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Aim To evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC) and to identify sources of prediction error (PE). Methods A prospective multicentre PK study was conducted in 40 myeloma patients of median age 60 (range:35–71) years using a 20 mg/m2 test dose administered 1–3 days prior to HDM (predominantly 180 mg/m2). PK data were collected post the test and high doses to compare predicted versus actual AUCs determined using the trapezoidal rule. Test and high dose infusion concentration, volume and duration and the time from preparation to infusion were compared using the paired Wilcoxin rank sign test. The impact of Melphalan administration parameters on PE was evaluated using the Mann–Whitney test. The predictive capacity of a previously published population PK (PopPK) model was also examined. Results Predicted HDM AUC was within 15% of the observed values in only 63% of patients when analysed using the trapezoidal rule and 70% of patients using PopPK. Test dose infusion concentration, volume, duration and time from preparation to infusion were significantly lower than for HDM (p n = 5) was associated with significantly lower PE than administration times of 16–60 min (n = 22), p ± 15%), but the differences were not significant (p = 0.078, 0.228, respectively). Conclusion Test dose PK has the potential to predict subsequent HDM exposure to achieve a target AUC once melphalan administration parameters are optimised to account for stability issues in the formulation.

Nonalcoholic fatty liver disease (NAFLD) has been associated with a condition known as the dysmetabolic iron overload syndrome, but the frequency and severity of iron overload in NAFLD is not well described. There is emerging evidence that mild to moderate excess hepatic iron can aggravate the risk of progression of NAFLD to nonalcoholic steatohepatitis and eventually cirrhosis. Mechanisms are postulated to be via reactive oxygen species, inflammatory cytokines, lipid oxidation, and oxidative stress. The aim of this review is to assess the evidence for true hepatic iron overload in NAFLD, to discuss the pathogenesis by which excess iron may be toxic, and to critically evaluate the studies designed to deplete iron by regular venesection. In brief, the studies are inconclusive due to heterogeneity in eligibility criteria, sample size, randomization, hepatic iron measurement, serial histological endpoints, target ferritin levels, length of venesection, and degree of confounding lifestyle intervention. We propose a trial designed to overcome the limitations of these studies.

This review aims to provide an expert consensus statement to address the role of gene-panel testing in the diagnosis, prognosis and management of adult myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes (MDS/MPN) in Australia. This consensus statement was developed by an expert group, actively involved in gene panel testing in the area of MDS/MPN in Australia. This work was led by the chairs of the MDS (A/Prof A. Enjeti) and MPN (A/Prof D. Ross) working parties of the Australasian Leukaemia and Lymphoma Group (ALLG). The authors were selected after an expression of interest process on the basis of active laboratory involvement in gene panel testing, a specific demonstrated interest in MDS/MPN and/or publication record in this field. The authors were then allocated sections for literature review to identify the specific genes of interest for each MDS/MPN entity. At least two authors reviewed each section and an overarching diagnostic algorithm was developed by a consensus amongst all authors.

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

Invasive fungal infections (IFI) are challenging to predict, diagnose and treat, and are associated with a particularly high mortality among patients with hematological malignancies. They are relatively uncommon in patients with lymphoma, compared with those with acute leukemia or undergoing allogeneic transplantation. We present a patient, autografted for recurrent lymphoma, with fever and refractory diarrhea persisting post engraftment, eventually attributable to disseminated mucor infection. This case illustrates the challenge of timely diagnosis and initiation of treatment for IFI in lymphoma patients, who do not routinely receive antifungal prophylaxis, and the importance of aggressive investigation and symptom-directed tissue sampling for evidence of IFI in febrile immunocompromised hosts not responding to broad-spectrum antibiotics.

Cyclosporine is an immunosuppressive agent to prevent acute graft versus host disease (GVHD) in patients undergoing a stem cell allograft. It has a narrow therapeutic range, and its metabolism can be affected by posaconazole, commonly used as antifungal prophylaxis post allograft. There is limited evidence on the optimal oral cyclosporine starting dose in this setting. A delicate balance is required in dose adjustments to avoid toxic levels while maintaining sufficient drug concentrations to prevent GVHD. We undertook a retrospective audit of 28 patients undergoing their first allograft who received posaconazole and commenced on a starting oral cyclosporine dose of 2 mg/kg twice daily. Our key findings were that this starting dose was too high, with all patients experiencing at least one toxicity and an overall low incidence of GVHD.

Intravenous high-dose methotrexate (HD-MTX) is a critical chemotherapeutic agent in hematological malignancies, however, data are lacking on how to predict and prevent toxicities such as kidney injury. We retrospectively analyzed 539 episodes of HD-MTX (≥1 g/m

Jarosite is a ferric iron sulfate mineral [(KFe3(SO4)2(OH)6] that is commonly formed in acidic environments that are rich in iron and sulfate, such as acid-sulfate soils or acid mine drainage. The stability of jarosite is important because the mineral contains embodied acidity and may scavenge trace elements by sorption and co-precipitation. Although stable under high Eh and low pH conditions, previous studies have shown that jarosite is prone to transformation by hydrolysis at circumneutral pH, or may undergo Fe(II)-catalysed transformation where ferrous ions are present [1-3]. Jarosite may be exposed to Fe(II) at circumneutral pH in reducing environments, such as in flooded acid-sulfate soils [2]. Jarosite is a member of the alunite supergroup and forms a solid solution series with alunite by substitution of Al for Fe. However, the effect of Al substitution on the stability of jarosite in the presence of Fe(II) has not previously been investigated. Here, we performed batch experiments using samples of a synthetic jarosite without aluminium substitution, and synthetic jarosite containing 7.3% Al-for-Fe substitution. Mineral samples were reacted with 0.5 mM and 5 mM Fe(II) at pH 7.1 (50 mM MOPS buffer) for up to 24 hours. Rietveld analysis of X-ray diffraction patterns was used to quantify mineral transformations and to determine the crystallinity of, and Al substitution in, product phases. Complete transformation of jarosite to mixtures of ferrihydrite, goethite and lepidocrocite occurred within several hours for all jarosite samples and Fe(II) treatments. The 10-fold increase in Fe(II) concentration resulted in a 50% increase in jarosite transformation rate, and pure jarosite transformed 110% to 280% faster than Al-substituted jarosite. The transformation products of Al-substituted jarosite contained a smaller proportion of lepidocrocite than the products of pure jarosite transformation, and the unit cell size of the lepidocrocite that initially formed from Al-substituted jarosite indicates that Al was substituted into the structure. These results demonstrate that structural Al can stabilise jarosite against transformation, which has implications for understanding the longevity of jarosite, and its importance to trace element cycling, in reducing environments.1. Welch, S. A., et al. (2008) Chem. Geol. 254: pp. 73-862. Karimian, N., et al. (2017) Environ. Sci. Technol. 51: pp. 4259-42683. Whitworth, A. J., et al. (2020) Chem. Geol. 554

Asciminib is the first tyrosine kinase inhibitor (TKI) to Specifically Target the ABL Myristoyl Pocket (STAMP). In the ASCEMBL Phase 3 randomised study comparing asciminib to bosutinib in patients with CML in chronic phase (CP) after ³2 prior TKIs, asciminib demonstrated superior efficacy and tolerability vs bosutinib (major molecular response (MMR) rate at week 96: 37.6% vs 15.8%, treatment discontinuation 7.7% vs 26.3%) (Rea et al, EHA 2022). Here we present the real-world clinical outcomes of TKI-resistant/ intolerant CML patients in Australia who received asciminib through a MAP approved by Novartis.

In post-mining rehabilitation, successful mine closure planning requires specific, measurable, achievable, relevant and time-bound (SMART) completion criteria, such as returning ecological communities to match a target level of similarity to reference sites. Soil microbiota are fundamentally linked to the restoration of degraded ecosystems, helping to underpin ecological functions and plant communities. High-throughput sequencing of soil eDNA to characterise these communities offers promise to help monitor and predict ecological progress towards reference states. Here we demonstrate a novel methodology for monitoring and evaluating ecological restoration using three long-term (>25 year) case study post-mining rehabilitation soil eDNA-based bacterial community datasets. Specifically, we developed rehabilitation trajectory assessments based on similarity to reference data from restoration chronosequence datasets. Recognising that numerous alternative options for microbiota data processing have potential to influence these assessments, we comprehensively examined the influence of standard versus compositional data analyses, different ecological distance measures, sequence grouping approaches, eliminating rare taxa, and the potential for excessive spatial autocorrelation to impact on results. Our approach reduces the complexity of information that often overwhelms ecologically-relevant patterns in microbiota studies, and enables prediction of recovery time, with explicit inclusion of uncertainty in assessments. We offer a step change in the development of quantitative microbiota-based SMART metrics for measuring rehabilitation success. Our approach may also have wider applications where restorative processes facilitate the shift of microbiota towards reference states.

Background A significant proportion (up to 37%) of patients (pts) with chronic phase (CP) CML experience either resistance or intolerance to first-line tyrosine kinase inhibitor (TKI) therapy within 5 years and transition to other treatment options(Heeg B, et al. 2021). There are limited data regarding experiences and unmet needs of pts receiving second and later TKI therapy for CML, particularly with respect to quality of life and emotional wellbeingand concerns around disease response and long-term outcome. The CML survey on unmet needs (SUN) research aims to further characterize in depth these unmet needs from the perspective of both the pts and treating physicians. Methods CML SUN consists of two sequential phases. Phase 1 entailed of 60-minute in-depth telephone qualitative interviews with adult pts on second line or later TKI treatment and physicians treating CML in France, Germany, Japan and the USA. The insights from this initial phase will inform the design of the second phase, a larger quantitative survey. This abstract reports the results of the Phase 1 qualitative research. Pts were recruited through physician referral, pt panels, pt advocacy groups and social networking service sources, while physicians treating CML were recruited via panels/databases. Key inclusion criteria can be found in Table 1. A semi-structured interview guide covering the same topics for both pts and physicians was used to conduct the interviews. The guide consisted of pre-determined but open-ended questions on the topics of perception of the disease, burden of disease, treatment journey, the impact of treatment change, adverse events (AEs), ideal treatment and needs which have not been previously identified or met. For each of the recorded interviews, a detailed content analysis was conducted to organize the collected data by themes and topics. This content analysis was used to compare responses between individuals within and across countries, and used to identify insights and trends. Results A total of 21 pts and 24 physicians were interviewed (Table 2: demographics). Physician: While physicians were mostly the ones to initiate treatment switch discussions with their pts, they typically did not provide pts with different treatment options and/or clear treatment goals when selecting 2 nd line or subsequent therapy. Most believed that pts & caregivers have minimal or no role in this matter. Therapy switch tended to happen faster if due to lack of treatment response rather than side effects which, unless severe or very frequent, were first treated symptomatically or with dose modification. Physicians felt that pts have minimal or no unmet needs requiring support when it comes to switching therapies. Patients: An almost equal proportion switched treatments due to resistance vs due to AEs. The need to switch TKI therapy induces anxiety and concerns for pts. Some pts downplayed their AEs either because of fear of triggering a therapy switch or trying to avoid being a burden. Most pts expressed the need to receive additional information on the necessity of therapy switch and on the potential therapy side effects. While physicians and pts had similar goals for the new treatment: to be effective and generally tolerable; physicians placed a higher priority to the efficacy of the treatment, whilst pts placed a higher priority to reducing the burden of AEs. Conclusions This first phase of this research has identified different perspectives and needs between CML pts and physicians in relation to change of TKI therapies, as well as potential divergencies between the two groups regarding their perception of unmet needs. This information will help design the second phase of the study which will further quantify the impact of these unmet needs in a larger population across a broad geography of 11 countries. This knowledge can be used to raise awareness and to develop support strategies to improve current CML management practices and the pt experience. Figure 1 Figure 1. Disclosures Pemberton-Whiteley: Acute Leukemia Advocates Network: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leukaemia Care: Current Employment; AbbVie, Agios, Amgen, Astellas, Autolus, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Incyte, Jazz, Janssen, Kite, Kyowa Kirin, Mallinckrodt, Novartis, Pfizer, Roche, Servier, Takeda: Consultancy, Other: Organizational grant funding, Speakers Bureau; WECAN (Workgroup of European Cancer Patient Advocacy Networks): Consultancy, Membership on an entity's Board of Directors or advisory committees; CML Advocates Network: Membership on an entity's Board of Directors or advisory committees. Cortes: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding. Clements: Novartis Oncology: Honoraria, Other: Member of advisory board; Takeda Pharmaceuticals: Honoraria; Pfizer Pharmaceuticals: Honoraria, Other: Educational Grant; Leukemia and Lymphoma Society NPO: Membership on an entity's Board of Directors or advisory committees, Other: Patient Financial Assistance; CML Advocates Network NPO / CML Horizons Conferences: Honoraria, Membership on an entity's Board of Directors or advisory committees; The MAX Foundation NPO: Honoraria. Ruiz: Novartis: Honoraria; Pfizer: Honoraria. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Machado: Pfizer Canada: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Lang: AstraZeneca: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Takahashi: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Kyowahakko-Kirin: Research Funding; Toyamakagaku: Research Funding; Ono: Research Funding. Deekes: Novartis: Honoraria. Moon: Novartis: Honoraria, Other: Member of advisory board. Grigg: Novartis: Honoraria, Other: Member of advisory board. Steagall: Novartis: Honoraria. Borowczak: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pilipovic: Novartis: Current Employment, Current equity holder in publicly-traded company. Frank: Novartis: Current Employment, Current equity holder in publicly-traded company. Constantinescu: Novartis: Other: Cristina Constantinescu is an employee of Ipsos, who were paid consultants to Novartis. Boquimpani: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pinth Pharma: Speakers Bureau.