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The Janus kinase signal transducer and activator of transcription (JAK / STAT) signalling, which is crucial in Philadelphia-negative myeloproliferative neoplasms’ (MPNs), is negatively regulated by molecules such as SOCS, CISH, and SHP1. SOCS2 methylation has been studied in MPN with conflicting results. Here we examine the methylation status of SOCS2 by specific methylation-specific polymerase chain reaction (MSP) in cell lines and 130 diagnostic prepheral blood samples from Ph-ve MPN. Furthermore, we tried to explain the mismatch of the methylation frequency by assigning the investigated MSP primers to the respective genes. Methylation was detected in normal controls using SOCS2-MSP primers in the 3 'translated exon sequence, but not with primers around the transcription start site in the 5' untranslated regions (5'UTR). SOCS2 was completely unmethylated in primary MPN samples and cell lines. In contrast, SOCS2 methylation when using MSP primers located at the 5'UTR is rare in all studies. In conclusion, SOCS2 methylation is rare in Ph-ve MPN. The appropriate MSP primers are important for an accurate estimate of the methylation frequency. The role of SOCS2 methylation in MPN pathogenesis requires further investigation.

The epidemiology, genetics, and thrombosis risk of MPNs among Arabs are largely unknown. This may be attributed to scarce epidemiological data, particularly from our region. Our study included 381 Kuwaiti nationals with Ph‐negative MPNs and a confirmed driver mutation involving JAK2 (exon 12 14), CALR, or MPL. This first regional study examines the demographics, clinical parameters, and thrombosis‐related attributes of the participants. This study reported a median age of 58 years, with females and males representing 54.9% and 45.1%, respectively. ET was the most frequent subtype of Ph‐negative MPNs in our population, accounting for 52.0% of the cases, followed by PV, found in 34.6% of the participants, and PMF, found in 8.4% of participants. The crude annual cumulative incidence of Ph‐negative MPNs in Kuwait ranged from 0.674 to 3.177 per 100,000 population across the study period. The most common driver mutation was JAK2V617F, with a frequency of 89.5%. At diagnosis, 19.2% of the patients presented with unexplained thrombosis, and almost half were of arterial origins. Males were more likely to present with arterial thrombosis than females (61.5% vs. 35.3%), whereas venous thrombotic events were more common in females than in males (47.1% vs. 17.9%; p‐value = 0.025). Ph‐negative MPNs in Kuwait are rare; however, thrombosis is a frequent complication, being documented in up to 19.2% of cases at presentation, more commonly at arterial sites. These findings call for thorough evaluation of patients with unexplained derangements in their hematological parameters during follow‐ups., This is a unique study that examined the epidemiology of Myeloproliferative Neoplasms among Arabs.

Objectives We aimed to investigate the prevalence of JAK2-V617F mutation and its association with hematologic parameters in polycythemia vera(PV), essential thrombocytosis(ET) and primary myelofibrosis(PMF) patients who have been tested for the mutation. Methods We retrospectively reviewed the records of 168 patients (82 males and 86 females) who were tested for JAK2-V617F mutation upon request of Hematology Clinic. JAK2-V617F mutation status, white blood cell (WBC) counts, platelet (PLT) counts, hemoglobin (Hb), hematocrit (Hct) levels and demographics of the patients were recorded. Results JAK2-V617F mutation was detected in 55.9% of the 168 patients. The mutation was observed in 58.2% of PV cases, in 54.4% of ET and in 54.5% of PMF cases. All patients were divided into two groups: mutation positive and negative. Age, WBC and PLT levels were significantly higher in mutation positive group (p Conclusion JAK2-V617F mutation is a very important parameter in diagnostic and prognostic evaluation. Thus, every patient suspected of having a myeloproliferative neoplasm should be screened for JAK2-V617F mutation.

This study aimed to address the clinical impact of recombination-activating gene (RAG1) expression and tumor suppressor IKZF1 gene deletions in Philadelphia negative B-cell precursor acute lymphoblastic leukemia (B-ALL) patients. Fifty newly diagnosed pediatric Philadelphia negative B-ALL patients were included in this study. Using Bone Marrow samples, RAG1 expression was assessed by real time PCR and IKZF1 deletions were determined by multiplex real-time quantitative PCR. The expression of RAG1 was significantly higher in B-ALL patients as compared to the controls (

Introduction: Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2A rearrangements (KMT2A-r), IKZF1 intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant. Methods: From October 2018 to December 2020, 95 patients with high-risk Ph-negative BCP-ALL without central nervous system involvement at diagnosis and in continuous complete remission after induction and consolidation 1, were prospectively included to start blinatumomab at week 12. One patient was excluded because of T-ALL phenotype (with CD19 aberrant expression). Patients with alloSCT indication and a stem cell source received blinatumomab 28 microg/d administered by continuous intravenous infusion (cIV) until transplant. A minimum of 4 weeks blinatumomab was recommended before proceeding to transplantation. All other patients received 5 cycles of blinatumomab 28 microg/day cIV (for 28 days), during consolidation 2 and 3 and at months 1/3/5 of the maintenance phase respectively. The primary objective was disease-free survival (DFS). Secondary objectives included post-blinatumomab MRD response at TP3 (after consolidation 2 or before alloSCT), overall survival (OS), and safety. Early results are reported here. Results: Median age was 35 years old (range, 18-60). Median white blood cell count (WBC) at diagnosis was 12 G/L (range, 1-449). Oncogenetic analyses allowed classifying ALL as Ph-like (18%), KMT2A-r (17%), DUX4/ERGdel (13%), ZNF384-r (11%), low hypodiploidy/near triploidy (7%), B-other (26%) or unknown (9%). An IKZF1del was found in 37/93 (40%). A TP1-MRD ≥ 0.01% was found in 46/94 patients (49%). Final risk group was HR for 45 patients and VHR for 49 patients. Last pre-blinatumomab MRD was Conclusion. In patients wih high-risk BCP-ALL, blinatumomab added to consolidation is safe and gives promising results. A comparison to similar patients treated in the same GRAALL-2014 study before October 2018 is planned with a longer follow-up. Figure 1 Figure 1. Disclosures Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Blinatumomab in frontline high-risk acute lymphoblastic leukemia

Background Myeloproliferative Philadelphia-negative Neoplasms (MPNs) are hematological cancers associated with chronic inflammation and endothelial dysfunction, conditions that may lead to development of premature atherosclerosis. Purpose To investigate whether biomarkers of inflammation and endothelial dysfunction are associated with the degree of atherosclerotic burden, measured by Coronary Artery Calcium Score (CACS), in patients with MPNs. Methods Patients with a validated MPN diagnosis; essential thrombocythemia (ET), polycythemia vera (PV) or myelofibrosis (MF), were recruited between 2016 and 2018 from one single specialized hematologic center. Patients filled out a standardized questionnaire on medical history, current medication, alcohol and smoking habits and family medical history. They were examined by cardiac computed tomography (CT), Endothelial Peripheral Arterial Tone (EndoPAT), and a range of blood analyses. The atherosclerotic burden was evaluated by CACS. High sensitivity C-reactive protein (hs-CRP) and Neutrophil:Lymphocyt Ratio (NLR) were used as indicators of chronic inflammation. EndoPAT was applied to evaluate endothelial dysfunction, which is linked to development of atherosclerosis. The JAK2V617F-mutation is a common gene mutation in MPN-patients. It affects the gene coding the Janus kinase 2 (JAK2) protein, and can be detected by qPCR of peripheral blood or bone marrow. The JAK2V617F-mutation is a risk factor associated with both chronic inflammation and endothelial dysfunction. Multivariable logistic regression analyses were used to identify associations between potential risk factors and a higher CACS value. Results Among 170 included patients, 161 patients completed cardiac CT (mean age 65.5 (SD 10.5), 52% men). Baseline data is presented in Table 1. JAK2V617F-mutation was found in 137 (85%) patients, 53 patients (35%, n=152) had hs-CRP>2.0 mg/L, 107 (67%, n=160) had NLR>2.15 and 32 (21%, n=154) had an abnormal EndoPAT. Overall, 66 patients (41%) had a CACS>100, with no significant difference between ET (41%), PV (42%) and MF (50%) (p=0.3). In patients with a history of ischemic heart disease (IHD), 92% had CACS>100, compared to 37% in patients without prior IHD (p=0.0003). Five independent factors associated with a CACS>100 were identified; age (OR: 1.3 [95% CI 1.1–1.4]), male sex (OR: 15.2 [95% CI 4.0–57.7]), prior IHD (OR: 15.9 [95% CI 1.2–202.4]), smoking (OR: 3.3 [95% CI 1.1–10.1]), and abnormal EndoPAT (OR: 4.8 [95% CI 1.1–20.0]) (Figure 1). Hs-CRP, NLR and JAK2V617F-mutation status were not significantly associated with CACS >100. Conclusion In this cohort of patients with MPNs, markers of chronic inflammation like hs-CRP and NLR were not associated with higher CACS, nor was the JAK2V617F-mutation. Traditional risk factors of cardiovascular disease seem to be sufficient to identify MPN patients with increased atherosclerotic burden, but measuring endothelial dysfunction provides additional information. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Department of Cardiology, Zealand University Hospital, Region Zealand, Denmark Table 1. Baseline characteristicsFigure 1. Odds ratio for CACS >100

Philadelphia negative Myeloproliferative Neoplasms (MPN) are a heterogeneous group of hematopoietic stem cell diseases. MPNs show different risk grades of thrombotic complications and acute myeloid leukemia evolution. In the last couple of decades, from JAK2 mutation detection in 2005 to the newer molecular trademarks studied through next generation sequencing, we are learning to approach MPNs from a deeper perspective. Here, we intend to elucidate the important factors affecting MPN clonal advantage and the reasons why some patients progress to more aggressive disease. Understanding these mechanisms is the key to developing new treatment approaches and targeted therapies for MPN patients.

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized collectively by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency. Although the natural history of these neoplasms can be measured sometimes in decades more than years, the cytogenetics analysis can offer useful information regarding the prognosis. Cytogenetics has a well-established prognostic role in acute leukemias and in myelodysplastic syndromes, where it drives the clinical decisions. NGS techniques can find adverse mutations with clear prognostic value and are currently included in the prognostic evaluation of MPNs in scores such as MIPSS, GIPSS, MIPSS-PV, and MIPSS-ET. We suggest that cytogenetics (considering its availability and relative cost) has a role regarding prognostic and therapeutic decisions.

The optimal treatment for Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) has not been established in the high-intensity chemotherapy era. The outcomes of patients with Ph-negative ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched related or unrelated donor in CR1 (HSCT-MRD group and HSCT-MUD group) were obtained from a Japanese registry database. Patients aged 16–24 years and 25–65 years were analyzed separately, and their outcomes were compared to those of patients who continued high-intensity chemotherapy in CR1 in studies (202U group and 202O group) by the Japan Adult Leukemia Study Group (JALSG). In the HSCT-MRD group, patients younger than 25 years had lower overall survival (OS) than the 202U group, presumably due to the higher non-relapse mortality (NRM) in the HSCT-MRD group. Patients 25 years and older had similar OS to the 202O group. The lower relapse rate was counterbalanced by higher NRM in the HSCT-MRD group. In the HSCT-MUD group, patients in both age groups had similar OS to their corresponding groups in the JALSG studies. In conclusion, high-intensity chemotherapy may change the role of HSCT for Ph-negative ALL.

Haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) is a promising treatment option for patients with Ph-negative acute lymphoblastic leukemia (ALL). In this study, we retrospectively analyzed data from Ph-negative ALL patients who underwent haplo-PBSCT during their first complete remission (CR1), and compared the long-term outcomes between the standard-risk and high-risk patients. The 3-year probability of relapse was 7.6% and 16.7% for the standard- and high-risk group (

Clofarabine (CLO) and cyclophosphamide (CY) combinations were tested in late stage refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) with disappointing results and high-grade toxicity. We designed a sequential 5-day combination of CLO 40 mg/m

Background Patients with Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (MF), have a significant risk of venous thromboembolism (VTE). We aim to determine the trends in annual rates of VTE-related admissions, associated cost, length of stay (LOS), and in-hospital mortality in patients with MPN. Methods We identified patients with PV, ET, and MF from the Nationwide Inpatient Sample (NIS) database from 2006 to 2014 using ICD-9CM coding. Hospitalizations where VTE was among the top-three diagnoses were considered VTE-related. We compared in-hospital outcomes between VTE and non-VTE hospitalizations using chi-square and Mann–Whitney U-test and used linear regression for trend analysis. Results We identified 1,046,666 admissions with a diagnosis of MPN. Patients were predominantly white (65.6%), females (52.7%), with a median age of 66 years (range: 18–108). The predominant MPN was ET (54%). There was no difference in in-hospital mortality between groups (VTE: 3.4% vs. non-VTE: 3.2%; p = 0.12); however, VTE admissions had a longer LOS (median: 6 vs. 5 days; p The annual rate of VTE admissions decreased over time (2006: 3.94% vs. 2014: 2.43%; p ≤ 0.01), compared with non-VTE–related admissions. Conclusion In our study, VTE-related admissions had similar in-hospital mortality as compared with non-VTE–related admissions. The rates of hospitalizations due to VTE have decreased over time but are associated with a higher cost and LOS. Newer risk assessment tools may assist in preventing VTE in high-risk patients and optimizing resource utilization.

Introducción: la carga sintomática de pacientes con neoplasias mieloproliferativas crónicas Filadelfia negativas (NMC-PhN) afecta la calidad de vida (CV). Existen escalas para evaluar la magnitud de los síntomas, una de ellas, MPN-SAF-10. En nuestra región existe escasa información sobre CV de pacientes con NMC-PhN. Objetivos: estimar el puntaje de calidad de vida con la escala MPN-SAF-10 en pacientes con NMC-PhN atendidos en el Hospital de San José (Bogotá, Colombia) y explorar asociaciones entre el tiempo de tratamiento, carga de complicaciones y el efecto en la CV. Material y métodos: estudio de corte transversal analítico para evaluar CV basada en carga sintomática de pacientes con NMC-PhN del Hospital de San José (Bogotá, Colombia). Se realizó análisis descriptivo y estratificado de calidad de vida, tratamiento citorreductor y de diferentes complicaciones, así como pruebas de asociación de los puntajes de riesgo de cada enfermedad con sus respectivos puntajes de CV. Resultados: en 64 pacientes la escala MPN-SAF-10 documentó medianas de puntajes globales de CV de 3 (RIC 1-6), MPN-SAF-10 de 20 (RIC 8-32). Un 49% de los pacientes tuvo algún grado de alteración (30% moderada y 19% severa), sin diferencias entre las tres enfermedades. Los puntajes de CV no variaron entre las NMC-PhN. El tratamiento y duración del mismo no se correlacionaron con la escala de MPN-SAF-10 (hidroxiúrea r: - 0.27; ruxolitinib r: 0.12). Conclusiones: en pacientes con NMC-PhN, la evaluación de CV con la escala MPN-SAF-10 evidencia algún grado de afectación a pesar del tratamiento; ésta es útil para objetivar dicha afectacióny debe implementarse en la práctica clínica

Pediatric-inspired acute lymphoblastic leukemia (ALL) regimens are increasingly used in adult ALL [1]. These protocols universally feature asparaginase (ASP), a bacterial enzyme which deprives ALL ...

The last decade has been very important for the quantity of preclinical information obtained regarding chronic myeloproliferative neoplasms (MPNs) and the following will be dedicated to the translational implications of the new biological acquisitions. The overcoming of the mechanistic model of clonal evolution and the entry of chronic inflammation and dysimmunity into the new model are the elements on which to base a part of future therapeutic strategies. The innate immune system plays a major role in this context. Protagonists of the initiation and regulation of many pathological aspects, from cytokine storms to fibrosis, the NLRP3 and AIM2 inflammasomes guide and condition the natural history of the disease. For this reason, MPNs share many biological and clinical aspects with non-neoplastic diseases, such as autoimmune disorders. Finally, cardiovascular risk and disturbances in iron metabolism and myelopoiesis are also closely linked to the role of inflammasomes. Although targeted therapies are already being tested, an increase in knowledge on the subject is desirable and potentially translates into better care for patients with MPNs.

WOS: 000512371600003 Introduction: Philadelphia-negative myeloproliferative neoplasm (MPN) is a hematopoietic stem cell disorder consisting of essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) associated with myeloid cell proliferation without differentiation and maturation defects. It is characterized by hypercellular bone marrow and an increase in one or more cell lines in the peripheral blood. In the hematopoietic stem cell, Janus kinase 2 (JAK2), which is a cytoplasmic tyrosine kinase, remains constantly phosphorylated (active) as a result of the V617F somatic mutation in the pseudokinase region. Even if the phosphorylated JAK2 does not receive a stimulus, it performs signal transmission and causes continuous gene expression. This explains the excessive increase in one or more blood cell lines. NAD(P)H quinone oxidoreductase-1 (NQO1) is a phase 1 enzyme that prevents the formation of reactive and toxic semiquinone metabolites by reducing two electrons in one step. The C609T polymorphism of the NQO1 gene leads to loss of enzyme activity due to the enzyme becoming unstable. While enzyme activity is not observed in individuals with both mutant alleles, moderate activity is observed in heterozygous individuals. Studies have reported a relationship between NQO1 C609T polymorphism and various cancer types. In our study, it was aimed to investigate the possible relationship between NQO1 C609T polymorphism and MPN development. Methods: Our study group consisted of 119 MPN patients and 122 healthy controls. DNA isolation was performed from peripheral blood taken from the study groups. The JAK2 V617F mutation was detected using Real-time polymerase chain reaction (PCR), and NQO1 C609T gene polymorphism was detected using the PCR- restriction fragment length polymorphism method. SPSS 21.0 was used for statistical analysis. Results: No statistically significant difference was found between the patient and control groups in terms of NQO1 genotype distributions (p>0.05). When cases with ET, PMF, and PV were compared in terms of frequency of JAK2 V617F mutation, the rate in PV was higher (respectively; 62.5%, 61.5%, 78.6%). There was no relationship between JAK2 mutation positivity and NQO1*2 polymorphism. Conclusion: According to the results obtained from our study, there is no relationship between NQO1*2 polymorphism and MPN. Variants of the NQO1 enzyme, which is essential in detoxification and activation of procarcinogens, did not increase the formation of the JAK2 V617F mutation, which is common in MPN patients. It is thought that the results should be supported by increasing the number of patient and control groups. Istanbul University Scientific Research FundIstanbul University [BAP/23924] The study was supported by the Istanbul University Scientific Research Fund (project no: BAP/23924).

To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV (p = 0.9), however, both MF and PV groups had significantly higher SS than the ET group (p = 0.011 and p = 0.035, respectively) and healthy controls (p &lt, 0.0001 and p = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) (p = 0.012, HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) (p &lt, 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) (p &lt, 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively (p = 0.038, HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls (p = 0.001), but not between the patient cohorts with ET and PV and healthy controls (p = 0.999 and p = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression.

Since early 2020, the SARS-CoV-2 pandemic has a massive impact on health care systems worldwide. Patients with malignant diseases are assumed to be at increased risk for a worse outcome of SARS-CoV-2 infection, and therefore, guidance regarding prevention and management of the infection as well as safe administration of cancer-therapy is required. Here, we provide recommendations for the management of patients with malignant disease in the times of COVID-19. These recommendations were prepared by an international panel of experts and then consented by the EHA Scientific Working Group on Infection in Hematology. The primary aim is to enable clinicians to provide optimal cancer care as safely as possible, since the most important protection for patients with malignant disease is the best-possible control of the underlying disease.

Ras-related dexamethasone-induced 1 (RASD1) is abnormally expressed in many solid cancers. However, its potential role in adults with B-cell acute lymphoblastic leukemia (B-ALL) is unclear. Therefore, we aim to clarify the abnormal expression of the tumor-associated biomarker, RASD1, as a potential target for diagnosis and prognosis in adult Philadelphia-negative B-ALL. The expression of RASD1 was detected with RT-qPCR in 92 adults with de novo Ph-negative B-ALL and 40 healthy controls. The correlation between RASD1 transcript levels and relapse was assessed. RASD1 transcript levels in patients with Ph-negative B-ALL (median 81.76%, range 0.22%-1824.52%) were significantly higher than those in healthy controls (7.59%, 0.46%-38.66%; PRASD1 transcript levels had a lower 5-year relapse-free survival (RFS, 47.5% [32.9%, 62.1%] vs. 63.1% [49.0%, 77.2%]; P = 0.012) and a higher 5-year cumulative incidence of relapse (CIR, 52.0% [37.4%, 66.6%] vs. 36.2% [22.2%, 50.2%]; P = 0.013) especially in patients receiving chemotherapy only. Multivariate analysis showed that a low RASD1 transcript level was an independent risk factor for RFS (HR = 2.938 [1.427, 6.047], P = 0.003) and CIR (HR = 3.367 [1.668, 6.796], P = 0.001) in patients with Ph-negative B-ALL. RASD1 transcript levels were significantly higher in patients with Ph-negative B-ALL and a low RASD1 transcript level was independently correlated with increased relapse risk.

Introduction The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) develop in a biological continuum from the early cancer stages (ET/PV) to the advanced myelofibrosis stage characterized by huge splenomegaly, bone marrow failure and -fibrosis. Importantly, bone marrow fibrosis also increases from the early stages with reticulin fibrosis only and later deposition of mature collagen as well. Fibulins are glycoproteins that are important constituents of the extracellular matrix (ECM). Thus, fibulins have been shown to modulate cell morphology, growth, adhesion and motility. Dysregulation of fibulins has been reported in several cancers. In addition, upregulation of fibulins and elevated circulating fibulins have been reported in diseases - other than cancers -, in which chronic inflammation is an important pathogenetic factor, such as cardiovascular diseases. Thus, deregulated fibulins have been described in patients with type 2 diabetes mellitus. Herein, using whole blood gene expression profiling, we for the first time report deregulated fibulins in patients with MPNs. Aim To detect if genes associated with pre-atherosclerotic changes in type II diabetes are deregulated in patients with MPNs. Material and methods Gene expression microarrays were applied to generate gene expression profiles of whole blood from control subjects (n=21) and patients with ET (n=19), PV (n=41), and PMF (n=9). Total RNA was purified, amplified to biotin-labeled aRNA and hybridized to microarray chips. The statistical software R was applied to perform initial data processing and statistical analysis of gene expression changes between patients and control subjects. An FDR Results We identified 23,657, 25,567, and 17,417 probe sets which were significantly differentially expressed between controls and patients with ET, PV, and PMF, respectively (FDR < 0.05). We focused upon the top 15 upregulated genes from a previous gene expression microarray study performed on arterial tissue from patients with type 2 diabetes compared to non-diabetic patients undergoing artery bypass graft surgery. Several of these genes were significantly deregulated in patients with MPNs (Table 1). In patients with ET, FBLN1, FBLN2,FAM107A, IGF2, MEG3, and ELN were significantly upregulated and ZFP36L2 were significantly downregulated. In patients with PV, FBLN1, FBLN2, ELN, LEPR, FAM107A, IGF2, CRISPLD2, and MEG3 were significantly upregulated and ZFP36L2 and SERPINF1 were significantly downregulated. In patients with PMF, MEG3, LEPR, FBLN1, FAM107A, ELN, IGF2, and VWF were significantly upregulated and ZFP36L2 and SERPINF1 were significantly downregulated. Discussion and conclusions Fibulins regulate several cellular functions including tissue homeostasis and remodeling after injury, angiogenesis, and tumorigenesis. Thus, fibulins have been reported to be upregulated in several cancer types, in which deregulated fibulins have been associated with cancer invasiveness and disease progression. We have for the first time shown that fibulins are also highly deregulated in patients with MPNs. The significance of our findings is presently unknown but since interactions between fibulins and transforming growth factor (TGFbeta) have been demonstrated, upregulated fibulins may enhance the capacities of TGFbeta, which shares several of the regulatory functions excerted by fibulins. In the context of chronic inflammation being a driving force for MPN development during the biological continuum from early cancer stages to the advanced myelofibrosis stage and chronic inflammation likely also accelerates the development of atherosclerosis in MPNs, it is highly intriguing to note that fibulins are also elevated in arteries from patients with type 2 diabetes mellitus. Thus, upregulated fibulins in blood cells may actually indirectly reflect ongoing matrix modelling during atherosclerosis development, including remodeling and turnover of basement membranes in the inflamed endothelium. In conclusion, highly deregulated fibulins have been demonstrated in circulating blood cells by whole blood gene expression profiling. Further studies are needed to assess the significance of our findings in terms of potential associations to modelling of ECM in the bone marrow and during development of atherosclerosis in MPNs. Disclosures Hasselbalch: Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board.

A novel induction therapy, including intensive L-asparaginase, was designed in 2007 for patients aged

Background: It is still a matter of debate regarding the association of JAK2V617F mutation with thrombosis in BCR-ABL negative CMPN patients. The role of JAK2V617F mutation in increasing the thrombotic risk in CMPNs is yet unequivocal. Aims: To clarify the contribution of JAK2V617F mutation in thrombosis in CMPN patients. Settings and Design: This retrospective study was done to evaluate role of JAK2V617F mutation in thrombosis in CMPNs. Materials and Methods: 65 CMPN patients (PV, ET and PMF) were analyzed for JAK2V617F mutation using ARMS-PCR and detailed history of thrombosis was recorded in these patients. Statistical Analysis: P values were 2 tailed, and statistical significance was set at P < 0.05. Results: 46/65 were males and 19/65 were females [M: F: 2.4:1] with median age 46 years [range, 14-80 years]. Patients had median Hb 15.6 g/dl [range, 5.1-20.3], median TLC 10.7 × 109/l [range 2.4-216] and platelet count 360 × 109/l [range, 20-1859]. 32 were JAK2V617F positive and 33 were negative for this mutation. On comparing the prevalence of thrombosis in JAK2V617F positive patients with JAK2V617F negative patients, we observed that 20/32 (62.5%) JAK2V617F positive patients had thrombosis as compared to 16/33 (48%) in JAK2V617F negative patients (P = 0.04). We observed significant association of JAK2V617F mutation with thrombosis, however no association of this mutation with thrombosis was observed among the JAK2V617F negative patients. Conclusion: Our study suggests that JAK2V617F mutation may increase the risk of thrombosis in CMPNs. This finding could lead to risk stratification, setting up the treatment strategy in CMPNs.

Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have higher risks of developing thromboembolisms compared to the general population. International guidelines on the management of MPNs therefore include recommendations concerning thromboembolism prophylaxis. In clinical practice, strict adherence to guidelines may be challenging and dependent on factors such as physician experience, outpatient clinic setting, and access to therapy; however, no data exist on physician adherence or patient compliance to thromboembolism prophylaxis in MPNs.The Nordic Myeloproliferative Neoplasm Study Group (NMPN) performed a survey among Nordic hematology specialists with the aim of documenting the implementation of international recommendations in a region of Northern Europe with similar healthcare systems.The study showed that Nordic specialists managed their patients in accordance with international guidelines concerning medical intervention, but to a lesser degree regarding the management of additional cardiovascular risk factors. The survey also drew attention to the common clinical dilemma of combining antiaggregatory agents with vitamin K antagonists (VKA), or novel oral anticoagulants (NOAC), as well as phlebotomy limits in female polycythemia vera patients.The results of this study highlight the importance of considering all risk factors for thrombosis and an optimal collaboration with the primary healthcare sector.

Background: Elevated JAK2V617F allele burden is associated with enhanced expression of downstream target genes in Philadelphia negative chronic myeloproliferative neoplasms (CMPNs) which include PV, ET & PMF. Previous studies have shown the impact of JAK2V617F allele burden on clinical phenotype of CMPNs. However, there is no data from India regarding the association between JAK2V617F allele burden and clinical phenotype in PV. Aims/Settings and Design: We aimed to investigate the effect of allele burden on clinical phenotype in 90 JAK2V617F positive PV patients and to see its influence on disease related complications. Material and Methods: Allele burden of 90 JAK2V617F positive PV patients was quantified by Real-time polymerase chain reaction (RQ-PCR). Results: 74/90 (82.22%) were males and 16/90 (17.78%) were females (median 45 years, range 35-78). Patients with age >50 years had significantly higher JAK2V617F allele burden (median 40.15%, range 0.49–91.62 %) than patients with ≤ 50 years age (median 48.59 %, range 0.56–86.74 %; P < 0.032). Patients with splenomegaly had significantly higher JAK2V617F allele burden (mean 50.24%, range 6.91–84.17%) than patients without splenomegaly (mean 33.82 %, range 0.49–71.83 %; P < 0.017). Patients with higher allele burden (median 57.20, range 43.4–72.03%) had significantly raised thrombotic events than the patients with lower allele burden (median 37.38, range 0.49–84.17% P < 0.043). 49/90 (54%) were homozygous and 41/90 (46%) were heterozygous. Conclusions: Higher JAK2V617F allele burden showed association with increased age, splenomegaly and thrombotic events. Thus, it may be considered for prognostication and setting up the treatment protocol in PV patients.

Introduction: Myeloproliferative Neoplasms (MPNs) are group of clonal hematopoietic stem cell (HSC) disorders characterised by overproduction of myeloid cells and are associated with an acquired genetic mutation of JAK2V617F. The 2008 WHO MPNs classification grouped the related disorders naming them Philadelphia negative MPNs. These included polycythemia vera, essential thrombocythemia, pre-fibrotic myelofibrosis and primary myelofibrosis which are the focus of this review. The etiology of MPNs remains unknown. Epidemiological studies have indicated there are associations between environmental, lifestyle factors and host characteristic with pathogenesis of MPNs. The aim of this review is to summarize all published data investigating smoking, obesity, gender and exposure to benzene as contributing risk factors and establish their association with developing MPNs. Methods: Medline, Embase, Pubmed databases were systematically searched for relevant published articles with date restrictions of March 2003 to March 2020. The published studies using epidemiological study designs i.e. case control, cohort and cross-sectional studies were identified. Scanning of reference lists and the grey literature was also undertaken. Articles written in English language were included. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Manual review of filtered records excluded inappropriate publications. Two investigators evaluated the full text of selected articles independently analysed the content qualitatively using the Newcastle-Ottawa Scale. Results: A total of 23 published articles met the inclusion criteria, reporting data on the impact of smoking and obesity, the effects of exposure to benzene and gender on MPNs pathogenesis. A significant association was found between smoking and development of MPNs explained by the substantial increase in the levels of several proinflammatory mediators and systematic oxidative stress causing hyperstimulation of myeloid compartments. The upregulation of JAK-STAT and NF-kB signalling pathway and several transcription factors in patients with MPNs who smokers are have been confirmed. Subsequently, these changes facilitate the clonal expansion of hematopoietic stem cells with JAK2V617F mutations. The literature did not confirm any significant association between obesity and risk of developing MPNs, but it cannot be ruled out as an contributing risk factor. The consequences of obesity have been explained in terms of changes in metabolic, endocrinologic, immunologic, and inflammatory systems which may lead to increase in the cell proliferation, cell mutation rate, dysregulate gene function, disturb DNA repair or induce epigenetic changes favouring the induction of neoplastic transformation. There is some evidence in the literature that in individuals exposed to benzene, there is a stimulation of erythropoietic progenitor cells with cytokine independent growth compared to non-exposed individuals. This spontaneous growth of erythroid progenitor cells is one of the hallmarks of MPNs but evidence to prove this hypothesis is uncertain. No strong association was found between exposure of benzene and MPNs but further investigation on effects of increased levels and duration of exposure will be beneficial. Host characteristics such as gender as contributing factors associated with MPNs has been explored in several studies. Gender has been classified as an independent modifier in JAK2V617F allele burden which influences genotype and clonal expansion resulting into allele burden variability, hence, partly responsible for to the differences in the development of the disease between males and females. Conclusion: The important role of predisposing factors such as environmental, lifestyle risk factors and host characteristic in the pathogenesis of MPNs cannot be eliminated. The significant association between smoking and developing MPNs has been confirmed. Gender can be classified as an independent modifier in JAK2V617F allele burden reflecting on the phenotypic heterogeneity of MPNs. The relationship between obesity and exposure to benzene with MPNs developments has not been established yet. The results from this review proposes a large, well-designed epidemiological research exploring these contributing factors. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Overall survival (OS) in adults with ALL remains around 40%, but treatment with asparaginase (ASP)-containing pediatric-inspired regimens demonstrated a 3- or 4-year OS of 67-76%, including in patients with T-cell ALL, with manageable toxicities (Geyer 2020, Stock 2019, DeAngelo 2015). Recent studies in adults with reduced pegaspargase (PEG-ASP) doses showed survival outcomes similar to those with standard doses, with reduced toxicities, including pancreatitis, hepatic and thromboembolic events (Derman 2020, Patel 2020). Calaspargase pegol (ASPARLAS; Cal-PEG), similar to PEG-ASP, is an E. coli L-asparaginase covalently conjugated to monomethoxy polyethylene glycol, but with a more chemically stable succinimidyl carbonate linker, providing sustained asparagine depletion with less frequent dosing (every 21 days). The efficacy and safety of Cal-PEG 2500 U/m 2, vs PEG-ASP 2500 U/m 2, was evaluated in 2 multicenter, randomized clinical trials (AALL07P4 [n=166] and DFCI 11-001 [n=239]) in newly diagnosed patients with ALL ≤21 years. Complete remission (CR), minimal residual disease (MRD), event-free survival (EFS), and OS were similar in both arms, with a 94% 5-year OS for Cal-PEG. The safety profile was consistent with that of PEG-ASP, with similar rates of hypersensitivity, pancreatitis, thrombosis, and hyperbilirubinemia (Vrooman 2021). Plasma asparaginase activity (PAA) levels were ≥0.1 U/mL 25 days after the induction dose in 95% of patients (Angiolillo 2014). The absence of a standardized treatment and the inadequate outcome of adult treatment regimens, as well as a lack of targeted immunotherapies for T-ALL, highlight a critical unmet need for improved therapeutic approaches. A treatment protocol with less frequent Cal-PEG administration due to a more sustained asparaginase activity as well as age- and weight-based dose adjustments may improve clinical outcomes without added toxicities, and possibly extend the upper age limit of ASP-containing regimen for older adults. Trial Design: We present a clinical trial design of an ongoing, multicenter, phase 2/3 study (NCT04817761) assessing the safety and anti-leukemic activity of Cal-PEG in newly diagnosed patients with Philadelphia-negative B- or T-cell ALL. Patients aged ≥22 years are eligible with ECOG performance status 0-2, no known history of pancreatitis, coagulopathy, CNS thrombosis or severe hepatic impairment. This trial comprises two parts: dose confirmation run-in (part 1) and the expansion phase (part 2). Part 1 is open for enrollment and is the focus of this abstract. Starting doses of Cal-PEG are based on the patients' age and BMI, with older patient groups assigned to lower doses (Table 1). A minimum of 4 (initial cohort) and up to 8 patients will be admitted per patient group. A total of 6 Cal-PEG doses will be administered during the treatment period as part of a multiagent chemotherapy regimen based on CALGB 10403 trial (Figure 1; Table 2), with end of treatment visit 1 year after the induction dose, and an additional 2 years of survival follow-up. The primary endpoints in part 1 are 1) the safety of Cal-PEG, including incidence of pre-defined unacceptable toxicities (UT) within 30 days after the induction dose and 2) PAA profiles, including achieving PAA ≥0.1 U/mL at pre-specified time points. Secondary endpoints include immunogenicity, CR, end of induction and consolidation MRD, and 1-, 2- and 3-year EFS, disease-free survival, and OS. Bayesian optimal interval design (BOIN) will be used to evaluate UT with specified boundaries for dose confirmation, expansion, or reduction. For each patient group, the observed UT rate at a dose level will be compared with the safety boundary (23.6%) and toxicity boundary (35.8%) to guide safety confirmation. PAA data from previous pediatric studies and each run-in cohort will also be used to confirm the tested dose through population PK modeling-based predictions. The decision to confirm or adjust the dose will be based on the accumulated safety and induction PAA data at end-of-cohort meetings with the investigators, sponsor and in consult with DSMB recommendations. Part 1 started in July 2021 and will enroll ≈16-32 patients at multiple sites in the US. Part 2 will commence once the safety and PAA data from part 1 are analyzed and the expansion doses are confirmed. Up to 122 patients are expected to be enrolled in both phases of the trial. Clinical trial information: NCT04817761 Figure 1 Figure 1. Disclosures Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Park: Kura Oncology: Consultancy; Autolus: Consultancy; Intellia: Consultancy; Affyimmune: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; BMS: Consultancy; PrecisionBio: Consultancy; Minerva: Consultancy; Innate Pharma: Consultancy; Curocel: Consultancy; Servier: Consultancy; Artiva: Consultancy. Emadi: Secura Bio.: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder. Abdul-Hay: Jazz: Other: Advisory Board, Speakers Bureau; Servier: Other: Advisory Board, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Takeda: Speakers Bureau. Cassaday: Kite/Gilead: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Webster: AmGen: Consultancy; Pfizer: Consultancy. Pandya: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Mogul: Servier Pharmaceuticals: Current Employment. Shvenke: Servier Pharmaceuticals: Current Employment. Zhu: Servier Pharmaceuticals: Current Employment. Tessier: Servier: Current Employment. DeAngelo: Abbvie: Research Funding; Incyte Corporation: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Agios: Consultancy; Autolus: Consultancy; Forty-Seven: Consultancy; Blueprint Medicines Corporation: Consultancy; Jazz: Consultancy; GlycoMimetics: Research Funding. OffLabel Disclosure: Calaspargase pegol is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years, with recommended dosage of 2,500 units/m2 intravenously no more frequently than every 21 days

The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineage compartments. Activation of JAK/STAT signaling is a major driver of all Ph-negative MPNs. During disease progression, MPN patients experience increased pro-inflammatory cytokine secretion, leading to remodeling of the bone marrow microenvironment and subsequent fibrosis. The JAK inhibitor ruxolitinib is an approved targeted therapy for MPN patients and has shown promise in its ability to reduce splenomegaly and the cytokine storm observed in patients. However, JAK inhibitors alone are not sufficient to reduce bone marrow fibrosis or to eliminate the JAK2-mutated clone. Furthermore, JAK inhibitor persistence, or reactivation of JAK/STAT signaling upon chronic JAK inhibitor treatment, has been observed in both MPN mouse models and MPN patients. Therefore, there is an urgent need for new treatment options in MPN. The tyrosine kinase RON, a member of the MET kinase family, has well-characterized roles in erythroblast proliferation and pro-inflammatory cytokine production. RON can be phosphorylated by JAK2 to stimulate erythroblast proliferation. However, the role of RON in MPN pathogenesis is unknown. We found that the ALK/MET/RON/ROS1 inhibitor crizotinib inhibited colony formation by MPN patient CD34+ cells, regardless of their disease subtype, mutation status, or JAK2 inhibitor treatment history (Figure 1A). To determine whether this is due to inhibition of the JAK/STAT signaling pathway, we performed phospho-flow cytometry of STAT3 and STAT5 in myelofibrosis patient erythroblasts treated with crizotinib ex vivo as well as Western blot analysis in the JAK2-mutated cell lines SET2 and HEL. We found that crizotinib inhibits the phosphorylation of JAK2, STAT3, and STAT5 (Figure 1B). Since crizotinib has not been reported to directly inhibit JAK2, we asked whether these effects of crizotinib in MPN cells could be explained by RON inhibition. Consistent with this hypothesis, we observed that shRNA knockdown of multiple RON isoforms also decreases the phosphorylation of JAK2, STAT5, and STAT3 in HEL cells (Figure 1C-D). To determine whether crizotinib can alter the MPN disease course in vivo, we tested crizotinib by oral gavage in the MPLW515L bone marrow transplant murine model of myelofibrosis at 100mg/kg daily for 2 weeks. We showed that crizotinib decreased the disease burden of MPL-W515L mice, as evidenced by decreased spleen and liver weights (Figure 1E). To determine the effects of RON genetic deletion on MPN pathogenesis, we tested whether genetic deletion of Stk (mouse gene for RON) impairs disease progression in the JAK2V617F bone marrow transplant MPN model by transplanting Stk-/- c-Kit+ bone marrow cells transduced with the JAK2V617F-GFP retrovirus into lethally irradiated recipients. We observed a significant delay in disease onset in Stk-/- transplant recipients compared to WT controls (Figure 1F). However, we found that Stk-/- mice have normal numbers of hematopoietic stem and progenitor cells, and normal bone marrow myeloid colony forming capacity, suggesting that RON is a safe therapeutic target. To determine whether RON plays a role in the JAK inhibitor persistence phenotype, we generated persistent cells by treating SET2 cells with increasing doses of ruxolitinib over 8 weeks, and confirmed persistent proliferation and JAK/STAT activation. Interestingly, we found that RON phosphorylation is enhanced in JAK inhibitor persistent cells, and that dual inhibition of RON and JAK2 overcomes JAK inhibitor persistence in SET2 cells (Figure 1G-H), suggesting that RON may potentiate the JAK2 persistence phenotype in response to ruxolitinib. Importantly, we showed by immunoprecipitation that phospho-RON and phospho-JAK2 physically interact in JAK inhibitor persistent SET2 cells, and that this interaction is disrupted by crizotinib (Figure 1I). In summary, our data demonstrate that RON kinase is a novel mediator of JAK/STAT signaling in MPNs, and that it plays a particularly important role in JAK inhibitor persistence. Our work suggests that therapeutic strategies to inhibit RON, such as crizotinib, should be investigated in MPN patients. Figure 1 Figure 1. Disclosures Halmos: Guardant Health: Membership on an entity's Board of Directors or advisory committees; Apollomics: Membership on an entity's Board of Directors or advisory committees; TPT: Membership on an entity's Board of Directors or advisory committees; Eli-Lilly: Research Funding; Advaxis: Research Funding; Blueprint: Research Funding; Elevation: Research Funding; Mirati: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: 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, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gritsman: iOnctura: Research Funding.

Introduction: Spleen and liver stiffness, investigated by transient elastography (TE), have been associated with marrow fibrosis in patients (pts) with Ph-negative myeloproliferative neoplasms (MPNs) (Iurlo et al, Br J Haematol. 2015; Webb et al, Ultrasound Q. 2015). Morover, spleen stiffness was found to be greater in Myelofibrosis (MF) and Polycythemia Vera (PV) compared to Essential Thrombocythemia (ET) (Benedetti et al, J Clin Med. 2020). Tissue stiffness can be assessed by ultrasound shear wave elastography (SWE), the two most common techniques being point SWE (pSWE) and bidimensional SWE (2D.SWE). Aims: The aims of this study are: 1) to identify TE differences between MPN pts and healthy volunteers (HV); 2) to evaluate specific TE features in pts with MF, PV and ET; 3) to assess whether spleen/liver stiffness may identify clinical-laboratory features associated with prognosis in MPNs Methods: In this monocentric study, MPN pts and HV received elastometric evaluation of spleen and liver stiffness by pSWE and 2D.SWE with an Esaote MyLab™9 ultrasound system. Spleen area, portal (PVD) and splenic vein diameter (SVD) were measured. Results: A total of 220 pts were included in this study: 142 (64.5%) MPN and 78 (35.5%) HV. MPN pts were affected by MF (63, 44.4%: 39 primary MF), PV (33, 23.2%) or ET (46, 32.4%). Compared to HV, MPN pts had greater median spleen maximal cross sectional area (79 vs 38 cm2, p Clinical and laboratory features of MPN pts are shown in Tab 1. Compared to PV and ET pts, MF pts had higher spleen (p Notably, higher median spleen area (p Notably, increased spleen fibrosis was significantly associated with thrombotic history (32.2 vs 24.3 kPa in pts without previous thrombosis, p=0.02). Also, MPN pts with splanchnic vein thrombosis had higher spleen (pSWE: p In MF pts, TE data did not correlate with DIPSS risk category. However, a higher spleen stiffness (pSWE/2D.SWE, p=0.09/ p=0.03), liver stiffness (pSWE/2D.SWE, p=0.001/p=0.01), PVD (p=0.002), and SVD (p=0.01) were associated with larger spleen length by palpation. Also, a reduced SVD was associated with the presence of ≥1 high molecular risk mutation (HMR) (p=0.04). As expected, MF pts treated with JAK-inhibitors showed larger spleen area (143.8 vs 83.7 cm 2, p=0.01) and higher spleen stiffness (34.3 vs 24 kPa, p=0.01) compared to pts under cytoreductive therapy. However, pts in spleen response at the time of TE had lower median SVD/PVD (p=0.05/p=0.07) and reduced spleen stiffness (sSWE/2D.SWE: 31.5/25.9 vs 39.0/32.8 in non-responders, p=0.01/p=0.04) In ET/PV, TE data were comparable in pts with/without a complete hematological response. However, IFN was associated with enlarged spleen area and stiffness compared to cytoreduction. Conclusions: TE evaluation effectively distinguishes MF pts from HV and ET/PV, while ET/PV show relevant similarities to each other and to HV. TE data were significantly associated with prognostically relevant features including marrow fibrosis and history of thrombosis in all MPNs, and presence of large splenomegaly and HMR in MF. Finally, TE data were significantly associated with spleen response in MF. Overall, spleen/liver stiffness may help in correct MPN diagnosis, and may provide clinical guidance, being associated with known prognostic factors and treatment outcome. Figure 1 Figure 1. Disclosures Cavo: Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau. Piscaglia: ESAOTE: Research Funding. Palandri: CTI: Consultancy; AOP: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees.

Backgound The Philadelphia-negative myeloproliferative neoplasms (MPNs) share similar molecular characteristics, in which the excessive myeloproliferations are driven by mutations in JAK2, CALR, MPL, and uncommon variants. More recently, the biological basis on acquisition of somatic mutations have been accumulated. However, symptoms, histomorphologic characteristics, and natural histories are different between MPN subsets. Although there are increasing evidences that inflammation have a key role in promoting MPN initiation and influencing disease evolution, characteristics of the bone marrow immune microenvironment between MPN subsets remains unclear exactly. Aims To characterize the bone marrow immune microenvironment of Philadelphia-negative MPNs, we carried out immune-related gene expression profiling of bone marrow aspirates (BMAs) from 33 MPN patients (6 PV, 6 ET, 6 early PMF, and 15 overt MF including 10 primary MF, 5 post-PV/ET MF) using nCounter Immunology Panel. Methods BMA samples collected at diagnosis using EDTA-coated tubes. Those samples were processed within 24 hours from collection to obtain mononuclear cells by density centrifugation using Ficoll-Paque. NanoString analysis using a 594-gene nCounter Immunology panel (Human v2 - nanoString) was performed on RNAs extracted from 33 MPN bone marrow aspirates. Results First, to investigate whether there are distinct gene expression signatures of immune cells between three subcategories of MPNs, we compared gene expression profiles (GEPs) between ET, PV, and overt PMF. Using a P-value cutoff of ≤0.05 and fold-change ≥ 2, 10 upregulated and 32 downregulated differentially expressed genes (DEGs) were identified in ET than PMF, and 9 upregulated and 11 downregulated DEGs were identified in PV than PMF, while we found no significant DEGs between ET versus PV, except seven genes. Second, we investigated differences in GEPs between early PMF and overt PMF. Thirty-two downregulated and 4 upregulated DEGs were identified in early PMF than overt PMF. Gene set analysis revealed that the expression of genes related to almost processes decreased in early PMF than overt PMF. Then, we questioned differences between PMF and post-PV/ET MF. Using a P-value cutoff of ≤0.05 and fold-change ≥ 2, 12 upregulated and 12 downregulated DEGs were identified. Next, we computed relative abundances of immune cell subpopulations, estimated based on expression counts from the entire panel of surveyed genes, and compared them between the subcategories of MPNs. The abundance measurement of exhausted CD8 + T cell genes were significantly lower in ET and PV, compared with overt PMF, suggesting T cell exhaustion was distinct in overt PMF, compared to ET and PV. Conclusions The results demonstrated that immune microenvironment signature was distinguishable in the subcategories of MPNs. In addition, inflammatory signature was enriched in the bone marrow of overt PMF and exhausted CD8 + T cell genes were distinct in overt PMT. Further investigation is warranted to determine the immunological factors critical for potential therapeutic targets to alleviate progress to myelofibrosis. Disclosures Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: Thromboembolism is a well-recognized complication of patients with Philadelphia negative myeloproliferative neoplasms (MPN), potentially due to an endothelial injury caused by the activation of inflammatory cytokines. Among the MPNs, Polycythemia vera (PV) seemed to be the most associated with thrombotic events; however, essential thrombocytosis (ET) and primary myelofibrosis (PMF) are also at higher risk than the general population. Furthermore, arterial and venous thromboembolisms account for higher mortality in this population, causing approximately 45% of all disease-associated fatal events. Previous studies have explored the combined outcomes of venous thromboembolism (VTE) on MPN patients; however, none of them focused primarily on pulmonary embolism (PE). Therefore, we aimed to identify any potential demographic, socioeconomic, or clinical characteristics associated with PE in a large cohort of MPN patients admitted to US hospitals. Methods: We inquired the Nationwide Inpatient Sample database to identify patients diagnosed with MPN from 2016-2018. We used the ICD-10 codes to identify the different types of MPN and compare patients with and without PE. The main outcomes were risk factors associated with PE and in-hospital mortality. We computed the chi-squared test and the Mann-Whitney U-test to compare the outcomes of patients with and without PE. We first conducted a univariate analysis. Clinically relevant characteristics and variables with a significant association (p Results: Among 82,087 identified patients with MPN, most of them were white (67.4%), female (54.6%), and had a median age of 63 (IQR 49-76). Of them, 1982 (2.4%) had a PE event during admission. There were no significant differences in age and sex between PE patients and non-PE patients. While there were higher proportions of White (68.3% vs. 67.4%) and Black patients (18.6% vs. 17%) in the PE group, there was a lower proportion of Hispanics (8.7% vs. 9.7%; p=0.007). Patients with PE also had a higher median Elixhauser comorbidity index (5 vs. 4, p Conclusions: In this large epidemiological study, we found that patients with MPN and PE had higher mortality than those without PE. Risk factors associated with the development of PE were concomitant obesity and coagulopathy. In addition to the known preventive therapies such as aspirin, phlebotomy, and cytoreductive agents, this study highlights the importance of controlling modifiable factors such as obesity in MPN patients. Future studies should confirm our findings and investigate strategies to prevention PE in this vulnerable population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Bleeding and thrombosis are prevalent across all myeloproliferative neoplasm (MPN) subtypes and have significant impact on morbidity and mortality. Although risk factors for thrombosis are well established, bleeding risk factors in these patients are poorly characterized. Identifying MPN patients at higher risk for bleeding could guide the duration of anticoagulation for patients with MPN associated thrombosis (balancing the risk between bleeding and thrombosis), select individuals at higher risk for bleeding during prophylactic anticoagulation, and predict for bleeding complications with surgical procedures. Methods: We performed a retrospective analysis of bleeding risk factors among consecutive adult MPN patients treated at Roswell Park Comprehensive Cancer Center. Bleeding events were classified as minor or major events as defined by the International Society of Thrombosis and Hemostasis (ISTH). The primary outcome of interest was time to initial bleeding after MPN diagnosis. Patient characteristics were summarized as range and medians (for continuous variables) and counts with percentages (for categorical variables) (Table 1). Cox regression was used to examine the associations between candidate risk factors with identified bleeding events in univariate and multivariable analyses. Variables with p Results: A total of 170-consecutive adult MPN patients were identified between 2005 and 2021. Median follow-up was 43.5 months (range 0.66-485.72). The rate of bleeding (major and minor) was 4.9/100 patient-years and rate of thrombosis was 5.4/100 patient-years (5.4/100 patient-years for arterial thrombosis and 2.9/100 patient-years for venous thrombosis). In univariable analysis, predictors of bleeding included age > 60 years (HR 2.8; 95% CI 1.47-5.34; p=0.001), diagnoses of primary myelofibrosis (PMF) (HR 2.98; 95% CI 1.29-6.9; p=0.01) and myelodysplastic syndrome/myeloproliferative neoplasm (MDS-MPN) overlap syndrome (HR 4.56, 95% CI1.91-10.88; p=0.0004), prior history of thrombosis (HR 3.3, 95% CI 1.27-8.8; p=0.01) and presence of ASXL1 (HR 4.13, 95% CI 2.13-8.04; p=0.0001), JAK2 V617F (HR 0.58; 95% CI 0.31-1.08; p=0.08) and TET2 mutations (HR 3.46; 95% CI 1.5-7.9; p=0.003). In multivariate analysis, the presence of JAK2 V617F (HR 4.8; 95% CI 1-21.5; p=0.03) and ASXL1 (HR 12.7, 95% CI 1.7-93; p=0.01) mutations were associated with increased risk of bleeding (Figure 2). Patients with polycythemia vera were at lower risk of bleeding (HR -3.5, 95% CI 0-0.8; p=0.03). Since ASXL1 mutation was associated with a higher risk of bleeding, we studied the association between ASXL1 mutation and other clinical variables. Patients with ASXL1 mutations were more likely to have a diagnosis of PMF and MDS-MPN overlap syndrome (p=0.0001), age > 60 years (p=0.0001), risk for thrombosis (p=0.04), lower hematocrit (p=0.009) and platelets (p=0.0003) but higher white blood cell count (WBC) (p= 0.04) (Figure 3). We then studied the correlation between ASXL1 mutation and factor VIII/Von Willebrand complex and factor V, the two most described abnormal coagulation factors in MPN. ASXL1 mutation was not associated with a statistically significant lower VWF Ag (p=0.07) or factor V (p=0.1) that could potentially explain the higher risk of bleeding seen with this mutation (figure 4). Conclusion: ASXL1 mutations are associated with a significantly higher risk of bleeding in adult MPN patients. The risk of bleeding with ASXL1 mutations was independent of prior thrombosis and was not associated with abnormalities in VWF profile or factor V. Confirmation of these findings in additional patients and studies of underlying platelet function to identify the possible mechanism of ASXL1 associated bleeding in these patients are ongoing. Figure 1 Figure 1. Disclosures Elshoury: Bristol Meyers Squibb: Other: advisory board. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Griffiths: Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Novartis: Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Genentech: Research Funding. Wang: Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Mana Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Background: Relapsed Acute Lymphoblastic Leukemia (ALL) is not curable with standard therapies. Effective outpatient treatment, allowing patients to maintain a good quality of life, while offering a meaningful chance of remission, is an appealing alternative to prolonged admission required for currently available multi-agent regimens. Vincristine sulfate liposomal injection (Marqibo) was approved in 2012 for treatment Ph-ALL in second or greater relapse, originally developed to overcome pharmacokinetic and pharmacodynamic limitations of vincristine. Approved dosing is 2.25 mg/m 2 without a dose cap. Pre-clinical studies showed it increases plasma circulation time, increases tumor tissue delivery, accumulates in tumor tissue, and slowly releases vincristine in tumor tissues rather than into systemic circulation. In a phase 2 trial, as a weekly administered single agent, CR/CRi rate was 20%, with median duration of 23 weeks and overall response rate of 35%. Blinatumomab is a murine recombinant single-chain antibody construct belonging to a class of bispecific T-cell engager (BITE) immuno-oncology. BITE molecules are designed to direct T-effector memory cells towards target cells, triggering cell-specific cytotoxicity. Blinatumomab specifically targets cells that express CD19 and the presence of both, CD19+ target cells and T cells are required for its cytotoxic activity. In previous phase 2 trials, responses to single agent blinatumomab in the relapsed setting were near 60%, although only 34% (44%, including partial and incomplete hematologic recovery) in the pivotal phase 3. Median duration of remission was only 7.3 months and half were very heavily pretreated. Here, we describe a trial designed to target ALL cells with Marquibo as a microtubule inhibitor and blinatumomab as a BiTE immuno-oncology therapy and evaluate whether this combination results in an effective and safe therapeutic option for relapsed/refractory ALL patients. We anticipate additive benefits of the regimen and define a clinically meaningful outcome as >75% (CR/CRi) rate and median progression-free survival (PFS) of ≥1 year. This higher rate of response is expected as many patients are using blinatumomab at first relapse, and therefore we anticipate less prior therapy than overall in the pivotal phase 3 study. Further, we hypothesize that the combination will result in a high rate of response, allowing enhanced immunologic recovery. Study Design/Methods: This is a phase 2, single arm, trial to evaluate the efficacy of blinatumomab and vincristine sulfate liposomal injection. The study will include up to 35 participants who are ≥18years of age, with Ph-, CD19+ ALL, and are either relapse or refractory to ≥2 prior regimens, have ≥5% blasts in the bone marrow or peripheral blood or persistent extranodal/marrow site or have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. The active study period includes a 3-week screening phase, followed by a treatment period (induction phase and consolidation phase) of up to 58 weeks (6 cycles), a safety follow-up 30 days later and a long-term follow-up period of up to 18 months. The induction phase includes two cycles of blinatumomab and liposomal vincristine. A single cycle is defined as 6 weeks in duration, which includes 4 weeks of continuous intravenous infusion (CIVI) of blinatumomab (initial dose 9 μg/day for first 7 days, then escalated to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by a 2-week treatment-free interval and 3 weekly doses of liposomal vincristine, administered intravenously at 2.25 mg/m 2, with no dose cap (per label),in the outpatient setting over 1 hour. Subjects who achieve at least stable disease within 2 induction cycles may continue to the consolidation phase to receive up to a maximum of 6 cycles under the same treatment schedule. The primary objectives are to evaluate whether the combination will result in a median PFS of ≥1 year, and if the CR/CRi rate is ≥75% following 2 cycles and duration of remission. Secondary outcomes will include evaluation of the rate of Minimal Residual Disease (MRD) and duration, the proportion of patients who are able to progress to allogeneic transplantation, the safety of blinatumomab and liposomal vincristine sulfate in combination and the effect of the combination and response on measures of immune reconstitution. Figure 1 Figure 1. Disclosures Rizzieri: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acrotech: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. Leonard: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Shah: Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy, Other: Expenses; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Precision Biosciences: Consultancy; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy.

Introduction Fertility is a complicated subject, it involves more than one individual, and it has profound psychological and economic implications. Moreover, it is affected by several factors, including age, presence of systemic disease, exposure to environmental toxins, medications, or radiation. Compared to the general population, fertility in patients with malignancy is a more complex topic. Cancer survivors, both male and female, may have reduced fertility due to cancer itself or the treatment received. This includes patients with Myeloproliferative neoplasms (MPN), especially that more patients are diagnosed at younger age and patients had good survival and quality of life. As a result, questions regarding fertility and fatherhood are rising, and the effect of the disease and treatment on male fertility is a big concern. There are limited studies that assessed fatherhood in Philadelphia-negative myeloproliferative neoplasms. Methods This is a single-center, mixed-design study (retrospective + phone interviews) conducted within the National Center for Cancer Care and Research. The aim is to evaluate fertility in the Philadelphia-negative MPN male patients and the effect of treatment received on male fertility and the outcome. Inclusion Criteria: Male patients, adult male patients aged >=18 years old, diagnosed with Philadelphia negative MPN (ET PV MF PMF) According to 2008 2016 WHO criteria and actively receiving treatment including tyrosine kinase inhibitors including (hydroxyurea, interferon, and ruxolitinib ) with the following: -patients with no previous fertility problems will be included in the study. -Patients with no known issues with regards to fertility (fertility is intact) will be included in the study. -Patients who developed fertility issues after diagnosis of Philadelphia negative MPN (ET PV MF PMF), who has been evaluated by an andrologist, and evaluation concluded it is related to treatment. Exclusion criteria: - Patient with Philadelphia positive MPN - Patients not fulfilling inclusion criteria are as follow: -Patient was known to have infertility before the diagnosis of Philadelphia-negative MPN. -Patient with infertility after Diagnosis of Philadelphia negative MPN (ET PV MF PMF): If a Clear underlying cause of infertility is not related to treatment, participants will be excluded from the study.if no evaluation was done for infertility or no clear cause for infertility, the patient will be excluded.The mother has documentation by gynecologist for infertility, or after examining the abortion, stillbirth or IUFD and checking the chromosomal analysis (any mother-related cause, whether endogenous or exogenous)will be excluded. Results: Of 120 patients interviewed, only 19 patients (15.7%) had met the inclusion criteria (Figure 1). The majority of patients had lost follow-up or cannot be contacted, and 29.1% of patients had their families completed by the time of diagnosis. The treatment received includes hydroxyurea, interferon, and ruxolitinib. The mode of delivery was normal vaginal delivery in 68% of the pregnancies. The total number of conceptions was 27; three stillbirths were reported; one intrauterine fetal death and one baby of a twin died in utero (table 1). Discussion and Conclusion: A significant percentage of patients diagnosed with Ph-negative MPN are young; the mean age of patients meeting the inclusion criteria at the time of diagnosis was 35 years. This means that a large number of patients are in the reproductive age group or are sexually active. Having a diagnosis of MPN will put these patients in huge psychological distress due to the unknown outcome about their fertility and sexual life and the fear of possible consequences on their children. The data showed that most MPN male patients on treatment had their offspring born normally with no delivery complications, no reported congenital anomaly or growth retardation, and no report of MPN-related cancers. Though, further studies with a larger sample size are required to fully understand the effect of medications on the outcome of fatherhood Philadelphia negative MPN patients. Nonetheless, a call for attention for better education to patients starting on medications addressing the possible psychological fear or concerns of having an unsatisfactory effect on their fertility/offspring, targeting better acceptance and adherence to treatment. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

7022 Background: Philadelphia-like Acute Lymphoblastic Leukemia (Ph-like ALL) is a high-risk subset of adult ALL. Until recently, there has not been a systematic platform to recognize this entity in clinical practice. Furthermore, data regarding the role of allogeneic hematopoietic cell transplantation (allo-HCT) is lacking. We conducted this study to identify patients with Ph-like ALL and describe their outcomes in comparison to Ph+ and Ph- ALL with emphasis on the role of allo-HCT. Methods: To identify cases of Ph-like ALL, available diagnostic cytogenetic pellets for patients in the Mayo Clinic ALL cohort (N=365) were tested using a targeted fluorescence in situ hybridization (FISH) panel developed by the Mayo Clinic Genomics Laboratory and includes probes to detect Ph-like-specific rearrangements (i.e., ABL1, ABL2, PDGFRB, JAK2 and CRLF2). Results: Thirty-three (9%) patients with Ph-like ALL were identified, the remaining patients were classified as Ph+ (N=132, 36%) or Ph- ALL (N=200, 55%). Patients with Ph-like ALL were younger (Median: 39 vs. 50 vs. 49 years, P=.01), had higher WBC (Median: 27.9 vs. 21.5 vs. 4.5 x109/L, P

e19038 Background: Sepsis is associated with increased mortality in patients with hematologic malignancies, especially in those receiving cytotoxic chemotherapy. The development of new therapies also increases the risk of infections in Philadelphia negative myeloproliferative neoplasms (MPN). However, the clinical implications and costs of sepsis in patients with polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF) have not been reported at a national level. Therefore, we aimed to determine the outcomes, hospitalization costs, and predictors of mortality in patients with MPN and sepsis. Methods: We retrieved adult patients with MPN from the Nationwide Inpatient Sample database from 2016-2018. We used the ICD-10 codes to identify and compare patients with and without sepsis. The main outcomes were hospital mortality and predictors of mortality. We computed the chi-squared test and the Mann-Whitney U-test. Mortality predictors are estimated using multivariate logistic regression and logistic fixed-effect methods to control for admission cohort and hospital time invariant characteristics. All analyses were performed using Stata Statistical Software version 14 (StataCorp, College Station, TX). Results: A total of 86,723 patients with MPN were identified. The majority of them were white (66.9%), female (54.3%), with a median age of 62 (IQR 47-76). The most common MPN was ET (84.3%), followed by PV (14.2%). Sepsis was diagnosed in 16,146 (18.6%) of the MPN patients. There was a significantly higher mortality in the sepsis group vs. the non-sepsis group (7.4% vs. 1.8%; p < 0.001), longer LOS (8 vs. 4 days; p < 0.001), and higher median hospitalization cost (US$74,128 vs. US$39,987; p < 0.001). In the multivariable analysis, sepsis was associated with higher mortality (OR: 4.74; CI 95%: 4.33-5.18; p < 0.001). Among the MPN, those with PMF and sepsis had a higher risk of death (OR: 2.21; CI 95%: 1.72-2.82; p < 0.001). Other significant variables associated with mortality were age > 65 (OR: 2.51; CI 95%: 2.14-2.95; p < 0.001), concomitant chronic heart failure (CHF) (OR: 1.57; CI 95%: 1.39-1.77; p < 0.001), chronic kidney disease (CKD) (OR: 1.22; CI 95%: 1.10-1.35; p < 0.001), and weight loss (OR: 2.12; CI 95%: 1.79-2.51; p < 0.001). There was no significant association with sex and race/ethinicity. Conclusions: On patients with MPN, sepsis was associated with higher mortality, hospitalization costs, and LOS. Additionally, those with increased age, CHF, CKD, weight loss, and PMF were also at increased risk of death. There should be more emphasis on assessing the risk of sepsis on MPN to prevent worse outcomes and higher costs. Further studies should focus on identifying the specific causes of sepsis in MPN and promoting early recognition.