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ObjectivesInforming research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.DesignIn the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.SettingUK stroke services.Participants3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.ResultsOf those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.ConclusionIt is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration numberISRCTN83290762; Post-results.

The 2017 National Comprehensive Cancer Network guidelines for acute myeloid leukemia have recommended performing bone marrow (BM) aspiration and BM trephine biopsy (BMTB) 14 to 21 days after starting induction therapy (commonly referred to as "day 14 [D14] marrow"). Those who do not achieve a hypoplastic marrow, with cellularity 20% and blasts 5%, are recommended to undergo 2-cycle induction (2CI). We performed a retrospective analysis to determine the impact of D14 BM characteristics in predicting for remission, association with overall survival (OS), and the effect of 2CI according to the D14 BM results.Patients aged 18 to 70 years undergoing induction therapy with standard "7 + 3" regimens were included. D14 cellularity was determined from BMTB samples and the blast percentage was assessed by morphology on BM aspiration and BMTB samples. The outcomes evaluated included the rates of complete remission (CR) and OS.A total of 486 patients with results from D14 BM evaluation were included in the present study. On multivariate analysis, cytogenetic risk and D14 blasts 5% were predictive of CR/CR with incomplete count recovery (P .001). Cytogenetic risk (P .001), age 60 years (P = .001), and D14 blasts 5% (P = .045) predicted for OS. 2CI was performed in 131 patients (27%). Patients with hypocellular D14 BM but residual blasts (n = 106) underwent 2CI in 46% of cases, with improved remission rates (43.9% vs. 72.0%; P = .004) but no difference in OS.The results from D14 BM evaluations are predictive of subsequent remission and OS. Our findings did not show a survival benefit with D14 BM-driven 2CI.

Background: Myeloproliferative neoplasms (MPNs) are a heterogenous group of chronic hematologic malignancies that lead to morbidity and early mortality primarily due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs, and are used commonly to guide therapeutic decisions (including allogenic stem cell transplant) in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients, and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively reported in this population. Methods: We conducted a retrospective review of patients evaluated at the Princess Margaret Cancer Centre (PMCC) between 1/1/2000 and 30/6/2021 for an MPN diagnosed at ≤45 years of age. Diagnoses were defined per 2016 WHO criteria using available information on chart review. Targeted mutational profiling of clinically relevant myeloid genes (49- or 54-gene panel) was previously performed on peripheral blood or bone marrow samples. Pathologic variants in ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1 Q157 were categorized as high-molecular risk (HMR). Categorical variables were compared using the χ2 test. Kaplan-Meier method was used for overall survival (OS) and time-to-event analysis; and were compared using the log-rank test. Results: A total of 237 patients with initial MPN diagnosis ≤45 years were included in the study, with median age of diagnosis 35 (range 12-45) years. MPN diagnosis included: essential thrombocythemia (ET, n=100), polycythemia vera (PV, n=75), prefibrotic primary myelofibrosis (Pre-PMF, N=29), overt PMF (n=24), and MPN-unclassifiable (MPN-u, n=9). Driver mutation data, available for 230 (97%) patients, were: JAK2 in 134 (56%), CALR in 70 (30%), MPL in 6 (2.5%), and triple-negative in 20 (8.4%) patients. Median follow-up was 10.2 (range 0.3-45.3) years, and median OS was the shortest for those with overt PMF (21.4 years, P=0.001) compared with PV (33.0 years), ET (31.4 years), and Pre-PMF (median OS not reached). No difference in OS based on driver mutation was observed. Progression to a secondary MF (SMF) was observed in 84 patients (47% of ET, 48% of PV) after median time of 19.7 years; with no difference in time to progression due to diagnosis or driver mutation. Progression to an accelerated/blast phase (AP/BP) was observed in 26 patients and was associated with diagnosis of overt PMF (P=0.04) and triple-negative for driver mutation (P=0.04). Thrombosis was observed in 61 (26%) patients: 34 (14%) patients with thrombosis prior to/concurrent with MPN diagnosis, and 34 (14%) patients with thrombosis after diagnosis. Splanchnic circulation thrombosis was found in 29 (12%) patients and 12 (5%) patients had Budd-Chiari syndrome. Portal hypertension was reported in 37 (16%) patients. CALR type-2 mutations were associated with the lowest frequency of total thrombosis (4%, P=0.02); while JAK2 had the greatest frequency of splanchnic circulation clot (17%, P=0.03). Targeted mutational profile was obtained for 202 (85%) of patients: 135 samples obtained during the initial disease phase, 51 samples during a secondary MF phase, and 16 during an AP/BP. For the patients with mutation analysis in the initial phase, 24 pathogenic mutations were observed in 16 (12%) patients including 3 patients with HMR mutations. The most frequent mutations observed were in TET2 (n=12, 9%), and ASXL1 (n=3, 2%). Presence of additional mutations did not predict OS, AP/BP progression, or thrombosis; though TET2 mutation was associated with shorter time to SMF progression in patients with PV/ET (P=0.002). Additional mutations were found in 34/51 (67%) patients in whom mutational analysis was first performed during a SMF disease phase. Conclusions: A long-term follow-up study of a large molecularly annotated cohort of AYA patients with MPN demonstrated excellent long-term survival for these patients. Overt PMF is associated with the lower OS and higher risk of AP/BP transformation. Thrombotic complications including splanchnic circulation thrombosis are frequent complications. Mutations aside from JAK2/MPL/CALR are uncommon and HMR mutations rare in the initial phase of MPN in the AYA population. Figure 1 Figure 1. Disclosures Gupta: Roche: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding; Constellation Pharma: Consultancy, Honoraria. Maze: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria; Takeda: Research Funding; PharmaEssentia: Research Funding; Kronos Bio: Research Funding.

The natural history of BCR-ABL1 negative myeloproliferative neoplasms (MPNs) is progression towards an overt myelofibrotic (MF) phase with variable risk to develop secondary acute myeloid leukemia. Current treatments include Janus kinase inhibitors (JAKi) which can temporarily alleviate MF-related symptoms but are non-curative and most patients eventually progress to a more advanced stage. Given the negative prognostic impact of bone marrow fibrosis in MPNs and generally poor outcome post JAKi failure, it would be important to identify in situ biomarkers that address the initiation, perpetuation and early reversal of the fibrotic reaction. The current clinical standard for bone marrow fibrosis assessment involves reticulin/trichrome stains that detect relatively static extracellular matrix products rather than the fibrosis driving cells directly. To address this, we have developed a smooth muscle actin stromal-vascular (SMA-CD34) dual immunohistochemical (IHC) technique amenable to morphologic scoring and complemented with a CellProfiler image analysis pipeline. SMA was prioritized over other validated stromal IHC markers given work by others in experimental models demonstrating SMA+ myofibroblasts to be the differentiated output of critical fibrosis inducing Gli1+ 'driver' mesenchymal stem/progenitor cells in MPN. Herein, we demonstrate the feasibility of our translational approach using a clinically annotated cohort of MF patients from the Princess Margaret Cancer Centre MPN Registry. After selecting for high quality (>1.0 cm) paired pre and post JAKi biopsies amenable to image and transcriptome-based analysis, the pilot cohort was comprised of 13 cases with 38% high-risk, 54% intermediate-2 and 8% intermediate-1 risk by DIPSS. Driver mutations were JAK2 V617F (77%), CALR (15%) and other (8%). JAKi therapies included ruxolitinib (31%) + pelabresib (23%), momelotinib (15%), itacitinib (15%) and pacritinib (8%). The SMA-CD34 stromal assessment at baseline revealed distinct interstitial myofibroblast patterns and vascular perturbations not captured by conventional clinical hematopathology assessment (e.g. SMA+ dilated sinusoids). A SMA-CD34 scoring system was developed using a 4-point scale representing normal (0 pts), increased vascularity (1 pt), focal interstitial SMA (2 pts), multifocal interstitial SMA (3 pts) and diffuse SMA (4 pts). Scoring was then performed by blinded hematopathologists. A trend towards JAK2 mutated MF cases demonstrating higher SMA grade at baseline was noted. Interestingly, variable trajectories in SMA scores emerged following treatment with JAKi. Specifically, SMA signals had increased in 15%, decreased in 46% and were stable in 38% post-JAKi when using a morphologic SMA grading scheme. When compared to reticulin fibrosis, the severity of SMA signals had diverged in 1/3 of the cases (e.g. SMA grade decreased, reticulin grade stable). To further complement the SMA-CD34 morphologic grading, a CellProfiler image analysis pipeline was developed yielding a non-vessel associated normalized SMA area metric as a supervised correlate of the clinical SMA scoring system (R 2 = 0.68). Additional supervised and unsupervised bioinformatic approaches for clustering of relevant SMA-CD34 features including an algorithm that informs SMA spatial patterns with respect to niche elements such as arterioles (CD34+SMA+), sinusoids (CD34+) and adipocytes is in development. Lastly, Nanostring Fibrosis V2 panel was employed on a subset that met RNA concentration and quality metrics. Exploratory interpretation showed significant differentially expressed genes in pre vs. post JAKi specimens related to lipid metabolism such as ADIPOR1, SCD, ELOVL6 as well as the chemokine CXCL16. This may suggest a link between fatty acid metabolism and inflammatory differentiation along the SMA-vascular axis in the bone marrow modulated by JAKi treatment. SMA-CD34 IHC stratifies MF bone marrow biopsies differentially from standard WHO reticulin/trichome grading providing a practical formalin-fixed paraffin embedded (FFPE) tissue-based biomarker for assessing fibrosis related bone marrow niche elements from archived clinical samples. While our pilot numbers precluded statistical evaluation by JAKi-type, clinical response and NGS mutational profile at this time, further studies are underway to validate the SMA-CD34 signature on a larger MF cohort. Figure 1 Figure 1. Disclosures Gupta: Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Incyte: Honoraria, Research Funding; Constellation Pharma: Consultancy, Honoraria; Pfizer: Consultancy.

Referral to hematology for anemia is common. In paroxysmal nocturnal hemoglobinuria (PNH), cells deficient in the glycosylphosphatidyl inositol (GPI) anchor are lysed by complement. Eculizumab improves overall survival and quality of life while reducing hemolysis, transfusion requirements, and thrombosis. We evaluated the frequency of screening for PNH in patients with unexplained anemia. Key clinical features, laboratory data, and investigations were recorded for patients referred for anemia since 2010, without a specific cause found. PNH testing was done by flow cytometry. 540 patients had: anemia not yet diagnosed (NYD, n=318 (including unexplained iron deficiency, n=92; DAT-negative hemolysis, n=9)); anemia of chronic disease, n=173; and pancytopenia NYD, n=49. 82.4% had LDH testing done; 85.0% total bilirubin; 78.7% reticulocyte counts; and 40.6% haptoglobin level; 131 (24.2%) had possible hemolysis. PNH testing was done in 56 (10.4%). Those screened for PNH were more likely to have: younger age (P=0.04); a history of thrombosis (P

Deterioration of hematologic parameters in lymphoma patients is often attributed to disease progression, comorbidities, or treatment effects. Second primary malignancies occur at increased frequency in CLL and must also be considered.

Lymphoproliferative disorders are prevalent in HIV-positive patients and the majority are aggressive [1]. The success of highly active antiretroviral therapy (HAART) has resulted in a substantial i...

We examined the prognostic impact of SES, estimated by census median household income, in 312 adult MDS patients. Age, progression to AML, use of recombinant erythropoietin, WHO diagnosis and IPSS risk category were independent predictors of survival but there was no association between SES and survival. Unexpectedly, progression to AML was more prevalent in the highest income quartile (HR 3.96 for highest vs. lowest; p = 0.0032). The previously demonstrated association of low SES with poor outcome MDS in the United States may have been driven primarily by reduced access to care rather than other SES-linked factors such as co-morbidity.