Australia and New Zealand consensus position statement: use of COVID-19 therapeutics in patients with haematological malignancies.

Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B-cell malignancies and on B-cell-targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID-19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de-isolation following COVID-19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID-19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID-19 Guidelines.

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic.

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

Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an MYD88 p.L265P mutation. Ibrutinib therapy was subsequently commenced, resulting in complete resolution of the skin disease. Despite an ongoing skin response, the patient developed progressive nodal disease at two months. Genomic analysis of the cutaneous tumor sample at baseline was compared to that of the inguinal lymph node upon progression, and revealed the acquisition of multiple genomic changes. These included several aberrations expected to bypass BTK inhibition, including two CARD11-activating mutations, and a deleterious mutation in the nuclear factor kappa B (NF-κB) negative regulator, NFKBIE. In addition, an IgH-IRF8 translocation was detected (which brings the IRF8 transcription factor under control of the immunoglobulin heavy chain locus), representing a third plausible mechanism contributing to ibrutinib resistance. Several copy-number changes occurred in both samples, including an amplification of 18q, which encodes the anti-apoptotic protein BCL2. We describe the first case of novel genomic changes of PCDLBCL-LT that occurred while on ibrutinib, providing important mechanistic insights into both pathogenesis and drug resistance.

Trends in the surgical management of stage 1 renal cell carcinoma: findings from a population-based study.

OBJECTIVES: To determine whether the use of nephron-sparing surgery (NSS) for treatment of stage 1 renal cell carcinoma (RCC) changed between 2009 and the end of 2013 in Australia. PATIENTS AND METHODS: All adult cases of RCC diagnosed in 2009, 2012 and 2013 were identified through the population-based Victorian Cancer Registry. For each identified patient, trained data-abstractors attended treating hospitals or clinician rooms to extract tumour and treatment data through medical record review. Multivariable logistic regression analyses were carried out to examine the significance of change in use of NSS over time, after adjusting for potential confounders. RESULTS: A total of 1 836 patients with RCC were identified. Of these, the proportion of cases with stage 1 tumours was 64% in 2009, 66% in 2012 and 69% in 2013. For T1a tumours, the proportion of patients residing in metropolitan areas receiving NSS increased from 43% in 2009 to 58% in 2012 (P < 0.05), and 69% in 2013 (P < 0.05). For patients residing in non-metropolitan areas, the proportion receiving NSS increased from 27% in 2009 to 49% in 2012, and 61% in 2013 (P < 0.01). Univariable logistic regression showed patients with moderate (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.35-0.94) or severe comorbidities (OR 0.58, 95% CI 0.33-0.99), residing in non-metropolitan areas (OR 0.65, 95% CI 0.47-0.90), were less likely to be treated by NSS, while those attending high-volume hospitals (≥30 cases/year: OR 1.79, 95% CI 1.21-2.65) and those with higher socio-economic status (OR 1.45, 95% CI 1.02-2.07) were more likely to be treated by NSS. In multivariable analyses, patients with T1a tumours in 2012 (OR 2.00, 95% CI 1.34-2.97) and 2013 (OR 3.15, 95% CI 2.13-4.68) were more likely to be treated by NSS than those in 2009. For T1b tumours, use of NSS increased from 8% in 2009 to 20% in 2013 (P < 0.05). CONCLUSION: This population-based study of the management of T1 renal tumours in Australia found that the use of NSS increased over the period 2009 to 2013. Between 2009 and 2013 clinical practice for the treatment of small renal tumours in Australia has increasingly conformed to international guidelines.

The addition of dexamethasone to bortezomib for patients with relapsed multiple myeloma improves outcome but ongoing maintenance therapy has minimal benefit.

Despite the common practice of combining dexamethasone (Dex) with bortezomib (Bz) in patients with multiple myeloma (MM), until now there has been few prospective trials undertaken. We undertook a trial that recapitulated the original APEX study except that dexamethasone was incorporated from cycle 1. We also incorporated an exploratory maintenance component to the study. Twenty sites enrolled 100 relapsed/or refractory MM patients utilizing eight 21 day cycles of IV Bz [1.3 mg/m(2) ; Day (D) 1, 4, 8, 11] and three 35 day cycles; Bz (1.3 mg/m(2) ; Day (D) 1, 8, 15, 22). Our study was registered at www.clinicaltrials.gov (NCT00335348). Patients with stable disease or better received maintenance Bz (1.3 mg/m(2) ) every 14 days until progression. Dexamethasone (20 mg) was given for 2 days with each Bz dose. A prospectively defined matched-analysis of primary (overall response rate; ORR) and secondary endpoints [Complete Response (CR) and time to progression (TTP)] compared our cohort to those on the Bz arm of the APEX trial. The addition of Dex improved ORR by 20% (56% vs. 36%) [odds ratio 0.44 (0.24-0.80)]. The median TTP was also significantly longer (10.1 vs. 5.1 months) (hazard ratio 0.50, 95% CI: 0.35-0.72, P = 0.0002) and our landmark analysis demonstrated that this was largely due to the early use of dexamethasone, as we were unable to demonstrate any benefit of bortezomib/dexamethasone maintenance therapy.

Emerging drugs for T-cell lymphoma.

INTRODUCTION: T-cell lymphomas are rare and conventional treatments are not typically curative. Integration of biologic agents into routine practice is especially difficult given the breadth of emerging drugs currently or recently in trials. AREAS COVERED: This is an overview of the management of T-cell lymphoma as it stands today. The authors review clinically active biological and novel chemotherapeutic agents, which have a niche in current practice or are being actively developed and have a potential future role in the management of this challenging group of diseases. Clinical trial data were retrieved from journals and current major conference proceedings following interrogation of online search engines EXPERT OPINION: Pralatrexate, the histone deacetylase inhibitors and brentuximab vedotin have reached the market and have provided new and useful treatment options. No novel agent has yet demonstrated a survival advantage for patients with this disease, or shown an ability to improve the low response rate to first-line chemotherapy that these diseases frequently exhibit. New randomized studies of these emerging drugs that may finally move the field forward with evidence of superiority from large Phase II and III trials currently open to accrual.

Dietary intake of animal-based products and likelihood of follicular lymphoma and survival: A population-based family case-control study.

Background: The association between dietary intake of foods of animal origin and follicular lymphoma (FL) risk and survival is uncertain. In this study, we examined the relationship between dietary intake of dairy foods and fats, meat, fish and seafoods, and the likelihood of FL and survival. Methods: We conducted a population-based family case-control study in Australia between 2011 and 2016 and included 710 cases, 303 siblings and 186 spouse/partner controls. We assessed dietary intake of animal products prior to diagnosis (the year before last) using a structured food frequency questionnaire and followed-up cases over a median of 6.9 years using record linkage to national death data. We examined associations with the likelihood of FL using logistic regression and used Cox regression to assess association with all-cause and FL-specific mortality among cases. Results: We observed an increased likelihood of FL with increasing daily quantity of oily fish consumption in the year before last (highest category OR = 1.96, CI = 1.02-3.77; p-trend 0.06) among cases and sibling controls, but no associations with spouse/partner controls. We found no association between the likelihood of FL and the consumption of other types of fish or seafood, meats or dairy foods and fats. In FL cases, we found no association between meat or oily fish intake and all-cause or FL-specific mortality. Conclusion: Our study showed suggestive evidence of a positive association between oily fish intake and the likelihood of FL, but findings varied by control type. Further investigation of the potential role of environmental contaminants in oily fish on FL etiology is warranted.

An Update on the Current Genomic Landscape of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Breast implant-associated lymphoma (BIA-ALCL) is a rare subtype of anaplastic large-cell lymphoma associated with breast prostheses. Most patients present with a localised periprosthetic effusion and are managed with removal of the implant and surrounding capsule. Less commonly, the lymphoma can form a mass associated with the capsule and rarely can present with disseminated disease. Recent series characterising the genomic landscape of BIA-ALCL have led to insights into the mechanisms of lymphomagenesis. Constitutive JAK/STAT pathway activation has emerged as a likely key component while, more recently, aberrancies in epigenetic regulators have been reported. This review describes the genomic characterisation reported to date and the insight these findings have provided into this rare entity.

Pralatrexate in relapsed/refractory T-cell lymphoma: a retrospective multicenter study.

We present a retrospective multicenter study of pralatrexate treatment outcomes in an Australian practice setting for patients with relapsed/refractory T-cell lymphoma who had failed 1+ systemic therapies, treated via a compassionate access program. Endpoints assessed included response rates, toxicities, and subsequent therapies. Progression-free survival (PFS), time to next treatment (TTNT), event-free survival (EFS), overall survival (OS), and time to best response, were assessed by Kaplan-Meier analysis. The study included 31 patients, with median age 69 years. We demonstrated ORR of 35.5% (n = 11), including 4 complete responses (13%) and 7 partial responses (23%). The predicted median OS was 10 months, with EFS of 9 months, and PFS of 9 months. Median TTNT was 8 months. Mucositis was the most commonly observed toxicity. This study - the second largest real-world cohort reported to date - underscores the importance of pralatrexate in relapsed/refractory T-cell lymphoma, as well as its acceptable toxicity profile.

Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells.

New diagnoses of multiple myeloma (MM) tend to occur after the age of 60, by which time thymic output is severely reduced. As a consequence, lymphocyte recovery after lymphopenia-inducing anti-MM therapies relies on homeostatic proliferation of peripheral T cells rather than replenishment by new thymic emigrants. To assess lymphocyte recovery and phenotype in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), we tracked CD4+ and CD8+ T cell populations at serial time points throughout treatment and compared them to age-matched healthy donors (HD). Anti-MM therapies and autologous stem cell transplant (ASCT) caused a permanent reduction in the CD4:8 ratio, a decrease in naïve CD4+ T cells, and an increase in effector memory T cells and PD1-expressing CD4+ T cells. Transcriptional profiling highlighted that genes associated with fatty acid ß-oxidation were upregulated in T cells in RRMM, suggesting increased reliance on mitochondrial respiration. High mitochondrial mass was seen in all T cell subsets in RRMM but with relatively suppressed reactive oxygen species and mitochondrial membrane potential, indicating mitochondrial dysfunction. These findings highlight that anti-MM and ASCT therapies perturb the composition of the T cell compartment and drive substantial metabolic remodeling, which may affect the fitness of T cells for immunotherapies. This is particularly pertinent to chimeric antigen receptor (CAR)-T therapy, which might be more efficacious if T cells were stored prior to ASCT rather than at relapse.

Statin-induced anti-HMGCR antibody-related immune-mediated necrotising myositis achieving complete remission with rituximab.

Statin-induced immune-mediated necrotising myopathy (IMNM) is a rare but increasingly recognised myositis. Many cases have positive antibodies to 3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR). The current treatment is ceasing the statin, but often immunosuppressive therapy is required as the antibodies persist, causing muscle necrosis. Despite the use of immunosuppressive medications, most commonly prednisolone, methotrexate, plasma exchange and/or intravenous immunoglobulin, some patients do not respond. We report the successful treatment with rituximab therapy for three patients with IMNM with positive anti-HMGCR antibodies. All three patients with statin-induced IMNM were elderly, with a disease history of 7-9 years, and had failed several immunosuppressive agents. They responded well to rituximab (induction and maintenance) therapy. They remain in remission with no symptoms and normal creatine kinase. One patient had normalisation of anti-HMGCR antibody level, and one patient's antibody level reduced significantly. Rituximab is an effective immunosuppressive treatment for patients with refractory IMNM.

A phase II study of a modified hyper-CVAD frontline therapy for patients with adverse risk diffuse large B-cell and peripheral T-cell non-Hodgkin lymphoma.

To improve complete remission (CR) rates by reducing toxicity and enhancing delivery, we created a modified hyper-CVAD/MA regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone/methotrexate, cytarabine) by reducing the cytarabine dose (3 g/m2 to 2 g/m2) and number of cycles (eight to six). We conducted a phase II trial in the pre-rituximab era in the intermediate-high international prognostic index (IPI) (≥2) de novo diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) (ACTRN12605000105640). CR rates were compared with reported IPI-stratified rates. Sixty-three patients (n = 26 PTCL; n = 37 DLBCL) were evaluated; median follow-up of 30 months. CR rates for PTCL and DLBCL patients were 46% and 49%, respectively, similar with reported CR rates with CHOP-like chemotherapy (p = .6). Of the patients, 51 (81%) experienced ≥1 unplanned hospital admission; only 41 (65%) completed six cycles. The cytarabine modifications did not prevent significant toxicity. Modified hyper-CVAD/MA resulted in similar outcomes to CHOP-like chemotherapy in aggressive lymphomas and was associated with significant toxicity.

Global measures of peripheral blood-derived DNA methylation as a risk factor in the development of mature B-cell neoplasms.

AIM: To examine whether peripheral blood methylation is associated with risk of developing mature B-cell neoplasms (MBCNs). MATERIALS & METHODS: We conducted a case-control study nested within a large prospective cohort. Peripheral blood was collected from healthy participants. Cases of MBCN were identified by linkage to cancer registries. Methylation was measured using the Infinium(®) HumanMethylation450. RESULTS: During a median of 10.6-year follow-up, 438 MBCN cases were evaluated. Global hypomethylation was associated with increased risk of MBCN (odds ratio: 2.27, [95% CI: 1.59-3.25]). Within high CpG promoter regions, hypermethylation was associated with increased risk (odds ratio: 1.76 [95% CI: 1.25-2.48]). Promoter hypermethylation was observed in HOXA9 and CDH1 genes. CONCLUSION: Aberrant global DNA methylation is detectable in peripheral blood collected years before diagnosis and is associated with increased risk of MBCN, suggesting changes to DNA methylation are an early event in MBCN development.

Inflammatory Pseudotumor of the Spleen.

Isolated splenic inflammatory pseudotumors (IPT) are extremely rare, typically benign, inflammatory lesions with varied clinical presentations that pose a diagnostic challenge to clinicians due to their similarity in appearance to neoplasms. We present the case of a young woman diagnosed with a splenic IPT following investigation for persistent anemia, raised inflammatory markers, and polyclonal hypergammaglobulinemia, whose symptoms resolved completely following splenectomy. This case highlights the need to consider this diagnosis when evaluating patients with a splenic mass of unknown etiology.