Background In primary central nervous system lymphoma (PCNSL), venous thromboembolism (VTE) can cause significant morbidity and hinder chemotherapy delivery. Objectives To assess VTE incidence, timing and adequacy of inpatient and outpatient VTE prophylaxis in patients with PCNSL receiving chemoimmunotherapy with curative intent. Patients/Methods We reviewed patients diagnosed with PCNSL between 1997 and 2018 who received methotrexate, procarbazine, and vincristine ± Rituximab. Patient demographics, VTE prophylaxis and incidence, adverse events of anticoagulation, and survival outcomes were collected. Results Fifty‐one PCNSL patients were included (median 67 years [range, 32‐87], 30 males [59%]). Thirteen patients (25%, 95% confidence interval [CI], 14‐40) developed VTE at a median of 1.6 months from diagnosis (range, 0‐4). Patients with Khorana Risk Score ≥2 were more likely to have VTE than those with a KRS < 2 (60% vs 15%; P = .01). Eighty‐five percent had deviations from inpatient VTE prophylaxis guidelines, and outpatient prophylaxis was not routinely administered. Three patients required inferior vena cava filters. Hemorrhagic complications of anticoagulation included an intracranial hemorrhage from therapeutic anticoagulation and three cases of major bleeding from prophylactic anticoagulation. No patients died from VTE or its treatment. Conclusions Patients with newly diagnosed PCNSL are at high risk of VTE. Further research is required into optimal VTE prophylaxis in PCNSL.

There is an unmet need for novel therapies with distinct modes of action to offer clinical benefit for patients with myelofibrosis (MF) who become resistant or intolerant to JAK inhibitors. Lysine-specific demethylase-1 (LSD1) is a histone demethylase critical for self-renewal potential of malignant myeloid cells for hematopoietic differentiation, e.g., LSD1 licenses maturation of megakaryocytes, one cell type critical to the pathogenesis of MF. Bomedemstat is an orally active LSD1 inhibitor that in mouse models of MPNs reduced peripheral cell counts, splenomegaly, inflammatory cytokines, marrow fibrosis, mutant cell burden and overall survival (Jutzi et al. 2018). IMG-7289-CTP-102 is a global, open-label Phase 1/2 study evaluating bomedemstat dosed once daily in MF patients (NCT03136185). Data from this ongoing study are presented. Key eligibility criteria include IPSS int.-1 or -2 or high-risk patients refractory or resistant to, inadequately controlled by or intolerant of available approved therapy, or in the Investigator's judgment, are not candidates for available approved therapy, peripheral blast count ≤10%, absolute neutrophil count ≥0.5 x 10 9/L, and platelet count ≥100 x 10 9/L. Key objectives are safety and reduction of spleen volume (SVR) by MRI/CT and total symptoms scores (TSS) using the MPN-SAF instrument. Serial bone marrow (BM) biopsies and imaging studies are read centrally. Of 261 genes recurrently mutated in AML/MPN/MDS, germline and somatic baseline and follow-up sequencing is conducted to quantify existing or new mutant alleles frequencies (MAF). Dosing is individually tailored using platelet count as a biomarker of bomedemstat activity on megakaryocyte function, targeting a range between 50-100 x 10 9/L and titrating as needed. At data cutoff (15 July 2021), the study is fully enrolled with 89 patients: 49% primary MF, 30% post-essential thrombocythemia-MF, 21% post-polycythemia vera-MF. Median age is 68 (35-88) with 52% males. Prior treatment with ruxolitinib was reported in 81% (72/89), 43% (38/89) had also received up to 3 different treatments. 30% of patients (25/83) had received ≥1 RBC transfusion prior to dosing. By IPSS, 54% were high-risk, 40% int.-2, and 6% int.-1. At screening (N=88), sequencing to an average depth of &gt;1000, JAK2 was mutated in 70%, CALR in 22%, and MPL in 7%; 64% had ≥2 mutations of which 66% had high-molecular risk mutations in ASXL1, IDH1/2, EZH2 and/or SRSF2. The median duration of treatment is 17 weeks (2-102). Of all enrolled patients for whom data is available (evaluable) at 24 weeks for TSS with baseline value ≥20, 89% recorded a reduction in TSS (mean change -36%; -81% to 21%) with 39% reporting ≥50% reduction. Of all patients evaluable for SVR at 24 weeks (N=27), 78% had a reduction in spleen volume from baseline (mean SVR: -4%; -41% to 107%) with 37% showing ≥20% SVR. Of evaluable patients (N=29), 86% had stable (∆&lt;±1.0 g/dL) or improved hemoglobin (&gt;1.0 g/dL). Of patients evaluable for BM fibrosis scoring post-baseline (N=29), 17% improved by 1 grade and 66% were stable. Serially sequencing 43 patients, MAFs in one or more alleles were reduced in 42% with 1 patient in complete molecular remission, and stable in 44%. Clones with JAK2 and/or ASXL1 mutations were most frequently reduced. MAF reduction also correlated with efficacy: SV and/or TSS were improved in patients in whom MAFs were also decreased. No new mutations were identified in any patient. No patient transformed to AML during this study. The most common non-hematologic AEs reported by patients were diarrhea and dysgeusia, each at 28% (25/89). There have been 13 related SAEs with 3 Grade 2, 9 Grade 3 and 1 Grade 4 (thrombocytopenia). Thirty-nine patients remain on study. Early terminations (&lt;24 weeks) due to AEs occurred in 13 (15%) patients with 5 related to bomedemstat, and 15 discontinued for other reasons. There have been no safety signals, DLTs, or deaths related to drug. In a patient population with advanced disease, a heavy mutation burden and limited treatment options, once-daily bomedemstat as monotherapy had an acceptable tolerability profile, relieved symptoms, reduced spleen volume and improved anemia without any significant safety signals. Additionally, reductions in the allele frequency of both driver and high molecular risk mutations were observed and correlated with improved efficacy metrics. The study is now fully enrolled and additional data will be presented. Disclosures Yacoub: Cara: Current equity holder in publicly-traded company; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dynavex: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Ardelyx: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in publicly-traded company. Bradley: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gerds: AbbVie: Consultancy; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; PharmaEssentia Corporation: Consultancy; Constellation: Consultancy; Novartis: Consultancy. Shortt: Amgen: Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Mead: Abbvie: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau. Göthert: AOP Orphan Pharmaceuticals: Honoraria, Other: Travel reimbursement; zr pharma&: Honoraria; Proteros Biostructures: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel reimbursement; Incyte: Consultancy, Honoraria, Other: Travel reimbursement; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel reimbursement. Koschmieder: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Shire: Honoraria, Other; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Abbvie: Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Image Biosciences: Other: Travel support; Alexion: Other: Travel support; CTI: Membership on an entity's Board of Directors or advisory committees, Other; Karthos: Other: Travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding. Jones: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Peppe: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Natsoulis: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Hong: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc.: Ended employment in the past 24 months. Harrison: BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Incyte Corporation: Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Ross: Keros Therapeutics: Consultancy, Honoraria; Bristol Myers Squib: 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. Talpaz: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Celgene: Consultancy; Takeda: Other: Grant/research support . Rienhoff: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company.

No abstract

Utilising tissue whole exome sequencing (WES) and circulating tumor cell-free DNA (ctDNA), this Australasian Leukaemia & Lymphoma Group (ALLG) translational study sought to characterise primary and acquired molecular determinants of response and resistance of MZL to zanubrutinib for patients treated on the MAGNOLIA clinical trial. WES was performed on baseline tumor samples obtained from 18 patients. For seven patients, ctDNA was interrogated using a bespoke hybrid-capture next-generation sequencing (NGS) assay for 48 targeted genes. Somatic mutations were correlated with objective response data and survival analysis using Fisher's exact test and Kaplan-Meier (log-rank) method respectively. Baseline WES identified mutations in 33/48 (69%) prioritised genes. NFkB, NOTCH or BCR pathway genes were implicated in samples for 16/18 (89%) patients. KMT2D mutations (n=11) were most common followed by FAT1 (n=9), NOTCH1, NOTCH2, TNFAIP3 (n=5) and MYD88 (n=4). MYD88 or TNFAIP3 mutations correlated with improved PFS (not reached (NR) vs 11.1 months, p: 0.008, HR: 0.09, 95% CI: 0.01-0.52); KMT2D mutations trended to worse PFS (PFS: 13.40 months vs NR, p: 0.05, HR 6.5, 95%CI: 1.00-37.78). Acquired resistance mutations PLCG2 (R665W/R742P) and BTK (C481Y/C481F) were detected in two patients whose disease progressed. A BTK E41K non-catalytic activating mutation was identified prior to treatment in one zanubrutinib-refractory patient. MYD88, TNFAIP3 and KMT2D mutations correlate with PFS in patients with rrMZL 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.