Nicholas Williams, Joe Lee, Luiza Moore, et al. and Jyoti Nangalia
Conclusions: MPN originate from driver mutation acquisition very early in life, even before birth, with life-long clonal expansion and evolution, establishing a new paradigm for blood cancer development. Early detection of mutant-JAK2 together with the determination of clonal expansion rates could provide opportunities for early interventions aimed at minimizing thrombotic risk and targeting the mutant clone in at-risk individuals.
Charlotte A Bradbury, Rosemary Greenwood, Julie Pell, et al.
Conclusions: This is the first randomised trial using MMF to treat ITP, demonstrating good efficacy and tolerability, even with the inclusion of elderly patients (27.5% were >70 years, 15.8% >75 years). Therefore, MMF may be considered an effective, well tolerated first line treatment option, alongside a short course of steroids, for some patients with ITP, approximately halving the risk of refractory or relapsed ITP. At final follow up, 56% of patients treated with corticosteroid alone had not required 2nd line treatment, which is higher than previous reports. It is unclear why some aspects of QoL were worse in the MMF group. This is an important reminder that disease response and patient experience may not correlate and emphasises the importance of including PROM outcomes within trials. For ITP, to date, PROMs have only been systematically evaluated in the TPO-RA randomised controlled trials.
The FLIGHT trial received ethical approval from NRES Committee South West and is registered, (EudraCT Number: 2017-001171-23. ClinicalTrials.gov number: NCT03156452). This abstract presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0815-20016). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Lindsey Montefiori, Sonja Seliger, Zhaohui Gu, et al.
Conclusions: This large-scale analysis has not only identified a new subtype-defining lesion in leukemia and a new mechanism of enhancer generation in cancer (BETA) but has also resolved two controversies. First, genotypic alterations transcend immunophenotype in the classification of lineage ambiguous leukemias, with BCL11B rearrangements unifying a subgroup of T/myeloid MPAL, ETP-ALL and poorly differentiated AML that often differ only by cMPO expression. This recapitulates prior observation of ZNF384-rearrangement defining a subtype of B-ALL and B/myeloid MPAL. Second, chromatin topology analysis demonstrates enhancer hijacking of BCL11B in a primitive stem/progenitor cell, and thus, at least for a subset of cases, a hematopoietic stem cell is the cell of origin for T/myeloid antigen-expressing lineage ambiguous leukemias.
LBA-4 Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs)
Andreas Hochhaus, Carla Boquimpani, Delphine Rea, et al.
Conclusions: In this first controlled study comparing treatments for resistant/intolerant (R/I) pts with CML, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with BOS (primary objective), deeper MR rates, and a favorable safety profile. These results support the use of asciminib as a new treatment option in CML, particularly in R/I pts who received ≥2 prior TKIs.
Diletta Fontana, Mario Mauri, Rossella Renso, et al.
Conclusions: The reduced activity of mutant ETNK1 leads to the accumulation of new mutations through the reduced competition of P-Et with succinate, increased mitochondrial activity and ROS production. This mechanism can be blocked, at least in vitro, by P-Et supplementation, suppressing the accumulation of new mutations mediated by the ETNK1-dependent mutator phenotype. In vivo studies will address the therapeutic potential of P-Et.
LBA-6 First Data from the Phase 3 HOPE-B Gene Therapy Trial: Efficacy and Safety of Etranacogene Dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in Adults with Severe or Moderate-Severe Hemophilia B Treated Irrespective of Pre-Existing Anti-Capsid Neutralizing Antibodies
Steven W. Pipe, Michael Recht, Nigel S. Key, et al.
Conclusions: The first co-primary endpoint of this study was met. This is the first report of a Phase 3 study in HB and the largest gene therapy trial cohort to date. Following a single dose of etranacogene dezaparvovec, FIX activity increased, without the need for prophylactic immunosuppression, into the mild-to-normal range at 26wks in pts with severe/moderately severe HB. Importantly, this included pts with titers of pre-existing anti-AAV5 NAbs. Pts were able to discontinue prophylaxis and bleeding was abolished in the majority. The safety profile was consistent with early phase AAV5 studies and together these data support a favorable safety and efficacy profile for etranacogene dezaparvovec