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Following vaccinia vaccination, vesicle formation at the site occurs in 95% of primary vaccinees and is thought to indicate virus replication and vaccine efficacy. Little is known about virus replication and immune response in those who do not develop a vesicle. We used PCR to detect vaccinia in various sites following receipt of the smallpox vaccine in those with and without vesicle formation. Among 80 participants, 74 developed and 6 failed to develop a vesicle. Vaccinia DNA was detected in the blood, in the oropharynx, on the dressing, and on the hands of 5%, 11%, 4%, and 0% of those with vesicle formation and of 33%, 17%, 0%, and 17% of those without vesicle formation, respectively (p > 0.05 for each site). The detection of systemic vaccinia DNA in vaccinees without vesicle formation challenges the current understanding that lack of vesicle formation indicates lack of virus replication, the prerequisite to immune response. [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) and myelodysplastic syndrome (MDS) are hematopoietic stem cell disorders associated with cytopenias and red blood cell (RBC) transfusion dependence. Iron overload (IO) as a consequence of RBC transfusion dependence and its effect on outcomes in MF has not been formally studied. However, IO is a demonstrated poor prognostic feature in patients with MDS and congenital or acquired chronic anemias. Evidence that iron chelation therapy (ICT) reduces the deleterious effects of IO in MDS has led to speculation of benefit in MF. However, data supporting the use of ICT in MF is lacking. Neither disease has clear consensus guidelines for the use of ICT. Moreover, JAK–STAT inhibition, the cornerstone of MF treatment, often contributes to anemia and transfusional requirements. This manuscript reviews known and potential implications of IO in MF and highlights the need for prospective clinical investigations of ICT with consideration in the setting of JAK2 inhibitor therapy. [ABSTRACT FROM AUTHOR]

Summary Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3′ to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2 , that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death. [ABSTRACT FROM AUTHOR]

Primary myelofibrosis (PMF) is a clonal hematologic malignancy with a variable disease course; survival ranges from months to years. Historically, only allogeneic hematopoietic stem cell transplantation (alloHSCT) has demonstrated an ability to alter the natural history of PMF, but high treatment-related mortality risks limit the utility of alloHSCT to a minority of patients with PMF or myelofibrosis secondary to other myeloproliferative neoplasms. The recent development of therapies that regulate the Janus kinase-signal transducer and activator of transcription signaling pathway has changed the treatment landscape from primarily palliative treatment to potential disease modification. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Emergency medical services (EMS), hospital emergency departments, and cardiologists have taken steps to reduce time to reperfusion therapy by implementation of aggressive acute myocardial infarction treatment and triage protocols. Data indicate that significant myocardial salvage requires reperfusion within 2 hours, and the current American College of Cardiology guideline is 90 minutes after hospital emergency department admission. Materials and Methods: To minimize delays in time to reperfusion in an urban-rural North Carolina County, Guilford County EMS and the Moses Cone Hospital have collaborated to implement transmission of EMS electrocardiographs (ECGs) to the emergency department. The study population included 92 patients who were transported by EMS and received primary coronary intervention during the second, third, and fourth years after initiation of this intervention in 1993. Results: The median time from symptom onset to the initial ECG was 77 minutes. There was an additional 23 minutes between the availability of this ECG and the arrival of the patient at the emergency department. In the first year of the intervention, the time from hospital arrival to percutaneous coronary intervention was 80 minutes. In years 2 through 4, they were 93, 85, and 94 minutes, respectively. In 2003, 10 years after the intervention, the time from hospital arrival to percutaneous coronary intervention was 113 minutes. Conclusion: Initial gains in the time from hospital arrival to percutaneous coronary intervention, attributed to acquisition of the ECG in the prehospital setting, were not sustained over 10 years. [Copyright &y& Elsevier]

Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50–1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov , NCT04067336 , and the EU Clinical Trials register, EudraCT 2019-001545-41. From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50–1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4–30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. Kura Oncology. [ABSTRACT FROM AUTHOR]

The terrorist attacks on the World Trade Center (WTC) had an unprecedented environmental impact, exposing people to aerosolized dust and potential carcinogens. Firefighters who responded to this disaster have a 19% higher risk of developing cancer compared to the general population. Clonal hematopoiesis (CH) is the acquisition of somatic mutations in blood cells, linked to increased incidence of blood cancer, cardiovascular disease and all-cause mortality. In our pilot study, we observed an increased rate of CH mutations in relatively elderly WTC-exposed firefighters (Nat. Med. 2022). Our larger cohort study, with higher proportion of younger individuals, showed a higher burden of CH (14% vs. 7%; OR, 3.39; 95% CI, 1.86-6.16) among WTC-exposed firefighters versus two control groups: non-exposed firefighters and civilians. Even though DNMT3A and TET2 were the top two most mutated genes, the subsequent spectrum of mutations was distinct in the younger first responders. Frequently mutated genes included KMT2C/D, LRP1B, APC, FH, ATM, etc. The odds of leukemia were elevated (3.7% vs 0.6%; OR, 5.66; 95% CI, 1.22-25.87) in WTC-exposed responders with CH compared to those without CH. Oropharyngeal administration of WTC-dust impaired hematopoietic stem cell (HSC) function in mice. We utilized a novel non-conditioned Tet2+/- bone marrow transplantation-based model of CH and found that WTC-dust exposure accelerated Tet2-mediated CH, increased inflammation, and IL-1 Receptor accessory protein (IL1RAP) expression on Tet2+/- HSC. Genetic deletion of IL1RAP rescued the expansion of Tet2-mediated CH after WTC-dust exposure. Our study uncovers novel CH mutations in young WTC-exposed firefighters and found IL1RAP as a key pathway in CH development. This research offers vital insights into the health effects of disaster dust exposure, improving interventions to reduce disease risk. [ABSTRACT FROM AUTHOR]

Background: Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies.Methods: We did an open-label, phase 1, dose-escalation study at seven clinics in the USA. We recruited patients aged at least 18 years with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkin's lymphoma, who had received one or more previous lines of therapy, with measurable and assessable disease, and adequate organ system function. Patients self-administered an umbralisib oral tablet once per day in 28-day cycles, with dose escalation done in a traditional 3 + 3 design to establish safety and determine the maximum tolerated dose. In initial cohorts, patients took umbralisib in a fasting state at a starting dose of 50 mg, increasing to 100, 200, 400, 800, 1200, and 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. Subsequent cohorts self-administered a micronised formulation of umbralisib tablet in a fed state at an initial dose of 200 mg, increased in increments to 400, 800, 1200, and 1800 mg until the maximum tolerated dose or the maximal dose level was accrued. In August, 2014, all patients still on study were transitioned to 800 mg of the micronised formulation and dosing of the initial formulation was discontinued. The primary endpoints of the study were investigator-assessed safety in all treated patients (the safety population), the maximum tolerated dose, and the pharmacokinetics of umbralisib. Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766.Findings: Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow-up was 4·7 cycles (IQR 2·0-14·0) or 133 days (IQR 55-335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 [43%] of 90 patients), nausea (38 [42%]), and fatigue (28 [31%]). The most common grade 3 or 4 adverse events were neutropenia (in 12 [13%] patients), anaemia (eight [9%]) and thrombocytopenia (six [7%]). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib.Interpretation: Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kδ inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting.Funding: TG Therapeutics. [ABSTRACT FROM AUTHOR]

The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF- KIT wt ); and AML with normal cytogenetics and mutations in NPM1 ( NPM1 mut ); or biallelic mutations in CEBPA ( CEBPA mut/mut ), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias. This study compared clinical and genotypic characteristics of 60 patients with favorable-risk AML, excluding APL, and demonstrated significant differences between them. Patients with NPM1 mut AML were significantly older than those in the other groups. Targeted next-generation sequencing on DNA from peripheral blood or bone marrow revealed significantly more mutations in NPM1 mut AML than the other favorable-risk diseases, especially in genes related to DNA splicing and methylation. CEBPA mut/mut AMLs exhibited more mutations in transcription-related genes. Patients with NPM1 mut AML and CEBPA mut/mut AML show significantly reduced overall survival in comparison with CBF- KIT wt AML. These findings emphasize that favorable-risk AML patients have divergent outcomes and that differences in clinical and genotypic characteristics should be considered in their evaluation and management. [ABSTRACT FROM AUTHOR]

Background: The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy.Methods: We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312.Findings: Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m2 and 28 to 90 mg/m2) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m2 on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m2 on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort).Interpretation: More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care.Funding: Astex Pharmaceuticals and Stand Up To Cancer. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) is often indicated and formal transplant referral guidelines exist for pts with AML and HR MDS. However, the proportion of transplant-eligible pts not referred is largely unknown. We therefore assessed HSCT referral patterns, including potential barriers to referral, in pts with ND MDS and AML enrolled in the Connect® MDS/AML Disease Registry (NCT01688011), a large, US, multicenter, prospective observational cohort study of pts with ND AML (aged ≥ 55 years) or MDS (aged ≥ 18 years). We evaluated pt data, including transplant referral decisions collected at enrollment and every 3 months, from pts enrolled from Dec 2013 to Jul 2019. HR MDS and AML pts were included; AML pts were grouped by ELN 2010 risk groups into IR AML (Int-1 and Int-2 risk), or AR AML (adverse risk). Differences in transplant referral rates were assessed using a chi-square t-test (significance P < 0.05) in pts with HR MDS. Baseline characteristics of 720 pts with IR AML, AR AML, and HR MDS enrolled at 22 academic (AC) and 119 community/government (CO/GOV) sites are shown (Table). Median time in the Registry was 8.1 (range 0.1–62.9) months. Pts at CO/GOV sites were less likely to be considered for transplant by the treating physician than pts at AC sites (28% vs 43%; P < 0.001); of those considered, there was no difference in the transplant rates between the 2 site types (43% vs 36%; P = 0.290). For 358 pts deemed transplant ineligible, the most common reasons were comorbidities at AC sites and age at CO/GOV sites (Fig. A). Median age of ineligible pts was 77 (range 56–94) years. 7 pts were ineligible because of favorable cytogenetics; however, all had HR MDS, IR AML, or AR AML. In a subset of 262 pts (AC = 79; CO/GOV = 183) identified by investigators as likely potential transplant candidates based on age, comorbidity grade, frailty score, and ECOG PS, pts at AC sites were more likely to be considered for transplant than pts at CO/GOV sites (58% vs 43%; P = 0.020) with age the most common reason for transplant ineligibility (Fig. B) at both sites. Rates of consideration for transplant were lower at CO/GOV sites than AC sites. Among pts identified as potential transplant candidates, rates of consideration were lower at CO/GOV sites suggesting that further education may be needed to ensure referral of all pts who would benefit from transplant. [ABSTRACT FROM AUTHOR]

• PI3k-δ is the most abundant PI3K subunit among monocytic leukemia samples. • CMML patient samples are uniquely sensitive to PI3K-δ inhibition by umbralisib. • Ruxolitinib and umbralisib synergistically decrease growth in CMML patient samples. • This combination can simultaneously suppress STAT5, ERK, S6, and AKT signaling. Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome characterized by monocytic proliferation in the presence of dysplastic bone marrow changes, inflammatory symptoms, and propensity for transformation to acute myeloid leukemia (AML), with a poor prognosis and limited treatment options. Unlike the α and β isoforms, the phosphatidylinositol-3-kinase (PI3K)–δ signaling protein is predominantly expressed by hematopoietic cells and therefore has garnered interest as a potential target for the treatment of lymphomas and leukemias. We revealed a pattern of increased PIK3CD:PIK3CA ratio in monocytic M5 AML patients and cell lines, and this ratio correlated with responsiveness to pharmacological PI3K-δ inhibition in vitro. Because CMML is a disease defined by monocytic clonal proliferation, we tested the PI3K-δ inhibitor umbralisib as a single agent and in combination with the JAK1/2 inhibitor ruxolitinib, in CMML. Our ex vivo experiments with primary CMML patient samples revealed synergistic inhibition of viability and clonogenicity with this combination. Phospho-specific flow cytometry revealed that dual inhibition had the unique ability to decrease STAT5, ERK, AKT, and S6 phosphorylation simultaneously, which offers a mechanistic hypothesis for the enhanced efficacy of the combination treatment. These preclinical data indicate promising activity by co-inhibition of PI3K-δ and JAK1/2 and support the use of ruxolitinib + umbralisib combination therapy in CMML under active clinical investigation. [ABSTRACT FROM AUTHOR]

Drugs targeting chromatin-modifying enzymes have entered clinical trials for myeloid malignancies, including INCB059872, a selective irreversible inhibitor of Lysine-Specific Demethylase 1 (LSD1). While initial studies of LSD1 inhibitors suggested these compounds may be used to induce differentiation of acute myeloid leukemia (AML), the mechanisms underlying this effect and dose-limiting toxicities are not well understood. Here, we used precision nuclear run-on sequencing (PRO-seq) and ChIP-seq in AML cell lines to probe for the earliest regulatory events associated with INCB059872 treatment. The changes in nascent transcription could be traced back to a loss of CoREST activity and activation of GFI1-regulated genes. INCB059872 is in phase I clinical trials, and we evaluated a pre-treatment bone marrow sample of a patient who showed a clinical response to INCB059872 while being treated with azacitidine. We used single-cell RNA-sequencing (scRNA-seq) to show that INCB059872 caused a shift in gene expression that was again associated with GFI1/GFI1B regulation. Finally, we treated mice with INCB059872 and performed scRNA-seq of lineage-negative bone marrow cells, which showed that INCB059872 triggered accumulation of megakaryocyte early progenitor cells with gene expression hallmarks of stem cells. Accumulation of these stem/progenitor cells may contribute to the thrombocytopenia observed in patients treated with LSD1 inhibitors. [ABSTRACT FROM AUTHOR]