantle cell lymphoma (MCL) is an uncommon and typically aggressive form of lymphoma. Although often initially chemosensitive, relapse is common. Several induction and conditioning regimens are used in transplant-eligible patients, and the optimal approach remains unknown. We performed an international, retrospective study of transplant-eligible patients to assess impact of induction chemoimmunotherapy and conditioning regimens on clinical outcomes. We identified 228 patients meeting inclusion criteria. Baseline characteristics were similar among the induction groups except for some variation in age. The type of induction chemoimmunotherapy received did not influence overall response rates (ORRs) (0.43), progression-free survival (PFS) (P >.67), or overall survival (OS) (P >.35) on multivariate analysis (PFS and OS). Delivery of autologous stem cell transplant (ASCT) was associated with favorable PFS and OS (0.01) on univariate analysis only; this benefit was not seen on multivariate analysis-PFS (0.36) and OS (0.21). Compared with busulfan and melphalan (BuMel), the use of the carmustine, etoposide, cytarabine, melphalan (BEAM)-conditioning regimen was associated with inferior PFS (HR = 2.0 [95% CI 1.1-3.6], 0.02) but not OS (HR = 1.1 [95% CI 0.5-2.3], 0.81) on univariate analysis only. Within the limits of a retrospective study and modest power for some comparisons, type of induction therapy did not influence ORR, PFS, or OS for transplant-eligible patients with MCL. International efforts are required to perform randomized clinical trials evaluating chemoimmunotherapy induction regimens.Copyright © 2019 John Wiley & Sons, Ltd.

Background: Primary CNS lymphoma (PCNSL) is a rare and poor-prognostic disease. While randomised studies including IELSG32 have confirmed chemoimmunotherapy regimens containing methotrexate, cytarabine and rituximab as standard of care, the role of ASCT or WBRT consolidative strategies are associated with significant toxicities and questionable benefit. Furthermore, many PCNSL patients are precluded from ASCT or WBRT due to age and co-morbidities. Aim(s): This study seeks to assess outcomes of R-MPV/Ara-C chemotherapy in older (>=60yo) PCNSL patients. Method(s): Patients presenting with PCNSL (WHO Criteria: 2008) and treated with curative intent using R-MPV/Ara-C (Morris PG et al. J Clin Oncol. 2013;31(31):3971-9) were identified at 2 university hospitals: Monash Health (November 2009-December 2016) and St. Vincent's Hospital (June 2003-October 2012). Patients were separated according to age (i.e >60 vs <=60yo). Risk-stratification was as per IELSG criteria. In the >60yo cohort, consolidative WBRT was omitted for patients in complete remission (CR) as per institutional practices. Only cases with biopsy-proven PCNSL and adequate information (i.e. baseline characteristics, treatment and outcome) were included. Outcome analysis was restricted to the rituximab cohort. Overall survival (OS) and progression free survival (PFS) were modelled by Cox regression. The Mann-Whitney and Fischer's exact test were used to calculate p-values for continuous and discrete variables, respectively. Result(s): 44 patients were identified, 38 received R-MPV/ARA-C as per protocol (excluded: received other chemotherapy regimens: 6). Of these, 27 (71%) were >60yo (median: 67.5, range 38-86, p<0.0001) and 74% were intermediate-risk as per IELSG criteria (p>0.999). Therapy was well tolerated; 78% of older patients completed MTX therapy (vs 100%, p= 0.154), but with more frequent dose-attenuation (48% vs 9%, p: 0.003). WBRT was rarely used in the older cohort (11% vs 91%, p <0.0001). Despite th

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

Mantle cell lymphoma (MCL) is an uncommon and typically aggressive form of lymphoma. Although often initially chemosensitive, relapse is common. Several induction and conditioning regimens are used in transplant-eligible patients, and the optimal approach remains unknown. We performed an international, retrospective study of transplant-eligible patients to assess impact of induction chemoimmunotherapy and conditioning regimens on clinical outcomes. We identified 228 patients meeting inclusion criteria. Baseline characteristics were similar among the induction groups except for some variation in age. The type of induction chemoimmunotherapy received did not influence overall response rates (ORRs) (0.43), progression-free survival (PFS) (P > .67), or overall survival (OS) (P > .35) on multivariate analysis (PFS and OS). Delivery of autologous stem cell transplant (ASCT) was associated with favorable PFS and OS (0.01) on univariate analysis only; this benefit was not seen on multivariate analysis-PFS (0.36) and OS (0.21). Compared with busulfan and melphalan (BuMel), the use of the carmustine, etoposide, cytarabine, melphalan (BEAM)-conditioning regimen was associated with inferior PFS (HR = 2.0 [95% CI 1.1-3.6], 0.02) but not OS (HR = 1.1 [95% CI 0.5-2.3], 0.81) on univariate analysis only. Within the limits of a retrospective study and modest power for some comparisons, type of induction therapy did not influence ORR, PFS, or OS for transplant-eligible patients with MCL. International efforts are required to perform randomized clinical trials evaluating chemoimmunotherapy induction regimens.