BackgroundThree diagnostic scoring systems have been developed to improve the identification of patients with transthyretin cardiac amyloidosis (ATTR-CA) in patients presenting with heart failure with preserved ejection fraction (HFpEF). The ATTR-CM, AMY and T-Amylo scores have been validated, though data comparing their performance are lacking. We sought to compare the diagnostic accuracy of the three scores in an Australian cohort.MethodsWe conducted a retrospective cohort study across two separate healthcare centres from 2018 to 2024 comprising all patients diagnosed with ATTR-CA and all consecutive patients presenting to a HFpEF clinic who were screened for ATTR-CA. All three scores were calculated retrospectively. A multivariable logistic regression model was used to identify significant variables.ResultsA total of 454 patients were included with ATTR-CA being diagnosed in 140 patients (30.8%). The T-Amylo score (area under the curve: 879; 95% CI 0.841 – 0.917) and ATTR-CM score (area under the curve of 0.875; 95% CI 0.840-0.911) both demonstrated very good discriminative capacity for ATTR-CA while the AMY score displayed a moderate discriminative capacity (area under the curve of 0.755; 95% CI 0.705-0.805).ConclusionsBoth the ATTR-CM and T-Amylo scores displayed very good performance in identifying patients at high risk for ATTR-CA in patients with known HFpEF.

ABSTRACT Background Immunosuppressive therapy (IST) is standard first‐line treatment for severe aplastic anaemia (AA) in patients ineligible for allogeneic transplantation. Thrombopoietin receptor agonists (TPO‐RAs) are increasingly added to IST to improve haematologic recovery, but long‐term safety remains uncertain. Methods We conducted a PRISMA‐guided systematic review and meta‐analysis. MEDLINE, EMBASE and CENTRAL were searched from inception to April 2025. Randomised controlled trials and observational studies comparing TPO‐RA plus IST with IST alone were analysed separately using random‐effects models. The primary outcome was overall haematologic response at 6 months; secondary outcomes included response at 3 and 12 months, complete response, survival, relapse and clonal evolution. Results Twenty studies (2 randomised and 18 observational) were included. In randomised trials, TPO‐RA plus IST showed a non‐significant trend towards higher overall response at 6 months (OR 2.01; 95% CI 0.76–5.28), while complete response was significantly higher at 3 and 6 months. Observational studies consistently demonstrated higher overall and complete response rates. No significant differences were observed in survival, relapse or clonal evolution. Conclusion Limited randomised evidence does not demonstrate statistically significant benefit across all outcomes, while observational data suggest potential haematologic advantages. Further high‐quality trials are required to clarify the effectiveness and long‐term safety of adding a TPO‐RA to IST in AA. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission

ABSTRACT:Prognostic risk categorization aids treatment selection for patients with acute myeloid leukemia (AML). Although the European LeukemiaNet (ELN) classifications (2017 and 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, their application to patients receiving less intensive therapy, such as azacitidine plus venetoclax, has been less satisfactory. In response, a 4-gene classifier that stratifies older patients with AML unfit for intensive chemotherapy into those with higher benefit (wild type), intermediate benefit (FLT3-internal tandem duplication [ITD] or NRAS/KRAS mutation), or lower benefit (TP53 mutation) after azacitidine plus venetoclax treatment was developed. We hypothesized that this 4-gene classifier may also have prognostic utility in patients receiving low-dose cytarabine (LDAC) plus venetoclax. Surprisingly, neither the ELN 2022 criteria nor the 4-gene azacitidine-venetoclax classifier model adequately stratified prognosis in a cohort of 139 patients receiving LDAC plus venetoclax. Patients with concurrent NPM1 and FLT3-ITD/RAS variants performed surprisingly well with LDAC plus venetoclax (complete remission [CR]/CR with incomplete blood count recovery [CRi] rate, 92%; median overall survival [OS], 29.67 months). Data-driven (sequential bootstrapping and tree-based) and empirical analyses identified complex karyotype and/or presence of TP53 mutation as prognostically relevant molecular/cytogenetic risk markers. Patients with complex karyotype and/or TP53 mutation displayed poor clinical outcomes (CR/CRi, 25%; median OS, 3.48 months). Notably, 74% of the study population lacked these poor prognostic markers and had a 67% CR/CRi rate with a median OS of 14.92 months. Overall, these data support the importance of molecular subclassification in defining treatment outcomes to venetoclax-based therapies. These trials were registered at www.clinicaltrials.gov as #NCT02287233 and #NCT03069352.

Paediatric-inspired acute lymphoblastic leukaemia (ALL) regimens have led to improved leukaemic outcomes in adults. However, avascular necrosis (AVN) has emerged as a debilitating orthopaedic complication. AVN is likely multifactorial, with corticosteroids and asparaginase therapy playing key roles in its pathogenesis. We assessed the incidence and potential risk factors for AVN, in older adolescent and adult patients with ALL treated with the FRALLE-93 protocol across three Australian tertiary centres. AVN occurred in 24% of 59 patients, primarily affecting hip and knee joints. Diagnosis occurred at a median of 11.7 months from commencement of chemotherapy. No association was identified between AVN risk and sex, age, BMI, smoking status and vitamin D level. The majority of patients required orthopaedic intervention (64%). Approximately two thirds had chronic pain or impaired mobility. AVN risk in adult patients with ALL receiving FRALLE protocols appears at least comparable to rates reported in paediatric cohorts.

Venetoclax plus azacitidine represents a key advance for older, unfit patients with acute myeloid leukemia (AML). The chemotherapy and venetoclax in elderly AML trial (CAVEAT) was first to combine venetoclax with intensive chemotherapy in newly diagnosed patients ≥65 years. In this final analysis, 85 patients (median age 71 years) were followed for a median of 41.8 months. The CAVEAT induction combined cytarabine and idarubicin with 5 dose levels of venetoclax (50-600 mg) for up to 14 days. Two additional cohorts explored adjusted-dose venetoclax (50 mg, 100 mg) with posaconazole. CAVEAT induction was well tolerated, with low mortality (4%) and limited high-grade gastrointestinal toxicity (4%). Delayed hematological recovery after consolidation was ameliorated by omitting idarubicin from post-remission therapy. The overall response rate (ORR: CR + CRh + CRi) was 75% with a median overall survival (OS) of 19.3 months (95% CI 11.1-31.3). Among de novo AML, ORR was 88% and median OS 33.1 months (95% CI 19.3-54.3). Almost one-third have not relapsed, many benefiting from prolonged treatment-free remission (median 17.9 months). CAVEAT induction was well tolerated and associated with high ORR that was durable, particularly for de novo AML. CAVEAT represents an effective time-limited treatment option for fit older patients with AML. (https://www.anzctr.org.au; ACTRN12616000445471).

Exercise and nutrition interventions are not part of routine care for those undergoing autologous stem cell transplant (autoSCT). We aimed to explore estimates of effect, safety and feasibility of multidisciplinary prehabilitation for improving physical capacity after autoSCT. This single-blinded, parallel, two-armed pilot randomized trial included adults receiving autoSCT. Participants were randomized to twice-weekly, supervised, tailored exercise and fortnightly telephone-based nutrition education, for up to 8-weeks prior to autoSCT (n = 11) or usual care (n = 11). Blinded assessments occurred at baseline (T0), pre-transplant (T1), and 4-weeks post-transplant (T2). The primary outcome was physical capacity (6-min walk test). Secondary measures included recruitment rate, adverse events, exercise adherence, physical status, nutritional status, health-related quality of life, and health service outcomes. Positive estimates of effect for walking capacity in favour of the experimental group were demonstrated at T2 (MD + 141 m, 95

Background The efficacy and safety of avatrombopag, a second generation thrombopoietin-receptor agonist, in the treatment of newly diagnosed severe aplastic anemia (sAA) is being evaluated in the DIAAMOND-Ava-FIRST trial. Herein, we report somatic and germline molecular findings of this study in which treatment-naïve patients received avatrombopag in combination with immunosuppressive therapy (IST; equine ATG and ciclosporin). Methods Enrolled patients (pts) received IST plus oral avatrombopag at a maximum dose of 60mg for an initial six months (mths; standard), with those achieving a partial response eligible to receive a further six mths of avatrombopag (extended). At baseline, occult germline disease was screened for with use of a 37-gene inherited bone marrow failure (IBMF) NGS hybridisation-based capture panel. Cellular (bone marrow aspirate) and cell free (peripheral blood) DNA samples were obtained at baseline, 6, 12, 18 and 24 mths and were analysed using a targeted unique molecular index-corrected hematological malignancy NGS panel. Whole genome NGS copy number variation (CNV) analysis was performed by comparing read counts from on and off target reads to a pooled reference comprising normal samples to correct for enrichment and sequencing biases. Avatrombopag therapy has now been completed for enrolled pts, with a median follow up of 20.4 mths (IQR (8.9, 23.4)). Results 56 eligible pts (male:female 1.33:1) with a median age 58 years (yrs) (range 18-78 yrs) were enrolled. IBMF testing did not reveal occult germline disease in any pt (two pts had non-suspicious variants of uncertain significance (in GATA2 and RTEL1)). Somatic profiling at baseline (excluding PIGA), demonstrated that 15 pts (27%) had somatic mutations; 9 (16%) had 1 mutation, 5 (9%) had 2 mutations, and 1 pt (2%) had more than 2 mutations. Patients with detectable somatic mutations were typically older compared to those with no detectable mutations (median age 65 v 50 yrs). DNMT3A was the most frequently mutated gene at baseline, followed by PIGA, ASXL1, and TET2. 47 pts had both baseline and 6 mth somatic data available, with mutations present in 21 (45%) of these pts at 6 mths. Newly emergent mutations at 6 mths were most frequent in ASXL1, DNMT3A, PIGA and U2AF1. The presence of mutations at baseline did not correlate with complete response (p=0.49) or overall response (p=0.31) at 6 mths. 13 pts received extended avatrombopag therapy for a total of 12 mths, with this extended therapy group demonstrating enrichment of somatic mutations at baseline (≥1 mutation 58% vs 20% standard, ≥2 mutations 42% vs 0% standard) and at 12 mths (≥1 mutation 83% v 48% standard, ≥2 mutations 67% v 20% standard) and a trend to higher median variant allele frequencies compared with the standard therapy arm (14.2% v 8% at 12 mths and 24.2% v 12.1% at 24 mths, p=0.08). 2 pts developed myelodysplastic syndrome (MDS); at 12 mths and 18 mths, with both pts harbouring ASXL1 mutations at the time of MDS development. One of the pts who developed MDS had received extended avatrombopag therapy to 12 mths. 22/53 pts (42%) had a PNH clone by flow cytometry reported at baseline; of these 8 (36%) had a PIGA mutation detected. There were no PIGA mutations detected in the absence of a PNH clone. Baseline NGS CNV analysis was performed in 52 pts and detected trisomy 8 in 1 pt (concordant with conventional cytogenetics (CG) result), acquired loss of heterozygosity in 1p, 6p and 13q in 1 ptBCOR duplication in 1 pt and a duplication of Xq21.33 involving DIAPH2 in 1 pt. CG at baseline failed in 23/56 pts (41%), with no detectable chromosomal aberrations from NGS CNV analysis in this group. Finally, we analysed cell-free DNA from the cohort which showed broad concordance between mutations detected in the cellular and cell free compartments, however the cell free DNA compartment samples did reveal further clonal complexity at baseline in 5/46 (11%) pt samples with mutations detected that were not detected in the cellular compartment (in TP53, BRAF, MAP2K1 and DNMT3A). Conclusion Molecular profiling of pts with sAA treated with avatrombopag demonstrated that clonal hematopoiesis is common at baseline, with an increase in pts with clonal hematopoiesis observed at 6 and 12 months after commencing therapy, with enrichment of somatic mutations in those who received extended duration of avatrombopag. Moreover, further genomic complexity may be revealed in this subgroup from cell-free DNA analysis.

Introduction The randomised trial of (pre-allogeneic transplant) 2:1 sorafenib to placebo plus intensive chemotherapy in Flt3-ITD AML (Blood, 2023 Dec 7) did not meet the primary end-point of improved event-free survival (EFS) after a median 49 months of follow-up. To investigate changes in the lipidome of AML, we studied up to 810 lipid species in this cohort of AML patients, in paired samples from at diagnosis to post-induction chemotherapy, and a smaller number at relapse. Methods From the 98 AML patients recruited to the above trial, bone marrow (BM) and peripheral blood (PB) cells and plasma samples were available for lipidome analyses from 47 patients. Post sample protein extraction and quality control (QC), we had 15 BM cells; 11 BM plasma; 29 PB cells and 28 PB plasma samples paired from at diagnosis to post-induction chemotherapy timepoints. There were combined BM and PB cells and plasma from 4 patients at relapse for analysis. All QC viable BM and PB cell and plasma samples together with 3 separate QC samples underwent lipid extraction for liquid chromatography-tandem mass spectrometry (LC-MS) analysis using an Agilent 1290 Infinity I/II LC machine. Following separation by LC, lipids were assessed via Agilent 6495C Triple Quadrupole Mass Spectrometer for abundance quantification. Relative lipid abundances were categorised into lipid classes and species. Two-way ANOVAs was performed to analyse the potential effect of Sorafenib on AML lipid abundances. Repeated Measures (RM) ANOVAs were run to identify differences in lipid abundances across clinical timepoints. Student t-tests were performed on differences of lipid species of interest. All p values underwent Benjamini-Hochberg (BH) corrections to decrease the false discovery rate. Significance was set at p≤ 0.05 for all analyses. Results The initial analysis was aimed to identify the effect of the FLT 3 inhibitor, Sorafenib on lipid abundances in Flt3-ITD AML cases. The lipidome of all 4 sample cohorts (BM and PB cells and BM and PB plasma) showed no statistical differences in lipid abundance across Sorafenib and placebo groups, paired from at diagnosis to post-induction timepoints. Subsequently, all lipid analyses were grouped as one cellular sample i.e. BM cells or PB cells for each respective timepoint of AML at diagnosis, post-induction or at relapse. Comparative lipid analyses of AML BM cells at diagnosis to post induction chemotherapy showed an increase in total phospholipids, in particular phosphatidylcholine (PC, p=1.21E-03), phosphatidyl ethanolamine (PE, p=2.54E-03) and phospholipids of ³4 PUFA (polyunsaturated fatty acids, p=4.62E-11) composition whilst phospholipids of MUFA (monounsaturated fatty acids) composition were reduced (p=2.54E-09) in AML cells at diagnosis. These same statistically significant differences in lipid class and species were seen in AML PB cell sample analyses at diagnosis in comparison to post induction timepoints. Deeper analyses of PUFA species based on carbon:double bond numbers shows PUFA 20:4 (p=2.64E-10) and 22:6 (p=3.87E-03) species were significantly higher in Flt3-ITD AML cells at diagnosis compared to post-induction chemotherapy. Further, these PUFA species, for example, PUFA 20:4 amount (p=9.91E-14) re-increases in relapsed AML cells in comparison to post-induction cells. These lipid species measurements allowed formulation of an estimated cellular (phospholipid) peroxidation index (CPI) based on relative hydrogen atom transfer rate constants of fatty acids. The CPI in both AML BM (p=2.33E-12) and PB (p=1.06E-12) cells was higher at diagnosis compared to post-chemotherapy, and also, re-increased in AML relapsed cells compared to post-induction i.e. remission samples. Conclusions PUFA phospholipids are sensitive to lipid peroxidation, a critical process in iron-dependent ferroptosis. In contrast MUFA phospholipids are relatively resistant to lipid peroxidation and hence, ferroptosis. The CPI is an indirect read-out of ferroptosis sensitivity. These lipidome results suggest Flt3-ITD AML cells, both at diagnosis and at relapse have high levels of lipid peroxidation and hence, may be sensitive to ferroptosis.

Introduction Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA.Methods and analysis Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a ‘go/no-go’ decision is made by evaluating the posterior probability of the events of interests.Ethics and dissemination The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication.Trial registration number ACTRN12619001042134, ACTRN12619001043123.

Inter-tumoral T cell dysfunction and efficacy of immune checkpoint inhibitors (ICI) in follicular lymphoma (FL) has been well described. However, few studies have examined peripheral blood immunity at diagnosis or the impact of frontline ICI on circulating immunity in FL.

The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.

Background We have previously reported outcomes for patients (pts) receiving venetoclax (VEN) combined with intensive chemotherapy in fit older pts ≥65 years with newly diagnosed AML (Chua et al, JCO 2020). In contrast to younger populations, NPM1(mut) does confer favorable prognosis in older AML populations. Our prior studies indicate that VEN-based therapies in older pts have promising efficacy in NPM1(mut) AML (DiNardo et al, Blood 2020). To characterise this further, we performed a posthoc analysis of the efficacy of single agent VEN and in combination with chemotherapy in NPM1(mut) AML in the CAVEAT study and explored mechanisms of treatment failure using a multi-omic approach. Methods NPM1 MRD was performed using RT-qPCR (sensitivity 10 -6). Integrated analysis from bulk sequencing (targeted 42-gene NGS, whole exome/genome sequencing (WES/WGS), RNAseq), single cell (sc) proteogenomic and transcriptomic assessments (scDNA plus surface protein, Tapestri MissioBio; scRNAseq, 10x Genomics) were performed. Flow cytometry included analysis of BCL-2, BCL-XL, MCL1 and BFL1 expression. Results Of 85 pts enrolled on the CAVEAT study, 20 had NPM1(mut). Median age of NPM1(mut) vs (wt) was 71 vs 70 years. At a median follow-up of 38.6 months, CR/CRi rates and median OS for NPM1(mut) vs (wt) was 85% vs 72% (p=0.37), and 43.9 vs 15.1 months (p=0.04), respectively. Pts received a 7-day VEN monotherapy pre-phase prior to CAVEAT induction with paired bone marrow (BM) assessments pre- and at day 8 to evaluate VEN sensitivity. NPM1(mut) pts had a greater median relative blast reduction after 7-day VEN at -66% (range -7 to -98%), compared to -37% (range +51 to -94%) for NPM1(wt) (p=0.03). 18/20 NPM1(mut) sub-group pts completed induction and 17 had serial NPM1 MRD assessments. The NPM1(mut) level fell a median of 4.55-log 10 following induction, with 6 (35%) pts achieving MRD negative (MRDneg) status. After all consolidation, 12/16 (75%) were MRDneg. 12/12 (100%) pts in long-term follow up remain MRDneg. We investigated the mechanisms of resistance in the 5/20 pts with NPM1(mut) whose disease was primary refractory (RD; n=1) or had acquired secondary resistance (Fig). Two patients (CAL-045, CAL-021) had shown BM blast reductions of ≥45% during VEN pre-phase. Subsequently, at the time of clinical treatment failure, both were NPM1(mut) MRD negative indicating eradication of the starting NPM1(mut) clone and early evolution of a new NPM1(wt) population as the mechanism of resistance. Detailed genomic analysis of CAL-045 showed that a TET2/CBL/NPM1(mut) clone was eradicated, with persistence of TET2 and TET2/CBL(mut) clones lacking NPM1(mut) at the time of refractory disease. scRNAseq analysis of these NPM1(wt) clones revealed a pro-inflammatory signature with elevation in BFL1, a pro-survival gene not targeted by VEN (Fig). In patient CAL-021, NPM1(mut) was also absent with the emergence of nonsense/frameshift BAX variants at relapse as previously described (Moujalled et al, Blood 2022). BAX deficiency is associated with resistance to BH3-mimetics. Two other cases (CAL-014, CAL-020) showed BM blast reductions of <45% during VEN pre-phase. In CAL-014, the expansion of an NPM1 subclone was associated with FLT3-ITD. WES revealed evolution of FLT3-ITD loss of heterozygosity at relapse. Flow cytometric analysis demonstrated disproportionate upregulation of intracellular MCL-1 (Fig). In case CAL-020, no obvious genetic determinants of resistance were identified at relapse, with persistence of a DNMT3A/ KIT/ NPM1(mut) clone (VAF~50%). Whole transcriptome analysis revealed skewed expression of a KIT(mut)allele (from 45% to 88%) at relapse, and protein assessment by flow cytometry revealed marked upregulation of BCL-XL (Fig). Conclusion VEN in combination with intensive chemotherapy for NPM1(mut) AML pts ≥65 years resulted in rapid and deep responses ( NPM1(mut) MRD-negativity) that are associated with prolonged remissions and OS. Mechanisms of treatment failure among pts with NPM1(mut) are diverse and may include kinase-linked upregulation of alternative BCL-2 family pro-survival members or disruption of downstream pro-apoptotic BAX.

Background Autologous stem cell transplant is a common procedure for people with haematological malignancies. While effective at improving survival, autologous stem cell transplant recipients may have a lengthy hospital admission and experience debilitating side-effects such as fatigue, pain and deconditioning that may prolong recovery. Prehabilitation comprising exercise and nutrition intervention before stem cell transplant aims to optimise physical capacity before the procedure to enhance functional recovery after transplant. However, few studies have evaluated prehabilitation in this setting. We aim to explore preliminary efficacy of improving physical capacity of prehabilitation for people undergoing autologous stem cell transplant. Methods The PIRATE study is a single-blinded, parallel two-armed pilot randomised trial of multidisciplinary prehabilitation delivered prior to autologous stem cell transplantation. Twenty-two patients with haematological malignancy waitlisted for transplant will be recruited from a tertiary haematology unit. The intervention will include up to 8 weeks of twice-weekly, supervised tailored exercise and fortnightly nutrition education delivered via phone, in the lead up to autologous stem cell transplant. Blinded assessments will be completed at week 13, approximately 4 weeks after transplant and health service measures collected at week 25 approximately 12 weeks after transplant. The primary outcome is to assess changes in physical capacity using the 6-minute walk test. Secondary measures are time to engraftment, C-reactive protein, physical activity (accelerometer), grip strength, health-related quality of life (EORTC QLQ-C30 and HDC29 supplement), self-efficacy and recording of adverse events. Health service data including hospital length of stay, hospital readmissions, emergency department presentations and urgent symptom clinic presentation at will also be recorded. Discussion This trial will inform design of a future definitive randomised controlled trial and implementation of prehabilitation for people receiving autologous stem cell transplant by providing data on efficacy and safety. Trial registration The PIRATE Trial has been approved by the Eastern Health Human Research Ethics Committee (E20/003/61055) and is funded by the Eastern Health Foundation. This trial is registered with the Australian New Zealand Clinical Trials Registry ACTRN12620000496910. Registered April 20, 2020.

Classic Hodgkin lymphoma (cHL) prognostication primarily relies on clinical and radiological factors. Despite this, a subset of patients still progress. Immunohistochemistry (IHC) based biomarkers on diagnostic tissue have not been routinely used for prognostication. A multicentre retrospective analysis identified 62 patients with cHL. IHC on diagnostic tissues was used to stain Reed-Sternberg cells (RS) cells for STAT1, pSTAT3, p53 and tumour microenvironment for CD68 and PD-1. IHC stains were scored by anatomical pathologists blinded to patients and their outcomes and correlated with survival. Strong intensity of STAT1 and pSTAT3 staining correlated with improved overall survival (OS), with hazard ratios (HR) of 0.21 [95% confidence interval (CI) 0.06-0.76] and 0.22 (95% CI 0.06-0.84), respectively. Similarly, the median OS for weak versus strong STAT1 or pSTAT3 staining was 8.8 years versus not reached. Other IHC stains did not correlate with prognosis. In this cohort of cHL patients, downregulation of immunohistochemical STAT1 or pSTAT3 in RS cells is associated with inferior OS, suggesting STAT transcription within the pathognomonic RS cells may have tumour suppressor function and may be a potential biomarker for cHL prognosis.

Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P = .61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P = .08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P = .028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.

Background Venetoclax (VEN) plus azacitidine has an established role in the management of older patients (pts) with AML (DiNardo, NEJM 2020). To explore the feasibility of intensive chemotherapy combined with VEN in older pts with newly diagnosed AML, we conducted the CAVEAT trial (Chua et al, JCO 2020). We now present an updated analysis of this trial (with >3 years median follow-up), reporting on the optimal dose of VEN with chemotherapy, with and without posaconazole (POSA), the deliverability of consolidation therapy, characteristics of treatment failure and observation of substantial treatment-free remission in subsets of pts using this time-limited, short-course regimen. Methods The CAVEAT study enrolled pts aged ≥65 years with de novo or secondary/therapy-related AML (sAML) considered suitable for intensive chemotherapy. Five VEN dose escalation cohorts (50-100-200-400-600 mg) were explored initially. Two additional cohorts examined the safety of adjusted dosing of VEN (50 or 100 mg) during anti-fungal prophylaxis with the strong CYP3A4 inhibitor POSA. For induction, VEN was administered over 14 days, commencing with a 7-day pre-chemo dose ramp-up, followed by a 7-day overlap with 5+2 chemotherapy (cytarabine 100mg/m2/d IVI d1-5 and idarubicin 12mg/m2 IV d2-3). Consolidation (CONS) with 2+1 chemotherapy (below), followed by up to 7 cycles of VEN monotherapy maintenance was planned. Results Data cut-off: 31MAR2022. A total of 69 pts are included in this analysis (first pt 17JUL2016, last pt 15MAY2020). Median age was 71 years (range 63-80). Poor risk features included sAML (42%), adverse karyotype (28%) and prior HMA (23%). From the dose escalation phase, the VEN 600 mg cohort was well tolerated (30-day mortality 6%). Induction with VEN-POSA (n=18) was also well tolerated (30-day mortality 0%) with 3 DLTs observed: 2 hematologic (1 in each cohort) and 1 due to pulmonary infiltrates occurring on d2 induction (suspected to be allopurinol hypersensitivity). No clinical TLS was observed. Although hematologic recovery was satisfactory after VEN-POSA induction, recovery was considerably longer in the VEN (100mg)-POSA cohort after CONS1 compared to VEN (50mg)-POSA for both neutrophils (median 64 vs 44d to 0.5 x109/L) and platelets (median not reached vs 26d to 50 x109/L). Therefore, if POSA is used concurrently, VEN 50 mg is recommended. Alternatively, if VEN 600 mg is used, POSA should commence only after completion of VEN. In the VEN 600 mg cohort, significant delays in hematological recovery were also observed after multiple rounds of attenuated CONS (VEN d1-14, bolus doses of cytarabine 100 mg/m2 d1-2, idarubicin 12 mg/m2 on d1), limiting deliverability (median CONS cycles 1; range 1-3). By intention-to-treat, the overall response (CR/CRi) rate was 73%. CR/CRi was 90% in de novo AML (vs 51% in sAML), 84% in intermediate karyotype (vs 69% in adverse), 76% and 83% in NPM1 and IDH2 mutant AML, respectively. With a median follow-up of 37 months (m), the median overall survival (OS) was 15.4m. Median OS was 31.3m in de novo AML (40% alive at 36m) and 30.3m in intermediate karyotype AML (38% alive at 36m). In the VEN 600 mg cohort, median OS was 24.1m (36% alive at 36m). As CAVEAT delivered just one intensive cycle of therapy, followed by limited post remission therapy (median time on therapy 7.7m), we next assessed the duration of treatment-free remission (TFR) among responders. Among pts achieving CR/CRi, 20/51 (39%) experienced TFR (Fig 1). The median TFR was 22.1m (range 4.6-48.3m). At data cut-off, 12 (24%) have ongoing TFR. Notably, 15/20 (75%) with TFR had an NPM1 or IDH2 mutation at diagnosis. 11 out of 14 evaluable pts with NPM1 mutation had mutation clearance by RT-qPCR, including 3 with NPM1 negative disease at time of failure (1 refractory, 2 relapse). Two pts with persistently mutated NPM1 at relapse had a concomitant FLT3-ITD or KIT mutation. The mutation landscape at relapse is shown (Fig 1) Conclusion VEN combined with modified intensive chemotherapy achieved high response rates in older pts with newly diagnosed AML. With long-term follow-up, the time-limited CAVEAT schedule enabled pts, especially with mutated NPM1 or IDH2, to experience a durable treatment-free remission. Cumulative hematological toxicity is limiting, prompting us to now explore non-anthracycline CONS (low dose cytarabine 20mg/m2 SC d1-10 + VEN 400mg d1-7, for up to 4 cycles), followed by VEN monotherapy (400mg D1-14 q28d cycle x7). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Diflunisal is a non-steroidal anti-inflammatory drug that stabilises TTR tetramers, preventing dissociation into unstable, amyloidogenic monomers. However, efficacy and tolerance of diflunisal as long-term therapy for ATTR-CM is unknown. We sought to evaluate diflunisal as treatment for ATTR-CM at a single Australian amyloidosis service.