Approximately half of patients with myelodysplastic syndromes (MDS) relapse or are refractory to hypomethylating agents (HMAs) and experience poor clinical outcomes. We previously reported improved survival in a phase 1/2 clinical trial combining the HMA guadecitabine with a programmed death-ligand 1 (PD-L1) inhibitor (atezolizumab) in HMA-relapsed or HMA-refractory (HMA-R/R) MDS, yet the biological features associated with durable responses to this combined epigenetic and immunotherapy approach remain unclear. Here, we performed integrated bulk and single-cell transcriptomic profiling of bone marrow samples from patients treated on this trial to identify molecular and cellular features associated with survival. Long-term survival was associated with the presence of immunosuppressive myeloid cells and primed dendritic cells at baseline, together with therapy-induced immune reinvigoration characterized by interferon pathway activation and expansion of effector lymphocytes. In contrast, short-term survival was associated with persistent senescence-associated inflammatory programs in CD34+ bone marrow cells and elevated expression of immunosuppressive immune checkpoint molecules. These findings suggest that chronic inflammatory and senescent microenvironmental states constrain effective immune activation despite combined epigenetic and immune checkpoint therapy. Here, we identify distinct bone marrow microenvironments associated with patient survival after combined epigenetic and immune checkpoint therapy and suggest candidate biomarkers to guide patient stratification in HMA-R/R MDS.

Background:Ropeginterferon alfa-2b-njft (ropeg), a mono-PEGylated interferon-α, showed efficacy and safety in patients with hydroxyurea-intolerant/resistant essential thrombocythemia (ET) in the phase 3 SURPASS-ET largely conducted in Asia. Here we report the results from the EXCEED-ET study, which evaluated ropeg in both treatment-naïve and hydroxyurea pre-treated ET in North America. Methods:The single-arm, multicentre, phase 2b trial EXCEED-ET was conducted at 28 centers in the United States and Canada. Patients with ET enrolled were required to have a platelet count >450 × 109/L at screening. Patients were eligible regardless of prior cytoreductive therapy status and included both treatment-naïve and hydroxyurea-pretreated patients. Ropeg was subcutaneously administered in an accelerated titration schedule at 250 μg at Week 0, 350 μg at Week 2, and 500 μg from Week 4 and beyond. The primary endpoint was durable, modified European LeukemiaNet (ELN) response at both Months 10 and 13 (ClinicalTrials.gov identifier: NCT05482971). Findings:Between January 17, 2023, and May 15, 2025, 106 patients were screened and 91 were enrolled. At baseline, participant median age was 57 years (range, 22-84) with 57/91 (62.6%) being female and 71/91 (78.0%) being White. Among 91 patients enrolled, durable modified ELN response rate was 60.2% (95% CI, 49.0-71.4). The median time to hematologic response was only 8.4 weeks (95% CI: 8.1-11.9). Splenomegaly and symptom improvement or non progression occurred in 90/91 (98.9%) and 71/91 (78.0%), respectively. Seven of 91 (7.7%) patients with palpable spleen at baseline and all had an improvement in disease-related signs. The rates of molecular response for driver mutations at Month 13 as defined by ELN2009 criteria were 35.0% (7/20) for patients with JAK2V617F, 16.0% (4/25) for CALR, and 25.0% (2/8) for MPL mutations. One (1/1) TP53 mutation-positive patient showed a complete molecular response. Thrombosis and progression occurred in 3.4% (3/91) and 1.1% (1/91), respectively. Most treatment-emergent adverse events were mild, including fatigue (60%) and reversible transaminase elevations (58%). There was no grade 5 TEAE and one (1.1%) grade 4 TEAE (hepatitis toxic) which recovered without sequelae. Grade ≥3 TEAEs occurred in 27.5% (25/91) of the participants, most commonly with alanine aminotransferase and aspartate aminotransferase increases (4.4%; 4/91), neutrophil count decrease (4.4%; 4/91), fatigue (3.3%; 3/91) and lymphocyte count decrease (3.3%; 3/91). Treatment-related serious adverse events occurred in 5.5% (5/91) of patients. Pneumonia was the most common SAE, occurring in 2/91 (2.2%) patients. Ropeg-related discontinuations occurred in 9/91 (9.9%) patients. Interpretation:Ropeg showed efficacy and substantial molecular responses with good overall tolerability across a broad ET population. Funding:PharmaEssentia.

From 2017-2021, the American Society of Hematology (ASH) completed the largest study ever conducted of the hematology workforce in the United States (US). The study highlighted a deficit in the classical hematology (CH) workforce: despite very high CH clinical volumes encountered by practicing hematologists and medical oncologists, less than 5% of all hematology and medical oncology fellows reported having a career focus in CH. Underlying this was a lack of mentorship in CH compared to malignant hematology and solid tumor oncology. In this Viewpoint article, we discuss factors shaping the US hematology workforce and how decades of inadequate investment in mentorship, research, and subspecialty training contributed to low interest in CH among trainees. We present an overview of ASH's many initiatives to grow the hematology clinical and research workforce in the US and globally, for the future of the field.

A. Gating strategy applied on PBMCs samples evaluated by flow cytometry. CD8+ T cell memory was defined based on the expression of CD45RA and CCR7 (CD197). Cell surface phenotype (PD-1, CD39, and CD69) and intracellular activation (Ki-67) markers were quantified on CD8+ effector T cell (TEFF) based on indicated gates. B, CD8+ naïve and memory T cells in long-and short-survivors quantified before and after the treatment. C, Representative flow cytometry plots showing CD8+ T cells activation in PBMC samples from a short survivor. PD-1+ Ki-67+ expression on CD8+ T cells compared before and after the treatment.

List of Patients Who Experienced Immune-related Adverse Events AEs.

Isolation and DNA extraction of bone marrow cell populations; Targeted DNA sequencing; Peripheral blood mononuclear cell (PBMC) staining and flow cytometry analysis

Median overall survival was longer among patients whose T cells harbored ASXL1 mutations (green) than for those without the mutation (red) or with only myeloid mutations (blue), but ASXL1 mutation status was not associated with survival in a univariate analysis by the logrank test (p=0.11). In a multivariate analysis using a Cox proportional model and adjusted by age at study entry, gender, diagnosis, and the number of prior treatment regimens, ASXL1 was significantly associated with survival (p=0.001 based on likelihood ratio test).

A& B. Frequency (A) and intensity (B) of PD-1+ CD8+ T cells by gender) before (PRE), after second treatment cycle (C2D1 or C2D8; EARLY), and after third or fourth treatment cycle (C4D1, C4D8 or C5D1; LATE). CD8+ T cell expressing CD39 (C) and CD69 (D). F: females, M: males

Plain Language SummaryWhat is this summary about?This summary describes results from a phase 3 clinical trial called ASCERTAIN.Researchers compared two treatments in people with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML), either of which can develop into acute myeloid leukemia (AML). One group was treated with oral decitabine and cedazuridine (oral DEC-C) and the other with intravenous decitabine.Treatment was given in a series of cycles. In the first cycle, people were randomly assigned to receive oral DEC-C or intravenous decitabine and then switched to the other treatment in the second cycle. After the first two cycles, everyone received oral DEC-C. The aim was to compare whether the same amount of decitabine reached people's bloodstream in a certain time period after receiving oral DEC-C or intravenous decitabine (known as pharmacokinetics). Researchers also looked at how long people lived while taking treatment, how long people lived without developing AML, and the side effects from receiving treatment.What were the results?The amount of decitabine in the bloodstream during the first 5 days of treatment was almost the same (99% similar) between people who received oral DEC-C and those who received intravenous decitabine. Among people treated with oral DEC-C, the median overall survival was 31.8 months. Overall, people lived without developing AML for a median of 31.7 months. Among people who required red blood cell transfusion at the start of the trial, 52% achieved transfusion independence during the trial with oral DEC-C. Side effects of oral DEC-C were similar to those of intravenous decitabine,most commonly thrombocytopenia and neutropenia. There were five treatment-related deaths during the trial; two in the oral DEC-C group and three in the intravenous decitabine group.What do the results mean?Oral DEC-C was as effective, and had similar side effects, as treatment with intravenous decitabine. Although the trial did not focus on quality of life, oral medicines require fewer visits to a clinic compared with intravenous medicines, which could make it easier for people to stay on treatment. This trial supports using oral DEC-C for treating people with MDS or CMML.This is an abstract of the Plain Language Summary of Publication article.View the full Plain Language Summary PDF of this article to read the full-text AcknowledgementsWe thank Toniann Derion of Astex Pharmaceuticals (now Taiho Oncology, Inc., Pleasanton, CA, USA) for developing the clinical study report for this trial. We thank the Envision the Patient team, of Envision Pharma Group, for reviewing the use of patient-friendly language in this PLSP, and for organizing and providing feedback from a patient reviewer.Disclosure statementGuillermo Garcia-Manero has consulted for Acceleron; received honoraria and research funding from AbbVie, Astex Pharmaceuticals (now Taiho Oncology, Inc.), Bristol Myers Squibb, Curis, Genentech, and Novartis; received honoraria from Aprea; and received research funding from Gilead. James McCloskey has received research funding from Astex Pharmaceuticals (now Taiho Oncology, Inc.); consulted for AbbVie, Apellis, Bristol Myers Squibb, CTI BioPharma, Novartis, Pfizer, and Takeda; received honoraria from Bristol Myers Squibb, Blueprint, Incyte, Jazz, Novartis, Stemline, and Takeda; and is an equity holder in COTA Healthcare. Elizabeth A Griffiths has received research funding from Astex Pharmaceuticals (now Taiho Oncology, Inc.), Blueprint, and Celldex; received research funding from and consulted and served on advisory committees for Alexion and Bristol Myers Squibb/Celgene; consulted for and served on advisory committees for AbbVie, Apellis, AstraZeneca, CTI BioPharma, Genentech, Novartis, Taiho, and Takeda; and received honoraria from Aplastic Anemia and MDS International Foundation, Medicom, Physician Educational Resource, and Picnic Health. Karen W L Yee has consulted for Bristol Myers Squibb/Celgene, GSK, Jazz, Novartis, Pfizer, Shattuck, Taiho, and Takeda; received research funding from Astex Pharmaceuticals (now Taiho Oncology, Inc.), Forma, Genentech, Geron, Gilead, Janssen, Jazz, Novartis, Roche, Pfizer, and Treadwell; and received honoraria from AbbVie and Novartis. Amer M Zeidan has had leadership roles in boards or committees for AbbVie, Bristol Myers Squibb, Celgene, Geron, Gilead, Kura, and Novartis; received research funding from AbbVie, ADC Therapeutics, Amgen, Aprea, Astex Pharmaceuticals (now Taiho Oncology, Inc.), AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Cardiff Oncology, Celgene, Incyte, MedImmune, Novartis, Otsuka, Pfizer, Takeda, and Trovagene; consulted for AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, BeyondSpring, Bristol Myers Squibb, Boehringer Ingelheim, Cardiff Oncology, Cardinal Health, Celgene, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz, Kura, Novartis, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, and Tyme; received honoraria from AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, BeyondSpring, Bristol Myers Squibb, Boehringer Ingelheim, Cardiff Oncology, Cardinal, Celgene, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz, Kura, Novartis, Otsuka, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, and Tyme; and received travel expenses from Cardiff Oncology, Novartis, and Pfizer. Aref Al-Kali's institution has received research support from Astex Pharmaceuticals (now Taiho Oncology, Inc.). Mitchell Sabloff has served on advisory committees for AbbVie, Bristol Myers Squibb, Celgene, Jazz, Novartis, Pfizer, Roche, and Taiho, and served on advisory committees for and received research funding from Actinium and Astellas. Mary-Margaret Keating has served on advisory boards for AstraZeneca, BeiGene, Bristol Myers Squibb, Seattle Genetics, and Taiho. Salman Fazal has consulted for and received honoraria from Blueprint, CTI BioPharma, Gilead, GSK, Incyte, Janssen, Jazz, Karyopharm, Novartis, PharmaEssentia, Sanofi, Servier, Stemline, Taiho, and Takeda. Olatoyosi Odenike has consulted for AbbVie, Bristol Myers Squibb/Celgene, CTI BioPharma, Impact, Novartis, and Taiho, and his institution has received research funding from AbbVie, Agios, Aprea, Astex Pharmaceuticals (now Taiho Oncology, Inc.), AstraZeneca, Bristol Myers Squibb/Celgene, CTI BioPharma, Incyte, Janssen, Kartos, NS Pharma, and OncoTherapy. Amy E DeZern has served as chair of a data safety monitoring board for Geron and as 2023 Education Co-Chair and Vice Chair of the American Society of Hematology Committee on Educational Affairs; consulted for Taiho; and received honoraria from Bristol Myers Squibb, Gilead, and Novartis. Casey L O'Connell has received research funding from Astex Pharmaceuticals (now Taiho Oncology, Inc.) and Genentech. Gail J Roboz has consulted or served on advisory boards or data and safety monitoring committees for AbbVie, Actiunuim, Agios, Amgen, Astellas, AstraZeneca, Bluebird Bio, Blueprint, Bristol Myers Squibb, Catamaran, Celgene, Daiichi Sankyo, GSK, Helsinn, Janssen, Jasper, Jazz, Mesoblast, Novartis, Pfizer, Roche, Syndax, Takeda, and Trovagene, and received research support from Janssen. Lambert Busque has consulted for Novartis. Rena Buckstein has received honoraria and research funding from Bristol Myers Squibb and Taiho; received research funding from Takeda; and received honoraria from AbbVie. Brian Leber has received honoraria and served on advisory committees and speakers bureaus for AbbVie, Amgen, and Bristol Myers Squibb; consulted for, received honoraria, and served on advisory committees and speakers bureaus for Novartis and Pfizer. Aditi Shastri has consulted for and received research funding from Kymera, consulted for Janssen and Rigel, and received honoraria from National Association for Continuing Education. Mohammad Azab is a previous employee of and has consulted for Astex Pharmaceuticals (now Taiho Oncology, Inc.). Michael R Savona has consulted and/or served on advisory boards for and received travel expenses from Bristol Myers Squibb, CTI BioPharma, Forma, Geron, GSK, Rigel, Ryvu, Taiho, and Treadwell; is an equity holder in Empath Biosciences, Karyopharm, and Ryvu; and received research funding from ALX Oncology, Astex Pharmaceuticals (now Taiho Oncology, Inc.), Incyte, and Takeda. Aram Oganesian and Harold N Keer are employees of Astex Pharmaceuticals (now Taiho Oncology, Inc). H Joachim Deeg, Nancy Zhu, Nashat Y Gabrail, Joseph Maly, and Harshad Amin declare no competing interests. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Medical writing assistance was provided by Harlene Ghuman, PhD, of Envision Pharma Group, funded by Taiho Oncology, Inc.Patient reviewers on this PLSP have received honorarium from Future Oncology for their review work but have no other relevant financial relationships to disclose.FundingThis trial was funded by Astex Pharmaceuticals (now Taiho Oncology, Inc.). Taiho Oncology, Inc. was involved in the study design and the data collection and analysis, in the preparation of the manuscript, and in the decision to submit for publication. This manuscript was funded by Taiho Oncology, Inc.

Specific genes sequenced in bone marrow mononuclear cells.

A. Gating strategy applied for flow cytometry analysis of NK cell panel. Phenotype of NK cell (CD56dim CD16+ ) activation was quantified using expression of cell surface markers CD69, CD107a, CD45RA, and CD45RO based on the indicated gates. B. NK cell frequency before and after the treatment analyzed in PBMCs from 18 patient samples and grouped according long-and short-survivors. C. Frequency of NK cells expressing cell surface activation markers CD69, CD107a, and CD45RA and CD45RO measured in short-and long-survival groups before and after the treatment.

Grade 3 or Higher Toxicities or Toxicities Observed in 10% or More Patients – Excluding Those Defined as Unrelated or Unlikely Related to Protocol Treatment.

Representativeness of Study Participants

No new drugs have been approved for essential thrombocythemia (ET) treatment since the anagrelide approval in 1997. Ropeginterferon alfa-2b-njft (ropeg) is approved for polycythemia vera, providing a rationale for its use in ET. Its current dosing schema requires dose up-titrations with 50 mcg every 2 weeks and takes approximately 20 weeks to reach a plateau. The goal of this study is to assess the efficacy and safety of ropeg in ET using a higher initial dose and accelerated titration (HDAC) regimen. This is a single-arm, multicenter study in the US and Canada. Patients with ET receive ropeg at 250 mcg on Day 0, 350 mcg at Week 2, and 500 mcg from Week 4 onward with flexibility of dose adjustment. The primary endpoint is: platelets ≤400×109/L, white blood cells <10×109/L, improvement or non-progression of spleen size or major symptoms, and absence of hemorrhagic or thrombotic events, at months 10 and 13. Secondary endpoints include molecular response, safety and tolerability. A total of 91 patients were enrolled with 77 (84.6%) patients in the US and 14 (15.4%) in Canada. The last patient was enrolled on March 28, 2024. JAK2V617F was found in 52 (57.1%) patients while CALR and MPL mutations in 34 (37.4%) and 5 (5.5%), respectively. As of November 12, 2024, the discontinuation rate was 8.8%. The study results will be available in mid-2025. This study will provide efficacy, tolerability and safety, molecular response and quality of life data that will be critical in assessing ropeg for ET treatment.Clinical trial registrationClinicalTrials.gov, identifier NCT05482971.

Despite published algorithms for approaching the work-up of erythrocytosis, a significant proportion of patients are left with uncertainty as to its aetiology and prognosis. The term 'idiopathic erythrocytosis' (IE) is applied when known primary and secondary aetiologies have been ruled out. However, the assignment of secondary aetiologies is not always straightforward or evidence based, which can lead to misdiagnosis and heterogeneity in cohort studies. Furthermore, new studies have identified germline or somatic mutations that may affect prognosis. Epidemiological and cohort data are inconsistent as to whether IE increases the risk for complications such as arterial and venous thromboembolism, clonal transformation or comorbid conditions. Randomized trials assessing the role of phlebotomy for long-term management of IE have not been performed, so treatment remains a vexing problem for clinicians. Standardization of terminology and testing strategies, including comprehensive genetic screening in clinical research, are key to refining our understanding of IE.

Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

Almost 50% of patients with myelodysplastic syndrome (MDS) are refractory to first-line hypomethylating agents (HMAs), which presents a significant clinical challenge considering the lack of options for salvage. Past work revealed that immune checkpoint molecules on peripheral myeloblasts and immune cells are up-regulated after HMA treatment. Therefore, we conducted a Phase I/II clinical trial combining guadecitabine (an HMA) and atezolizumab (an immune checkpoint inhibitor) to treat HMA-relapsed or refractory (HMA-R/R) MDS patients. This combination therapy showed median overall survival of 15.1 months relative to historical controls (4-6 months). Here, we profiled the cell composition and gene expression signatures of cells from bone marrow aspirates from trial participants with short-term (<15 months) or long-term (>15 months) survival at single-cell resolution. Long-term survivors showed a significant reduction of immunosuppressive monocytes, and an expansion of effector lymphocytes after combination therapy. Further immune profiling suggests that gamma delta T cell activation through primed dendritic cells was associated with global interferon activation in the bone marrow microenvironment of long-term survivors. Short-term survivors exhibited elevated inflammation and senescence-like gene signatures that were not resolved by combination therapy. We propose that distinct bone marrow microenvironment features, such as senescence-associated inflammation or immunosuppressive monocyte presence, could improve patient stratification for HMA and immunotherapy combinations in HMA-R/R MDS patients.

Guadecitabine is a novel hypomethylating agent (HMA) resistant to deamination by cytidine deaminase. Patients with relapsed/refractory acute myeloid leukemia (AML) were randomly assigned to guadecitabine or a preselected treatment choice (TC) of high-intensity chemotherapy, low-intensity treatment with HMAs or low-dose cytarabine, or best supportive care (BSC). The primary end point was overall survival (OS). A total of 302 patients were randomly assigned to guadecitabine (n = 148) or TC (n = 154). Preselected TCs were low-intensity treatment (n = 233 [77%; mainly HMAs]), high-intensity chemotherapy (n = 63 [21%]), and BSC (n = 6 [2%]). The median OS were 6.4 and 5.4 months for guadecitabine and TC, respectively (hazard ratio 0.88 [95% con fidence interval, 0.67-1.14]; log-rank P = .33). Survival bene fit for guadecitabine was suggested in several prospective subgroups, including age <65 years, Eastern Cooperative Oncology Group performance status 0 to 1, refractory AML, and lower peripheral blood blasts <= 30%. Complete response (CR) + CR with partial hematologic recovery rates were 17% for guadecitabine vs 8% for TC ( P < .01); CR+CR with incomplete count recovery rates were 27% for guadecitabine vs 14% for TC ( P < .01). Safety was comparable for the 2 arms, but guadecitabine had a higher rate of grade >= 3 neutropenia (32% vs 17%; P < .01). This study did not demonstrate an OS bene fit for guadecitabine. Clinical response rates were higher for guadecitabine, with comparable safety to TC. There was an OS bene fit for guadecitabine in several prespeci fied subgroups. This study was registered at www.clinicaltrials.gov as #NCT02920008.

Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

Introduction: TEMPI Syndrome was first described in 2011 as a rare syndrome that typically presents with five core clinical characteristics specified by its acronym: telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting. Since its first description, cases have been reported with additional clinical features including other cutaneous findings, serous cavity effusions, and vascular events, including thrombosis and hemorrhage. The suggested diagnostic criteria include three major criteria that appear in all patients with TEMPI syndrome (telangiectasias, elevated erythropoietin (EPO) level and erythrocytosis, and monoclonal gammopathy) and two minor criteria that are not always present (perinephric fluid collections and intrapulmonary shunting). The possibility of an “other criterion” of venous thromboembolism (VTE) has been suggested, but there has been limited research to understand its true incidence. Several characteristics of TEMPI Syndrome are associated with VTE in other clinical contexts. There is an increased risk of VTE in disorders of erythrocytosis such as Polycythemia Vera, Chuvash Polycythemia, secondary erythrocytosis, and idiopathic erythrocytosis. In addition, monoclonal gammopathy (MG), both of undetermined significance (MGUS) and of clinical significance (MGCS), has a statistically significant association with VTE. Methods: To understand the incidence of VTE in TEMPI Syndrome, we reviewed the literature for all published cases of TEMPI Syndrome. The authors of each publication were contacted to provide clinical data including age, sex, TEMPI characteristics, type and timing of thrombosis if present, treatment of TEMPI, and whether the patient was undergoing phlebotomy. Results: We identified 42 patients with TEMPI Syndrome reported in the literature. Detailed clinical data on VTE was obtained for 14 patients. The three major clinical criteria were present in all 14 patients. Of the 14 patients, nine experienced at least one VTE event. For the 9 patients with VTE, the median age was 53 (36-67) and 56% were female. For the 5 patients without VTE, the median age was 56 (range 40-75) and 60% were female. Most patients had IgG Kappa MG which is the most common form of MG found in TEMPI Syndrome. However, one patient with VTE and two patients without VTE had IgA Lambda MG, while another patient with VTE had IgM Lambda MG. EPO levels varied; patients with VTE had EPO levels from 73.5 to >5000 mU/mL and patients without VTE had levels from 433 to 5728 mu/mL. The hematocrit ranged from 55-64% in patients with VTE and 51-59% in patients without VTE. Of the patients with VTE, the type included lower extremity DVT + pulmonary embolism (PE) (2), jugular venous thrombosis (2), upper extremity DVT alone (1), lower extremity DVT alone (1), cerebral venous sinus thrombosis (2), Superior Vena Cava thrombus (1), and cardiac apex thrombus (1). There were no arterial clotting events in any of the 14 patients. Conclusion: The prevalence of VTE in patients with TEMPI Syndrome is high, with at least 21.4% of known patients developing VTE during their clinical course. VTE in TEMPI Syndrome can occur as a PE, DVT, or atypical site thrombosis, but the small sample size limits analysis of specific risk factors. Details on thrombotic events are lacking in the literature and further attempts to obtain these data are underway. Clinicians should be aware of the risk of VTE in patients with TEMPI, particularly in unusual locations, and further research on the impact of treatments such as phlebotomy and myeloma-directed therapies is underway to distinguish pathophysiology