Variability of bone marrow biopsy reporting affects accuracy of diagnosis of myeloproliferative neoplasms: data from the ALLG MPN01 registry.

The Philadelphia-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of overlapping bone marrow disorders defined by characteristic peripheral blood counts and bone marrow morphological findings in conjunction with recurrent somatic mutations. The accurate diagnosis and subclassification of MPN relies upon careful reporting of bone marrow morphology combined with ancillary information in an integrated pathology report. This co-operative trial group study ALLG MPN01 (ANZCTR:12613000138785), led by the Australasian Leukaemia & Lymphoma Group (ALLG), aimed to describe the current approach to diagnosis of MPN in routine practice. Specifically, we assessed the frequency with which bone marrow biopsies were performed, and the adherence of reporting pathologists to recommendations contained in the revised 2016 WHO classification pertaining to MPN. We reviewed the diagnosis of 152 patients from eight institutions who were enrolled in a national MPN registry of the ALLG between 2010 and 2016. The ALLG MPN01 registry is now closed to recruitment. Key features were extracted from pathology reports provided to the registry. Bone marrow biopsies were performed in 112/152 cases (74%). The pathological information entered was concordant with the stated clinical diagnosis in 75/112 cases (67%). The main reasons for discordant results were incomplete descriptions of megakaryocyte topography and morphology, inconsistent grading of reticulin fibrosis, and failure to integrate the available morphological and ancillary clinicopathological information. In this retrospective audit, 26% of MPN patients did not undergo a diagnostic bone marrow biopsy. In those who did, the specific MPN subtype may not have been reported correctly in 33% of cases, as evidenced by inconsistent features reported or insufficient information to assess. A more standardised approach to bone marrow reporting is required to ensure accuracy of MPN diagnoses and consistent reporting to cancer registries and clinical trials.

How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Molecular associations of response to the new-generation BTK inhibitor zanubrutinib in marginal zone lymphoma.

Using tissue whole exome sequencing (WES) and circulating tumor cell-free DNA (ctDNA), this Australasian Leukaemia & Lymphoma Group translational study sought to characterize primary and acquired molecular determinants of response and resistance of marginal zone lymphoma (MZL) to zanubrutinib for patients treated in the MAGNOLIA clinical trial. WES was performed on baseline tumor samples obtained from 18 patients. For 7 patients, ctDNA sequence was interrogated using a bespoke hybrid-capture next-generation sequencing assay for 48 targeted genes. Somatic mutations were correlated with objective response data and survival analysis using Fisher exact test and Kaplan-Meier (log-rank) method, respectively. Baseline WES identified mutations in 33 of 48 (69%) prioritized genes. NF-κB, NOTCH, or B-cell receptor (BCR) pathway genes were implicated in samples from 16 of 18 patients (89%). KMT2D mutations (n = 11) were most common, followed by FAT1 (n = 9), NOTCH1, NOTCH2, TNFAIP3 (n = 5), and MYD88 (n = 4) mutations. MYD88 or TNFAIP3 mutations correlated with improved progression-free survival (PFS). KMT2D mutations trended to worse PFS. Acquired resistance mutations PLCG2 (R665W/R742P) and BTK (C481Y/C481F) were detected in 2 patients whose disease progressed. A BTK E41K noncatalytic activating mutation was identified before treatment in 1 patient who was zanubrutinib-refractory. MYD88, TNFAIP3, and KMT2D mutations correlate with PFS in patients with relapsed/refractory MZL treated with zanubrutinib. Detection of acquired BTK and PLCG2 mutations in ctDNA while on therapy is feasible and may herald clinical disease progression. This trial was registered at https://anzctr.org.au/ as #ACTRN12619000024145.

Complications of diabetes in urban Indigenous Australians: the DRUID study.

AIMS: To accurately assess the management and complications of type 2 diabetes in urban Indigenous Australians and compare the risk of complications with a general Australian population (AusDiab Study). METHODS: The Darwin Region Urban Indigenous Diabetes (DRUID) Study included 1004 volunteers aged >/=15 years; diabetes status was classifiable for 866. The assessment of diabetic complications and metabolic control was performed in participants with known diabetes (KDM) and diabetes newly diagnosed by the study (NDM) using an interviewer-administered questionnaire and clinical examination. RESULTS: Among 172 DRUID participants eligible for complications assessment, 135 were assessed, including 99 KDM (mean age 53 years) and 36 NDM (mean age 47 years). Percentages of KDM participants meeting therapeutic targets were: HbA1c<7%, 29%; blood pressure<130/80mmHg, 45%; total cholesterol<5.5mmol/L, 65%. Among KDM, 39% had albuminuria, 21% retinopathy, 12% peripheral vascular disease (PVD), 9% neuropathy. Factors independently associated with diabetic complications were: albuminuria-HbA1c, systolic blood pressure; retinopathy-diabetes duration; PVD-age. Compared to AusDiab participants after adjusting for other risk factors, DRUID participants had 2-3-fold increased risk of albuminuria and PVD and a non-significant increased risk of neuropathy, but no increased risk of retinopathy. CONCLUSIONS: Urban Indigenous Australians with diabetes are relatively young and have poor glycaemic control. Compared to the general Australian population with type 2 diabetes, they have greater adjusted risk of albuminuria and PVD but not retinopathy. Urgent action is required to prevent diabetes at a population level and improve diabetes management in this high-risk population.