Permanent URI for this collection
Browse
Recent Submissions
Publication Phase 2 study of the lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat in patients with polycythemia vera (PV)(American Society of Clinical Oncology, 2024-05-29) Rinaldi, Ciro; Rein, Lindsay; Livings, Alice; Innes, Andrew; Pettit, Kristen; Yeh, Paul; Larsen, Stephen; Watson, Anne-Marie; Leahy, Michael; Curto-Garcia, Natalia; Mahdi, Ali; Frewin, Rebecca; Qureshi, Haifz; Shatzel, Joseph; Vaughn, Jennifer; Tashi, Tsewang; Amin, Harshad; Ogbu, Uzor; Gumuscu, Burak; Ross, David; Frewin, Rebecca; Medical and DentalBackground: PV is a myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis that is driven by mutations in JAK2. Currently available treatments reduce thrombotic risk and symptom burden but have little impact on disease course or risk of progression to post-PV myelofibrosis (PPV-MF) or acute myeloid leukemia (AML). There remains a need for novel treatments that can alter the natural history of PV. LSD1 is an enzyme that regulates megakaryocytes and erythrocyte maturation. Bomedemstat is an irreversible inhibitor of LSD1 that has been shown to have manageable safety and clinically relevant activity in other JAK2-mutation–prevalent MPNs (essential thrombocythemia and myelofibrosis). Here, we describe the methods for an open-label phase 2 study (NCT05558696) that has been designed to evaluate the efficacy and safety of bomedemstat in patients with PV who are resistant to or intolerant of standard cytoreductive therapy. Methods: Eligible patients are ≥18 years, have a confirmed diagnosis of PV per World Health Organization 2016 diagnostic criteria, a bone marrow fibrosis score of grade 0 or 1, an ECOG performance status of 0-2, a platelet count of ≥250 × 109/L, an absolute neutrophil count of ≥1.5 × 109/L, and resistance to or intolerance of ≥1 standard cytoreductive therapy. All patients will receive bomedemstat at a starting dose of 40 mg/d by mouth for 36 weeks, with dose titration to a hematocrit target of <45% with no grade ≥1 thrombocytopenia. Treatment with bomedemstat can continue beyond week 36 in patients deriving clinical benefit. Clinic visits will occur every 2 weeks until week 12 and monthly thereafter. Adverse events will be graded per NCI CTCAE version 5.0 criteria and will be monitored for up to 30 days after treatment end. Transfusions or phlebotomy can be administered during treatment as needed. The primary end points are safety and the proportion of patients who achieve a reduction in hematocrit to <45% without phlebotomy by week 36. Secondary end points will be the durability of reduction in hematocrit <45% without phlebotomy; the incidence and durability of reduction in platelet count to ≤450 × 109/L and white blood cell count to <10 × 109/L; the incidence of new thrombotic or major hemorrhagic events; reduction in spleen volume by week 36 in patients with an enlarged spleen at baseline; progression to PPV-MF or myelodysplastic syndrome or transformation to AML; pharmacokinetics; and change in patient-reported symptom burden assessed using the MSAF v4.0 and PGIC. Exploratory end points include change in the concentration of circulating inflammatory cytokines and growth factors, change in mutant allele frequency of JAK2and other mutations, and change in bone marrow fibrosis grade. Approximately 20 patients will be enrolled. Recruitment for this study is currently underway in Australia, the United Kingdom, and the United States.Publication Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation(Ferrata Storti Foundation, 2024-03-28) Garderet, Laurent; Gras, Luuk; Koster, Linda; De Wreede, Liesbeth; Montserrat, Rovira; Vincent, Laure; Fenk, Roland; Karunanithi, Kamaraj; Deeren, Dries; Kaufmann, Martin; Kuball, Jürgen; Ozdogu, Hakan; Jesus Pascual Cascon, Maria; Passweg, Jakob; Rye, Adam; Salmenniemi, Urpu; Snowden, John; Toftmann Hansen, Charlotte; Leleu, Xavier; Gastaud, Lauris; Drozd Sokolowska, Joanna; Raj, Kavita; Beksac, Meral; Schönland, Stefan; Hayden, Patrick; McLornan, Donal; Rye, Adam; Medical and DentalThere is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We identified 51 LCDD patients in the European Society for Blood and Bone Marrow transplantation registry who had undergone upfront ASCT between 1995 and 2021. The median serum creatinine was 280 μmol/L and 45% required renal replacement therapy (RRT) at time of transplant. The melphalan dose was 100 mg/m2 in 23%, 140 mg/m2 in 55% and 200 mg/m2 in 21%. The rate of very good partial response or better improved from 41% pretransplant to 66% at day +100 post- ASCT. In RRT-independent patients, there was a modest improvement in renal function within the first 3 months; the median estimated glomerular filtration rate increased from 44 to 51 mL/min/1.73 m2. There was no further change between 3 and 12 months post-ASCT. No patient who was RRT-independent at ASCT became RRT dependent by day + 100 post-ASCT. Median follow- up post-ASCT was 84 months (interquartile range [IQR]: 46-122). At 6-years post ASCT, overall survival was 88% (95% confidence interval [CI]: 78-98) and PFS was 44% (95% CI: 28-60). The 2-year cumulative incidence of relapse and non-relapse mortality was 17% (95% CI: 6-27) and 2% (95% CI: 0-6), respectively. The cumulative incidence of renal transplantation at 4 years after ASCT was 27% (95% CI: 13-41) with renal transplantation performed between 6.3 and 52.9 months post-ASCT (median 24.7 months). ASCT represents a feasible option for LCDD patients even if RRT dependent at time of transplant. Outcomes are favorable with low non-relapse mortality and good long-term overall survival.Publication Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study(American Society of Hematology (ASH Publications)) Tivey, Ann; Shotton, Rohan; Eyre, Toby; Lewis, David; Stanton, Louise; Allchin, Rebecca; Walter, Harriet; Miall, Fiona; Zhao, Rui; Santarsieri, Anna; McCulloch, Rory; Bishton, Mark; Beech, Amy; Willimott, Victoria; Fowler, Nicole; Bedford, Claudia; Goddard, Jack; Protheroe, Sam; Everden, Angharad; Tucker, David; Wright, Josh; Dukka, Vasavi; Reeve, Miriam; Paneesha, Shankara; Prahladan, Mahesh; Hodson, Andrew; Qureshi, Iman; Koppana, Manasvi; Owen, Mary; Ediriwickrema, Kushani; Marr, Helen; Wilson, Jamie; Lambert, Jonathan; Wrench, David; Burney, Claire; Knott, Chloe; Talbot, Georgina; Gibb, Adam; Lord, Angela; Jackson, Barry; Stern, Simon; Sutton, Taylor; Webb, Amy; Wilson, Marketa; Thomas, Nicky; Norman, Jane; Davies, Elizabeth; Lowry, Lisa; Maddox, Jamie; Phillips, Neil; Crosbie, Nicola; Flont, Marcin; Nga, Emma; Virchis, Andres; Guerrero Camacho, Raisa; Swe, Wunna; Pillai, Arvind; Rees, Clare; Bailey, James; Jones, Steve; Smith, Susan; Sharpley, Faye; Hildyard, Catherine; Mohamedbhai, Sajir; Nicholson, Toby; Moule, Simon; Chaturvedi, Anshuman; Linton, Kim; McCulloch, Rory; Medical and DentalDuring the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.Publication Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline(Wiley, 2023-11-06) McLornan, Donal; Godfrey, Anna; Green, Anna; Frewin, Rebecca; Arami, Siamek; Brady, Jessica; Butt, Nauman; Cargo, Catherine; Ewing, Joanne; Francis, Sebastian; Garg, Mamta; Harrison, Claire; Innes, Andrew; Khan, Alesia; Knapper, Steve; Lambert, Jonathan; Mead, Adam; McGregor, Andrew; Neelakantan, Pratap; Psaila, Bethan; Somervaille, Tim; Woodley, Claire; Nangalia, Jyoti; Cross, Nicholas; McMullin, Mary Frances; Frewin, Rebecca; Medical and DentalNo abstract availablePublication Diagnosis and management of mantle cell lymphoma: A British Society for Haematology Guideline(Wiley, 2023-10-25) Eyre, Toby; Bishton, Mark; McCulloch, Rory; O'Reilly, Maeve; Sanderson, Robin; Menon, Geetha; Iyengar, Sunil; Lewis, David; Lambert, Jonathan; Linton, Kim; McKay, Pamela; McCulloch, Rory; Medical and DentalNo abstract availablePublication Clinical utility of investigations in triple-negative thrombocytosis: A real-world, multicentre evaluation of UK practice(Wiley, 2024-07-14) Godfrey, Anna; Sousos, Nikolaos; Frewin, Rebecca; Prahladan, Mahesh; Green, Anna; McGregor, Andrew; Khan, Alesia; Milne, Kate; Amin, Faisal; Torre, Elena; Gudgin, Emma; Lambert, Jonathan; Wilson, Andrew; Royston, Daniel; Harrison, Claire; Mead, Adam; Frewin, Rebecca; Medical and DentalDiagnosis of essential thrombocythaemia (ET) is challenging in patients lacking JAK2/CALR/MPL mutations. In a retrospective evaluation of 320 patients with 'triple-negative thrombocytosis', we assessed utility of bone marrow histology (90.9% of patients) and myeloid gene panel (MGP, 55.6%). Supportive histology ('myeloproliferative neoplasm-definite/probable', 36.8%) was associated with higher platelet counts and varied between centres. 14.6% MGP revealed significant variants: 3.4% JAK2/CALR/MPL and 11.2% other myeloid genes. Final clinical diagnosis was strongly predicted by histology, not MGP. 23.7% received cytoreduction (17.6% under 60 years). Real-world 'triple-negative' ET diagnosis currently depends heavily on histology; we advocate caution in MGP-negative cases and that specific guidelines are needed.