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Background: Anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) is a rare autoimmune disease which is managed by a range of specialities. There are limited data on treatment practices in Australia and New Zealand. Aims: To understand current patterns of acute AAV treatment in Australia and New Zealand. Methods: An online survey was conducted between July and October 2022 investigating physicians' views on the management of AAV, focusing on induction therapy. The survey contained questions pertaining to access to treatment and responses to clinical management scenarios. Eosinophilic granulomatosis with polyangiitis was not included. A chi‐squared test of independence was performed for statistical analysis. Results: From a total of 55 responses, plasma exchange was difficult to access for 44% of respondents, more so in rural centres, and they also had difficulty accessing infusion centres. New Zealand clinicians had more difficulty accessing rituximab, with only 44% reporting easy access compared with Australian clinicians (93%). With clinical management scenarios, there was variation in the dosing regimen of glucocorticoids and initiation of plasma exchange, with 42% of respondents prescribing a glucocorticoid regimen different from the standard of care, the 'reduced‐dose' arm of the Plasma Exchange and Glucocorticoids for the Treatment of ANCA‐Associated Vasculitis trial. The choice of cyclophosphamide or rituximab for induction therapy was based on patient characteristics and medical history. Conclusions: There is substantial variation in approaches to the acute management of AAV in Australia and New Zealand, including differences in resource availability. This variation in care demonstrates the need to implement current practice guidelines and institute contemporary monitoring of AAV management, to achieve best patient outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Cutaneous T-cell lymphoma (CTCL) is a rare and incurable disease, and patients currently experience a lack of treatment options in Australia. This analysis evaluated the cost-effectiveness of extracorporeal photopheresis (ECP) compared with standard of care therapy for the treatment of patients with erythrodermic (stage T4, M0) CTCL, who are refractory to previous systemic treatment.Methods: A Markov model was developed from the perspective of the Australian government. Health states were treatment specific and transition probabilities were modeled from time-to-next-treatment data from a published Australian observational study of ECP and comparator treatments. Quality of life utility values were based on psoriasis as a proxy for CTCL, which was validated by consultation with local clinicians. The time horizon for the model was 5 years. The ECP treatment regimen was compared with a weighted treatment comparator based on results of a treatment survey and Australian prescribing data.Results: ECP as a second-line treatment option for CTCL was less costly and more effective than other treatment strategies. ECP had an average cost saving of $37 592 and incremental quality-adjusted life-year gained of 0.20 to 0.21, attributed to patients being able to better tolerate ECP thus avoiding subsequent treatment with high-cost alternatives.Conclusions: This is the first published cost-utility analysis of ECP for CTCL. This analysis demonstrates that ECP is a cost-effective option for the treatment of patients with erythrodermic CTCL in Australia. [ABSTRACT FROM AUTHOR]

Pemphigus encompasses of a group of rare, and often severe, intraepidermal bullous dermatoses that are mediated by autoantibodies that act against adhesion proteins of the desmosome. The current international consensus is that the use of intravenous CD20 inhibitors should be first‐line in the management of moderate‐to‐severe cases of pemphigus, however Australia is yet to adopt this. Systemic corticosteroids, combined with conventional corticosteroid‐sparing immunosuppressive agents such as azathioprine, mycophenolate mofetil, cyclosporin and methotrexate is still recommended as first‐line therapy in Australia despite overwhelming evidence that combining rituximab with a rapid corticosteroid tapering regime is more effective in the treatment of moderate‐to‐severe pemphigus, and leads to fewer severe adverse effects. We propose a therapeutic approach that echoes the international consensus and recommend that rituximab, an anti‐CD20 monoclonal antibody, be listed in the formularies of Australian Public Hospitals and on the Pharmaceutical Benefits Scheme for use in moderate to severe pemphigus. [ABSTRACT FROM AUTHOR]

Background and Objectives: Management of refractory immune thrombocytopaenia (ITP) can be challenging. Amifostine, a thiophosphate prodrug, induces megakaryocyte maturation. In 2010, Fan et al. published results for 21 Chinese splenectomized patients, aged 13–92, with steroid‐refractory ITP. Nineteen patients (15 patients aged >18 years) achieved remission 2 months post‐amifostine. This is the first publication utilizing amifostine and rituximab in refractory ITP. Materials and Methods: At the Cairns Hospital in Australia, we identified five patients treated with amifostine and rituximab for refractory ITP. Amifostine IV 400 mg once daily was administered 5 days/week for 5 weeks as tolerated. Rituximab was administered concurrently with/preceding amifostine based on clinician preference. Data were obtained through medical records and follow‐up serology up to 5 years post‐amifostine was available. Results: Three cases demonstrated durable responses up to 5 years' follow‐up. One patient initially achieved remission but relapsed 1‐year post‐amifostine. One patient who did not have a splenectomy prior to amifostine did not respond. Conclusion: Three out of five patients achieved durable responses with amifostine and rituximab. Although there is confounding by rituximab, given its established low durable response rate, it is likely that the excellent long‐term responses achieved were a result of amifostine. Clinical trials with larger patient cohorts and further investigation are required to confirm the efficacy and mechanism of amifostine in ITP. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) and the marginal zone lymphoma (MZL) subtypes (nodal MZL, extra‐nodal MZL of mucosa‐associated lymphoid tissue (MALT lymphoma) and splenic MZL) are uncommon lymphoma subtypes, accounting for less than 5–10% of all non‐Hodgkin lymphoma. The evidence base for therapy is therefore limited and enrolment into clinical trials is preferred. Outcomes for patients with MCL have been steadily improving mainly due to the adoption of more intense strategies in younger patients, the use of rituximab maintenance and the recent introduction of bendamustine in older patients. MZL is a more heterogeneous group of cancer with both nodal, extra‐nodal and splenic subtypes. Extranodal MZL may be associated with autoimmune or infectious aetiologies, and can respond to eradication of the causative pathogen. Proton pump inhibitor plus dual antibiotics in Helicobacter pylori positive gastric MALT lymphoma is curative in many patients. Watchful waiting is appropriate in most patients with asymptomatic advanced stage disease, which tends to behave in a particularly indolent manner. Other options for symptomatic disease include splenectomy, chemoimmunotherapy with rituximab and, more recently, targeted therapies. [ABSTRACT FROM AUTHOR]

Outcomes with follicular lymphoma (FL) have improved in the modern era and median survival is now beyond 15 years. Therapeutic decisions need to consider this increased survival as well as recent clinical trial data and emerging treatments. In this context, we present here current approaches to front‐line management of FL in Australia. Treatment choices depend on the disease stage, tumour burden, the patient's age, symptoms, comorbidities and preferences. Only about 10–15% of patients with FL are diagnosed with early stage disease. For patients with low‐grade, early stage disease, radiotherapy (RT) is recommended. The addition of chemotherapy has been shown to increase progression‐free survival (PFS) but without demonstrated overall survival advantage. For patients with low‐tumour‐burden, advanced‐stage FL, immediate treatment may not be required and we recommend considering active monitoring. For stage III/IV disease that is symptomatic and/or with high tumour burden, established first‐line treatment is chemotherapy in combination with rituximab, often followed by rituximab maintenance. The listing of bendamustine and now obinutuzumab on the Pharmaceutical Benefits Scheme has expanded the first‐line treatment options in Australia to include bendamustine in combination with rituximab (without rituximab maintenance permitted) or with obinutuzumab plus 2 years obintuzumab maintenance. In the FL subgroup of the Study group indolent Lymphomas (StiL) trial, therapy with bendamustine plus rituximab significantly increased PFS compared with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone, without rituximab maintenance. Initial tolerability may be more favourable with bendamustine in combination with anti‐CD20 antibody therapy than other therapies overall, but clinical vigilance is still required because of concerns of late infectious toxicities associated with prolonged T‐cell depletion. [ABSTRACT FROM AUTHOR]

Background: The prognosis for primary CNS lymphoma has improved with the use of high-dose methotrexate-based chemotherapy, but patient outcomes remain poor. Rituximab, a chimeric monoclonal antibody that targets the CD20 cell surface protein, has substantial activity in systemic CD20-positive diffuse large B-cell lymphoma, but its efficacy in primary CNS lymphoma is unknown and low penetration of the large rituximab molecule through the blood-brain barrier could limit its effect. We aimed to investigate the addition of rituximab to a high-dose methotrexate-based chemotherapy regimen in patients with newly diagnosed primary CNS lymphoma.Methods: This intergroup, multicentre, open-label, randomised phase 3 study was done at 23 hospitals in the Netherlands, Australia, and New Zealand. Non-immunocompromised patients aged 18-70 years with newly diagnosed primary CNS lymphoma were randomly assigned (1:1) to receive methotrexate-based chemotherapy with or without intravenous rituximab. We used a web-based randomisation system with stratification by centre, age, and Eastern Cooperative Oncology Group-WHO performance status, and a minimisation procedure. All group assignment was open label and neither investigators nor patients were masked to allocation. All patients were treated with two 28-day cycles of induction chemotherapy, consisting of intravenous methotrexate 3 g per m2 on days 1 and 15, intravenous carmustine 100 mg per m2 on day 4, intravenous teniposide 100 mg per m2 on days 2 and 3, and oral prednisone 60 mg per m2 on days 1-5, with (R-MBVP) or without (MBVP) intravenous rituximab 375 mg per m2 on days 0, 7, 14, and 21 in cycle one and days 0 and 14 in cycle two. Patients with response at the end of induction subsequently received high-dose cytarabine and, in patients aged 60 years or younger, low-dose whole-brain radiotherapy. The primary endpoint was event-free survival, with events defined as not reaching complete response or complete response unconfirmed at the end of treatment, or progression or death after response; analysis was adjusted for age and performance score. Patients were analysed on a modified intention-to-treat basis. This trial is registered with the Nederlands Trial Register, number NTR2427, and the Australian New Zealand Clinical Trials Registry, number ACTRN12610000908033. The trial was closed on May 27, 2016, after achieving complete accrual, and follow-up is ongoing.Findings: Between Aug 3, 2010, and May 27, 2016, we recruited 200 patients (109 men and 91 women; median age was 61 years [IQR 55-67]). We randomly assigned 100 patients to MBVP and 99 patients to R-MBVP. One patient was randomly assigned to the R-MBVP group but found to be ineligible because of an incorrect diagnosis and was excluded from all analyses. After a median follow-up of 32·9 months (IQR 23·9-51·5), 98 patients had had an event (51 in the MBVP group and 47 in the R-MBVP group), of whom 79 had died (41 in the MBVP group and 38 in the R-MBVP group). Event-free survival at 1 year was 49% (95% CI 39-58) in the MBVP group (no rituximab) and 52% (42-61) in the R-MBVP group (with rituximab; hazard ratio 1·00, 95% CI 0·70-1·43, p=0·99). Grade 3 or 4 adverse events occurred in 58 (58%) patients in the MBVP group and 63 (64%) patients in the R-MBVP group, with infections (24 [24%] patients receiving MBVP vs 21 [21%] patients receiving R-MBVP), haematological toxicity (15 [15%] vs 12 [12%]), and nervous system disorders (ten [10%] vs 15 [15%]) being the most common. Life-threatening or fatal serious adverse events occurred in 12 (12%) patients in the MBVP group and ten (10%) patients in the R-MBVP group, and five (5%) patients in the MBVP group and three (3%) in the R-MBVP group died from treatment-related causes.Interpretation: We found no clear benefit of addition of rituximab to methotrexate, carmustine, teniposide, and prednisone chemotherapy in primary CNS lymphoma. Therefore, the results of this study do not support the use of rituximab as a component of standard treatment in primary CNS lymphoma.Funding: Roche, the Dutch Cancer Society, and Stichting STOPhersentumoren. [ABSTRACT FROM AUTHOR]

Idelalisib is a potent oral selective inhibitor of phosphatidylinositol 3‐kinase p110δ. It is approved in Australia for the treatment of relapsed chronic lymphocytic leukaemia and small cell lymphocytic lymphoma in combination with rituximab or ofatumumab in patients for whom chemoimmunotherapy is not considered suitable. Idelalisib is reimbursed by the Australian Government for use in combination with rituximab. It is also approved and reimbursed for use as monotherapy in patients with follicular lymphoma refractory to at least two prior systemic therapies including rituximab and an alkylating agent. Idelalisib has demonstrated significant benefits in progression‐free survival and overall survival in these patient populations; however, patients receiving idelalisib require monitoring and education due to significant toxicities, particularly diarrhoea, infections and hepatotoxicity. There is also the potential for drug interactions resulting in toxicity or subtherapeutic treatment levels. [ABSTRACT FROM AUTHOR]

We performed a single-center retrospective cohort study of 66 consecutive ABO incompatible kidney transplants (ABOiKT) performed without B-cell depleting therapy. Outcomes were compared to an earlier era performed with rituximab ( n = 18) and a contemporaneous cohort of ABO compatible live donor transplants (ABOcKT). Acute rejection within 3 months of transplant was significantly more common after rituximab-free ABOiKT compared to ABOiKT with rituximab (OR 8.8, p = 0.04) and ABOcKT (OR 2.9, p = 0.005) in adjusted analyses. Six recipients of rituximab-free ABOiKT experienced refractory antibody mediated rejection requiring splenectomy, and a further two incurred early graft loss with no such episodes amongst ABOiKT with rituximab or ABOcKT cohorts. Patient and graft survival were similar between groups over a median follow-up of 3.1 years. This observational evidence lends strong support to the continued inclusion of rituximab in desensitization protocols for ABOiKT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bleasel, Wan, Chadban, Ying, Gracey, Aouad, Chen, Utsiwegota, Mawson and Wyburn.)

Abstract: Background: Rituximab, an anti‐CD20 B‐cell depleting monoclonal antibody, is increasingly prescribed off‐label for a range of autoimmune diseases. There has not previously been an audit of off‐label rituximab use in the Northern Territory, where the majority of patients are Aboriginal. Aims: To evaluate retrospectively off‐label rituximab use in autoimmune diseases in the Top End of the Northern Territory. Methods: We performed a retrospective audit of 8 years of off‐label rituximab use at the Royal Darwin Hospital, the sole tertiary referral centre for the Darwin, Katherine and East Arnhem regions. Electronic and paper records were reviewed for demographic information, diagnosis/indication for rituximab, doses, previous/concomitant immunosuppression, clinical outcomes and specific adverse events. Results: Rituximab was prescribed off‐label to 66 patients for 24 autoimmune diseases. The majority of patients (62.1%) were Aboriginal and 60.6% female. The most common indications were refractory/relapsing disease despite standard therapies (68.7%) or severe disease with rituximab incorporated into an induction immunosuppressive regimen (19.4%). Systemic lupus erythematosus was the underlying diagnosis in 28.8% of cases. A clinically significant response was demonstrated in 74.2% of cases overall. There were 18 clinically significant infections; however, 13 were in patients receiving concurrent immunosuppressive therapy. There was a total of nine deaths from any cause. Conclusion: Rituximab has been used off‐label for a range of autoimmune diseases in this population with a high proportion of Aboriginal patients successfully and safely in the majority of cases. [ABSTRACT FROM AUTHOR]

Background: Chronic lymphocytic leukaemia (CLL) frequently responds to chemoimmunotherapy combining cytotoxic chemotherapy and monoclonal antibodies. However, CLL is associated with significant genetic heterogeneity, and some high-risk forms are known to be chemo-resistant and associated with early relapse. Aims: To review the current treatment paradigm of patients with high-risk disease, in particular those with del(17p) and TP53 variants. Results: A 'watch and wait' approach is recommended for all patients who are asymptomatic. When symptomatic, fluorescence in situ hybridisation testing should be performed and gene sequencing considered subsequently to identify del(17p) and TP53 variants respectively. In the front-line setting, treatment within a clinical trial is the preferred option. In the relapsed or refractory setting, patients with del(17p) or TP53 aberrations should be offered treatment with a novel agent, such as ibrutinib, idelalisibrituximab or venetoclax. However, of note, at the date of this publication venetoclax is not PBS reimbursed, and ibrutinib will not be reimbursed until 1 December 2017. Conclusion: Testing for del(17p) and TP53 variants identifies high-risk CLL that requires specialist management. [ABSTRACT FROM AUTHOR]

Background Tumour necrosis factor-alpha inhibitors (anti- TNFα) and anakinra are monoclonal antibodies against pro-inflammatory cytokines overexpressed in many systemic inflammatory diseases. In Australia, they are registered for the treatment of several rheumatological, gastroenterological and dermatological indications. Despite increasing observational evidence for their use in off-label indications, there is a paucity of outcome research from the Australian hospital sector. Aims To describe the off-label use of anti- TNFα and anakinra at a tertiary referral hospital in Queensland, Australia and consideration of a drug register to inform future clinical decision-making. Methods We performed an in-depth retrospective chart audit of off-label treatment with anti- TNFα or anakinra at the Royal Brisbane and Women's Hospital from mid-2010 to mid-2014, linking demographic, phenotypic, pathology and outcome data with these drugs. Results Off-label use was identified in 10 patients. The most frequent indications were sarcoidosis and dermatological conditions. Three patients required sequential therapy with a second anti- TNFα (total responses = 13). Complete response occurred in 46%, partial response in 38% and primary non-response in 8%. Response was unable to be determined in 8%. We recorded 14 adverse events (infections most common). Conclusion This study suggests that anti- TNFα may be beneficial for some off-label indications (e.g. sarcoidosis). However, the observational design of this study (and pre-existing research) limits the ability to infer causality and generalise results. We propose the creation of a mandatory drug register to monitor off-label use. Whilst comparative efficacy cannot be established without a matched placebo arm, a register would enable some reporting on effectiveness in rare diseases and identify infrequent but serious adverse events. [ABSTRACT FROM AUTHOR]

Kidney transplantation restores fertility in patients with end-stage renal disease, with many successful pregnancies after kidney transplantation being reported. However, there are little data regarding pregnancy in women transplanted under modern-era desensitisation protocols that utilise rituximab, plasma exchange and intravenous immunoglobulin, including ABO-incompatible transplants. Pregnancies in ABO-incompatible recipients can pose new challenges from an immunological perspective. Here, we report a case of successful pregnancy using in vitro fertilisation, in a renal transplant recipient who underwent desensitisation two years prior, that included use of rituximab and plasma exchange to receive an ABO-incompatible transplant from her husband and subsequent father of the baby. We believe this was the first case of successful pregnancy after ABO-incompatible kidney transplantation in Australia and New Zealand. This case also highlights the difficulties faced in conception following transplantation and demonstrates that in vitro fertilisation utilising ovulation induction can be successfully utilised for conception in this cohort. This recipient also had gestational diabetes, worsening renal function and preterm delivery which are important complications often seen in pregnancies of solid organ transplant recipients. [ABSTRACT FROM AUTHOR]

Background Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA). In 2009, the Australian TTP/TMA registry was established to collect data on patients presenting with TTP/TMA throughout Australia. Aim To summarise information on the diagnosis and management of patients with TTP collected in the first 5 years (2009-2014) of the Australian TTP registry. Methods Registry data from June 2009 to October 2014 were reviewed. Results Fifty-seven patients were identified with TTP (defined as ADAMTS13 activity <10%), accounting for 72 clinical episodes. ADAMTS13 inhibitor testing was performed in nine out of 57 patients (16%), reflecting the limited availability of accredited testing facilities. Sixty-seven out of 72 episodes were treated with therapeutic plasma exchange (PEx) using cryodepleted plasma (40% of episodes), fresh frozen plasma (36%) or a mixture (22%). Median exposure to plasma products was 55.9 L. PEx was commenced ≥2 days from stated diagnosis in 15% of episodes. Adverse reactions to PEx were common with documented allergic reactions (including life threatening) in 21% of episodes. Adjunctive immunosuppression was documented in 76% of episodes (corticosteroid 71% and rituximab 39%). Platelet transfusion was administered in 15% of episodes. Conclusions Data from the Australian TTP/TMA registry suggest a heterogenous approach to the diagnosis and management of TTP in Australia over the assessed period. These observations highlight areas for improvement and standardisation of practice, including comprehensive diagnostic testing, more immediate access to PEx and a more uniform approach to adjunctive immunosuppression and supportive care. [ABSTRACT FROM AUTHOR]

Based on the number of new cases (incidence), non-Hodgkin lymphoma is an increasingly common cancer in Australia and many developed countries. Until recently, mortality trends have been stable or slightly increasing. However, since the year 2000, mortality has decreased every year by an average of 5.1% per year (95% confidence interval (CI) −7.1 to −3.1%), whereas incidence has continued to increase at 0.9% per year (95%CI 0.6 to 1.2%). It was not possible with the population-based registry data available to us to untangle the causes of the decrease in mortality. The stable mortality rates during the 1990s (in the face of increasing incidence) might have been because of introduction of novel therapies such as autologous stem cell transplant for relapsed diffuse large cell lymphoma or the purine analogue-based therapy for indolent lymphomas. A plausible explanation for the large decrease in mortality since 2000 is the introduction of the monoclonal antibody rituximab. [ABSTRACT FROM AUTHOR]

Recently, obinutuzumab was included in the Australian Pharmaceutical Benefits Scheme for use in first line, advanced or bulky stage 2, follicular lymphoma, providing more immunochemotherapy treatment options available than ever before. Rituximab with chemotherapy has been the standard of care since reimbursement in the late 1990s; however, obinutuzumab-based regimens have shown superior progression-free survival in comparison to rituximab-based options, albeit at an increased risk of grade ≥3 adverse events. As median overall survival approaches 20 years or more, the long-term effects and sequencing of any strategy should be considered. Here we discuss the considerations for selection of front-line therapy, based on evidence and local Australian clinician experience, in the management of first line follicular lymphoma., (© 2019 John Wiley & Sons Australia, Ltd.)

Waldenström macroglobulinaemia ( WM) is an indolent B-cell malignancy characterised by the presence of immunoglobulin M ( IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab-induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib- and bortezomib-based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work-up and therapy of WM to assist Australian clinicians in the management of this disease. [ABSTRACT FROM AUTHOR]

Background: Elderly patients with diffuse large B-cell lymphoma (DLBCL) have an inferior prognosis, due in part to advanced age and pre-existing comorbidities, with reduced tolerability and deliverability of standard R-CHOP chemotherapy., Aims: To examine the deliverability, toxicity and efficacy of R-CHOP and the prevalence of the germinal and non-germinal phenotype DLBCL in an elderly Australian cohort., Methods: This retrospective analysis included patients ≥75 years diagnosed with DLBCL. Comprehensive chemotherapy and toxicity data were collected for patients treated with R-CHOP. Baseline demographics and chemotherapy characteristics were compared with progression-free (PFS) and overall survival (OS). Immunohistochemical staining identified the prevalence of the non-germinal centre (non-GCB) phenotype., Results: Of the 111 patients, 92 (83%) commenced R-CHOP with 26/92 (28%) receiving ≤4 cycles. Median average relative dose (ARD) was 0.80 (0.07-1.17). Median average relative dose intensity (ARDI) was 0.89 (0.33-1.18). Serious adverse events occurred in 77% of patients with ≥Gd3 adverse events in 74%. Overall response rate was 85%. Two-year PFS was 63% and OS 74%. ARD and performance status ≥2 were significant prognostic factors for PFS and OS but not ARDI. Non-GCB-phenotype was identified in 44/72 (61%) of patients with immunohistochemical data., Conclusion: Despite high response rates and respectable survival estimates, the absence of standard therapy in 17% of patients, and dose reductions and serious toxicity of R-CHOP in this Australian cohort highlights the need for the development of less toxic yet efficacious treatments for very elderly patients with DLBCL. The high prevalence of the non-GCB phenotype highlights the potential value of targeted biological therapy for this demographic., (© 2015 Royal Australasian College of Physicians.)

Background: Risk-stratification of diffuse large B-cell lymphoma (DLBCL) requires identification of patients with disease that is not cured, despite initial treatment with R-CHOP. The prognostic importance of the revised International Prognostic Index (R-IPI) and cell of origin of the malignant B cell are established in DLBCL. We aimed to develop a novel, easily applicable, tissue-based prognostic biomarker based on quantification of the tumour microenvironment that is independent of and additive to the R-IPI and cell of origin., Methods: We performed digital hybridisation on the NanoString platform to assess the relation between immune effector and inhibitory (checkpoint) genes in 252 formalin-fixed, paraffin-embedded DLBCL tissue specimens obtained from patients treated with R-CHOP. We used a tree-based survival model to quantify net antitumoral immunity (using ratios of immune effector to checkpoint genes) and to generate a cutoff as an outcome predictor in 158 of the 252 patients. We validated this model in tissue (n=233) and blood (n=140) samples from two independent cohorts treated with R-CHOP., Findings: T-cell and NK-cell immune effector molecule expression correlated with tumour-associated macrophage and PD-1/PD-L1 axis markers, consistent with malignant B cells triggering a dynamic checkpoint response to adapt to and evade immune surveillance. The ratio of CD4*CD8 to (CD163:CD68[M2])*PD-L1 was better able to stratify overall survival than was any one immune marker or combination, distinguishing groups with disparate 4-year overall survival. 94 (59%) of 158 patients had a score above the cutoff and 4-year overall survival of 92·1% (95% CI 82·9-96·7), and the remaining 64 (41%) patients had a score below the cutoff and 4-year overall survival of 47·0% (32·8-60·5; hazard ratio [HR] 8·3, 95% CI 4·3-17·3; p<0·0001). The CD4*CD8:M2*PD-L1 immune ratio was independent of and added to the R-IPI and cell of origin. Tissue findings in the independent tissue cohort accorded with those in our initial tissue cohort. 139 (60%) of 233 patients had a score above the cutoff and 4-year overall survival of 75·6% (95% CI 64·6-83·6), with the remaining 94 (40%) patients having a score below the cutoff (63·5% [52·5-72·7]; HR 1·9, 95% CI 1·1-3·3; p=0·0067)., Interpretation: Ratios of immune effectors to checkpoints augment the cell of origin and R-IPI in DLBCL and are applicable to paraffin-embedded biopsy specimens. These findings might have potential implications for selection of patients for checkpoint blockade within clinical trials., Funding: Leukaemia Foundation of Queensland, Kasey-Anne Oklobdzijato Memorial Fund, the Australasian Leukaemia and Lymphoma Group (Malcolm Broomhead Bequest), the Australian Cancer Research Foundation, and the Cancer Council of Queensland., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: Rituximab is one of nine biologic agents approved for the treatment of rheumatoid arthritis (RA) in Australia. The primary study objective was to analyze the factors that lead to the therapeutic decision to use rituximab in RA., Method: A cross-sectional, retrospective chart review was conducted to identify patients who were treated with rituximab and to evaluate their response to treatment., Results: Factors influencing the prescription of rituximab were identified. The most commonly reported reason for prescribing rituximab was the presence of comorbidities and the presence of seropositive disease. Median rituximab treatment duration was 32.5 months and mean number of treatment cycles was 4.1. Disease activity scores showed significant improvement from baseline to most recent visit. Rituximab treatment was well-tolerated in this group of RA patients., Conclusions: Rituximab was effective in a refractory group of RA patients and appears to be safe in a population with a high prevalence of comorbidities, including malignancy and recurrent infections/bronchiectasis. This study may assist rheumatologists in selecting appropriately targeted therapy in RA., (© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Background: Patients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL)., Methods: Asymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931., Findings: Between Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p<0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p<0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved., Interpretation: Rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma., Funding: Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Rituximab is a chimeric, anti-CD20 monoclonal antibody registered for the treatment of B-cell malignancies and refractory rheumatoid arthritis in Australia. In addition to these approved indications, there has been growing interest in the use of off-label rituximab in the management of a variety of diseases., Aims: To determine the current usage of off-label rituximab in Australia, we collected nationwide data., Methods: Information regarding patients receiving rituximab for off-label indications was prospectively collected for a 6-month period from Australian public hospitals. Data recorded included clinical indication, dosing schedule, previous therapy and efficacy assessment. The level of evidence for the use of rituximab was determined for each off-label indication., Results: During the 6-month period, a total of 364 instances of off-label rituximab use was recorded in the national database. A total of 63 underlying diagnoses was identified. These were subclassified into haematological disorders (19%), autoimmune connective tissue diseases (12%), vasculitis (12%), neurological disorders (12%), transplant-related uses (12%), haematological malignancies (11%), muscle disorders (8%), renal diseases (6%), dermatological conditions (5%), other conditions (2%) and ocular diseases (1%). Forty percent of these requests were supported only by level 4 evidence of benefit. Data highlighted the non-standardised approaches to drug approval mechanisms, dosing schedules and monitoring for efficacy., Conclusions: Off-label rituximab is prescribed for a diverse range of clinical conditions. Determining a safe and effective means of regulating this use within an evidence-based framework remains an ongoing challenge., (© 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.)

Background: The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects., Methods: In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907., Findings: The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03-119), 6-year event-free survival was 55·8% (95% CI 50·4-60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3-78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5-25·4, log-rank p<0·0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84·3% [95% CI 74·2-90·7] vs 71·0% [65·1-76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6-6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2-6·2) in the chemotherapy and rituximab group (Fisher's exact p=0·730)., Interpretation: Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone., Funding: Hoffmann-La Roche., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: To establish benchmark outcomes for combined modality treatment to be used in future prospective studies of osteolymphoma (primary bone lymphoma)., Methods and Materials: In 1999, the Trans-Tasman Radiation Oncology Group (TROG) invited the Australasian Leukemia and Lymphoma Group (ALLG) to collaborate on a prospective study of limited chemotherapy and radiotherapy for osteolymphoma. The treatment was designed to maintain efficacy but limit the risk of subsequent pathological fractures. Patient assessment included both functional imaging and isotope bone scanning. Treatment included three cycles of CHOP chemotherapy and radiation to a dose of 45 Gy in 25 fractions using a shrinking field technique., Results: The trial closed because of slow accrual after 33 patients had been entered. Accrual was noted to slow down after Rituximab became readily available in Australia. After a median follow-up of 4.3 years, the five-year overall survival and local control rates are estimated at 90% and 72% respectively. Three patients had fractures at presentation that persisted after treatment, one with recurrent lymphoma., Conclusions: Relatively high rates of survival were achieved but the number of local failures suggests that the dose of radiotherapy should remain higher than it is for other types of lymphoma. Disability after treatment due to pathological fracture was not seen., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown., Patients and Methods: Patients with CD20(+) DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT., Results: The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001)., Conclusion: In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP.

A retrospective review of patients receiving rituximab off label in a large teaching hospital was conducted between July 2002 and January 2006. The indication, dosing regimen, efficacy and cost of rituximab were evaluated. Rituximab was prescribed for three clinical indications; acute organ transplant rejection, post-transplant lymphoproliferative disease and autoimmune disease. On average, 600 mg of rituximab was prescribed weekly for 4 weeks, costing the hospital $108,739.37. We suggest an initial approval for a limited number of doses with subsequent approval dependent on improvement in predefined clinical or biochemical end-points. Furthermore, we suggest an Australia-wide central database be established to enable delineation of the optimal dosing schedule, as well as monitoring of clinical outcome.