Ruxolitinib treatment in myelofibrosis and polycythemia vera causes suboptimal humoral immune response following standard and booster vaccination with BNT162b2 mRNA COVID-19 vaccine.

Patients affected by myelofibrosis (MF) or polycythemia vera (PV) and treated with ruxolitinib are at high risk for severe coronavirus disease 2019. Now a vaccine against the virus SARS-CoV-2, which is responsible for this disease, is available. However, sensitivity to vaccines is usually lower in these patients. Moreover, fragile patients were not included in large trials investigating the efficacy of vaccines. Thus, little is known about the efficacy of this approach in this group of patients. In this prospective single-center study, we evaluated 43 patients (30 MF patients and 13 with PV) receiving ruxolitinib as a treatment for their myeloproliferative disease. We measured anti-spike and anti-nucleocapsid IgG against SARS-CoV2 15-30 days after the second and the third BNT162b2 mRNA vaccine booster dose. Patients receiving ruxolitinib showed an impaired antibody response to complete vaccination (2 doses), as 32.5% of patients did not develop any response. After the third booster dose with Comirnaty, results slightly improved, as 80% of these patients produced antibodies above the threshold positivity. However, the quantity of produced antibodies was well below that reached than those reported for healthy individuals. PV patients elicited a better response than patients affected by MF. Thus, different strategies should be considered for this high-risk group of patients.

Outcomes of SARS-CoV-2 infection in Ph-neg chronic myeloproliferative neoplasms: results from the EPICOVIDEHA registry.

Background: Patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) typically incur high rates of infections and both drugs and comorbidities may modulate infection risk. Objectives: The present study aims to assess the effect of immunosuppressive agents on clinical outcomes of MPN patients affected by the coronavirus disease 2019 (COVID-19). Design: This is an observational study. Methods: We specifically searched and analyzed MPN patients collected by EPICOVIDEHA online registry, which includes individuals with hematological malignancies diagnosed with COVID-19 since February 2020. Results: Overall, 398 patients with MPN were observed for a median of 76 days [interquartile range (IQR): 19-197] after detection of SARS-CoV2 infection. Median age was 69 years (IQR: 58-77) and 183 individuals (46%) had myelofibrosis (MF). Overall, 121 patients (30%) of the whole cohort received immunosuppressive therapies including steroids, immunomodulatory drugs, or JAK inhibitors. Hospitalization and consecutive admission to intensive care unit was required in 216 (54%) and 53 patients (13%), respectively. Risk factors for hospital admission were identified by multivariable logistic regression and include exposure to immunosuppressive therapies [odds ratio (OR): 2.186; 95% confidence interval (CI): 1.357-3.519], age ⩾70 years, and comorbidities. The fatality rate was 22% overall and the risk of death was independently increased by age ⩾70 years [hazard ratio (HR): 2.191; 95% CI: 1.363-3.521], previous comorbidities, and exposure to immunosuppressive therapies before the infection (HR: 2.143; 95% CI: 1.363-3.521). Conclusion: COVID-19 infection led to a particularly dismal outcome in MPN patients receiving immunosuppressive agents or reporting multiple comorbidities. Therefore, specific preventive strategies need to be tailored for such individuals. Plain language summary: EPICOVIDEHA registry reports inferior outcomes of COVID-19 in patients with Philadelphia-negative chronic myeloproliferative neoplasms receiving immunosuppressive therapies. Patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) incur high rates of infections during the course of their disease.The present study was aimed at assessing which patient characteristics predicted a worse outcome of SARS-COV-2 infection in individuals with MPN.To pursue this objective, the researchers analyzed the data collected by EPICOVIDEHA, an international online registry, which includes individuals with hematological malignancies diagnosed with COVID-19 since February 2020.The database provided clinical data of 398 patients with MPN incurring COVID-19:Patients were mostly elderly (median age was 69 years);Forty-six percent of them were affected by myelofibrosis, which is the most severe MPN;Moreover, 32% were receiving immunosuppressive therapies (JAK inhibitors, such as ruxolitinib, steroids, or immunomodulatory IMID drugs, such as thalidomide) before COVID-19.Hospitalization was required in 54% of the patients, and the risk of being hospitalized for severe COVID-19 was independently predicted byOlder age;Comorbidities;Exposure to immunosuppressive therapies.Overall, 22% of MPN patients deceased soon after COVID-19 and the risk of death was independently increased over twofold byOlder age;Comorbidities;Exposure to immunosuppressive therapies before the infection.In conclusion, COVID-19 infection led to a particularly dismal outcome in MPN patients receiving immunosuppressive agents, including JAK inhibitors, or reporting multiple comorbidities. Therefore, specific preventive strategies need to be tailored for such individuals.

SIGNIFICANT INCREASE IN NEWLY DIAGNOSED HEMATOLOGICAL MALIGNANCIES FOLLOWING LOCKDOWN EASE IN CROATIA

Background: Special epidemiological measures aimed at suppressing SARS-CoV-2 outbreak were introduced in Croatia in March 2020, thus reducing regular work capacity in hematological outpatient and inpatient care. In our hospital, this included relocating the entire Hematology Department to a remote location, reduction of hospital beds in the Hematology Inpatient Unit by approximately 60%, Day Clinic operating at a reduced capacity, and a complete suspension of Hematology Polyclinic during first lockdown. Aims: Herein we report our observation of unusually high incidence of newly diagnosed malignant hematological diseases following first lockdown ease in May/June 2020. Methods: We collected data of patients hospitalized in Hematology Department for 4 periods: May 1 - June 15, 2020 for the test arm, and the same calendar period during previous 3 years (May 1 - June 15 of each of the calendar years 2017, 2018 and 2019), for the control arm. The rationale for such design was that a phenomenon of re-establishing regular work capacity, following temporary restriction, was only observed in the test arm. The study included patients of both sexes older than 18 who were diagnosed with either: Hodgkin lymphoma (C81.0 -C81.9 according to the 10th ICD Revision), different types of non-Hodgkin lymphoma (subsections C82.0 - C83.9 and C85.1-C85), as well as multiple myeloma and malignant plasma cell neoplasms (C90.0 - C90.3). Excluded from our study were diagnoses of T/NK cell lymphoma (C84.0- C84.9;C86.0 - C86.6), malignant immunoproliferative diseases (C88.0 - C88.9), leukemias and other specified malignant neoplasms of lymphatic, hematopoietic and related tissues (C91.0 - C96.9) as well as polycythemia vera and non-malignant hematological diseases (D45 and D50 - D89 in ICD-10). Results: In years 2017-2019, similar numbers of patients were diagnosed with a hematological malignancy in our Department (n=4 for 2017, n=8 for 2018, n=4 for 2019) whereas in 2020, a total of 28 patients were diagnosed during the same calendar period (Hodgkin lymphoma: n=5, NHL n=12, multiple myeloma n=7, CLL/SLL n=4). Statistical analysis revealed a significant increase (p ≤0.05) of newly diagnosed hematological malignancies in May and first half of June 2020, when compared to the same calendar periods during previous three years. Further statistical analysis has not established significant differences in outcome (difference in EFS statistically insignificant, p=0.86), as we had expected in the short follow-up period. (Table Presented) Summary/Conclusion: Facilitating treatment of patients affected by the novel coronavirus represented a welcome change in healthcare system in early 2020, in our country and abroad. At the same time, however, the reduction of tertiary health care capacity aimed at population with hematological diseases presented serious risks for successful diagnosis and treatment outcome, a subject that gained wide attention in literature. It has been reported that, also due to psychological reasons, a fraction of patients delayed seeking medical attention after noticing symptoms. In our study we aimed at analyzing the effects of lockdown ease on the number of newly diagnosed hematological malignancies. We were able to demonstrate the effect of pandemic-related measures on detecting new disease cases. It remains to be clarified if a sudden surge in new diagnoses was due to delayed first physician's appointments/hospitalizations, as is suggested by available literature. The results of our study suggest that longer follow-up period will be required in order to clarify the effects of possible late diagnoses on the treatment outcome.

Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant in Patients with Philadelphia-Negative Myeloproliferative Neoplasm: A Single Center Experience.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral agent responsible for the coronavirus disease of 2019. The disease is primarily a respiratory illness; however, multisystem involvement is not uncommon. The infection is reported to be more severe in patients with multiple comorbidities and immunocompromised patients. Patients with hematological malignancies are immunocompromised and prone to develop severe SARS-CoV-2 infection. The SARS-CoV-2 had developed several mutations that resulted in different strains with different virulence and different degree of protection by vaccination or prior infection. The Omicron variant is reported to cause mild illness; however, the effect on patients with hematological malignancies like myeloproliferative neoplasms (MPNs) is not clear. We present patients with MPNs who had infection with the Omicron variant of the SARS-CoV-2 and their outcomes. METHODS: Retrospective data from the National Center for Cancer Care and Research records from December 20, 2021, to January 30, 2022. Participants were adults over the age of 18 years with Omicron infection who had been diagnosed with Philadelphia-negative MPNs, essential thrombocythemia, polycythemia vera (PV), and primary myelofibrosis according to the 2008/2016 WHO classification for MPN. RESULTS: Twenty-two patients with Philadelphia-negative MPN had Omicron infection. All patients had a mild disease according to the WHO classification of COVID-19 severity. Most of the patients had medical comorbidities, with hypertension being the most common comorbidity. However, only one patient with PV required hospitalization. DISCUSSION/CONCLUSIONS: In patients with Philadelphia-negative MPN, the Omicron variant of SARS-CoV-2 usually results in mild infection.

Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders.

The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.

Pegylated Interferon is an effective and well-tolerated cytroreductive agent in patients with myeloproliferative neoplasms aged over 60 years

Pegylated Interferon (PegIFN) is the recommended first-line cytoreductive therapy in patients aged <40 years with essential thrombocythaemia (ET) or polycythaemia vera (PV). However, its use in patients >60 years is often limited due to concerns about tolerability. In this study, we evaluate the efficacy and tolerability of PegIFN in patients >60 years at University College London Hospitals (UCLH). Using electronic medical records, we identified patients with ET, PV or myelofibrosis at UCLH who commenced treatment with PegIFN between 2010 and 2020 and were aged >60 years on starting therapy. Data were collected until April 2021 to allow a minimum of 1-year follow-up. Complete Haematological responses were defined as per standard European Leukaemia Net criteria. Adverse events (AE) were graded 1-5 according to Common Terminology Criteria for Adverse Events (CTCAE). Thrombosis risk was graded according to IPSET criteria for ET patients. Patients with PV were classed as high risk if they were aged >65 or had a previous history of thrombosis. Eighteen patients were included in the study. The median age was 75.1 years (range 63-91), 61% were female. Ten out of 18 (56%) had a diagnosis of ET, seven out of 18 (39%) of PV and 1/18 (6%) of post-ET myelofibrosis. Fifteen out of 18 (83%) were positive for JAK2 V617F, and two out of 18 (17%) were positive for CALR mutation. Ten out of 18 (56%) had significant cardiovascular co-morbidities at diagnosis. Five out of 18 (28%) had arterial or venous thromboembolic disease at diagnosis. Sixteen out of 18 (89%) were high-risk for thromboembolic events at diagnosis. Seventeen (94%) patients had PegIFN as a second-or thirdline agent. Of these, 15 out of 17 had received hydroxycarbamide (HU) as first-line therapy;two out of 17 had interferon alpha. PegIFN was started at a median age of 70 years (range 50-86) and continued for 5.7 years (range 2-13). Twelve out of 18 (67%) patients achieved complete remission (CR) on PegIFN monotherapy;1 out of 18 (6%) achieved CR on PegIFN and HU combination therapy, and the remaining 5 out of 18 (28%) achieved a partial remission (PR). The median time to CR was 5 months (range 1-40 months). Ten out of 18 (56%) had grade 1-2 AEs including skin rashes, cytopenia and fatigue. Three out of 18 (17%) developed a major thromboembolic event while on treatment (brachial artery embolism, transient ischaemic attack and a non-ST elevation myocardial infarction). Of these, two out of three failed to achieve a CR on PegIFN and required ongoing venesection. The third had suboptimal response due to dose escalation limited by grade 3 neutropenia. Thirteen patients (72%) remained on pegIFN at the end of the study period. Of those who discontinued, three out of five stopped due to cytopenias, one out of five died during the study period of Covid-19 infection and one out of five transformed to myelodysplastic syndrome. In this study, we present a group of patients who were at high risk for thrombosis due to their age and cardiovascular risk factors. The majority of AEs documented were grade 1-2, with only three out of 18 (17%) patients discontinuing due to AEs. The rate of CR 72% similar to that quoted in imminent studies including MPN-RC (Knudsen et al, 2018) and DALIAH trials (Mascarenhas et al, 2018), which recruited larger numbers of youngers ET and PV patients on PegIFN. Over 20% of MPN patients develop resistance or intolerance to HU (Sever et al, 2014);therefore, there is a need for alternative cytoreductive agents. Our study demonstrates PegIFN to be effective and well-tolerated for use in patients >60 years and is an excellent cytoreductive option in this cohort.

Patient experience of MPN/CML clinic communication during the covid pandemic

One hundred and sixty-five questionnaires were posted to patients who were regularly seen in the nurse-led haematology out-patient clinic. This is an established service that has been operating for approximately 14 years. These patients had all been seen prior to the Covid pandemic, and then during this period. The questionnaire was sent out in August 2021. These patients are treated for either chronic myeloid leukaemia (CML), myeloproliferative neoplasms (MPN) or non-primary polycythaemia/thrombocythaemia. The MPN patients were diagnosed with either essential thrombocythaemia, polycythaemia vera or myelofibrosis. One hundred and thirty-three questionnaires were returned by patients. This is an 81% response. Before the pandemic, patients were mainly seen face to face, with a small number by telephone or email. Patients were happy with this at the time. From March 2020, at the start of the Covid pandemic appointments were suddenly changed to telephone (96%), with a small number by email (2%) or face to face (2%). 96% of the telephone follow-up patients were happy with this method, as were all of the email follow-ups. Patients were asked how they would prefer to be communicated with in the future. The majority of patients would prefer a face to face or telephone appointment. Text, email and video consultations were generally unpopular. People found it easier to communicate face to face, and preferred seeing a healthcare professional this way. A recurring theme was that telephone appointments were acceptable, on the understanding that if there was a change in their condition, a face-to-face appointment could be booked. Patients who worked were very supportive of telephone appointments. People generally felt 'safer' having their appointments remotely, and their blood tests carried out nearer to where they live, instead of at the hospital. Very few patients wanted to have text, video calls or email in the future-they preferred the personal contact, and many did not have the necessary equipment. Issues of long waits in the Pathology department and the difficulty of car-parking at the hospital prepandemic were mentioned by patients. Patients were very happy with the nurse-led haematology clinics. They liked the continuity, and having a point of contact. Over the time of the pandemic, processes were changed, with more use of electronic prescribing, different ways of documenting discussions, and non-paper requesting of blood tests. Together with increased use of email and the telephone, this has meant that services have been continued despite staff being isolated at home. There are increasing numbers of nurse-led clinics in Haematology, and these have been shown to be cost-effective and safe, providing holistic care and continuity (Thompson et al 2012). As services are redesigned, it is important to consider the views of the patients who are users of the clinics. The Covid pandemic has forced changes to healthcare services, and there may be long-term effects on the way that services are delivered in Haematology for patients with chronic conditions. Resilience needs to be built into the way that patients are monitored in the future, to ensure that they can continue without interruption, both during and post pandemic.

Cerebral venous thrombosis and myeloproliferative neoplasms: A three-center study of 74 consecutive cases

Background The recent association of cerebral venous thrombosis (CVT) with COVID-19 vaccinations (JAMA;2021;325, N Engl J Med 2021;384) motivated the current review of CVT and MPN. Our objectives were, i) provide an estimation of the incidence of CVT in the context of MPN, followed by a description of clinical phenotype and therapeutic strategies, ii) determine long term outlook in terms of recurrent thromboses, hemorrhage, and survival, iii) identify salient features which distinguish MPN associated from COVID vaccine- related CVT. Methods 74 consecutive MPN patients with CVT that underwent evaluation at the Mayo Clinic, Rochester MN, USA (n=36), Catholic University, Rome, Italy, (n=23), and University of Florence, Italy (n=15) between 1991 and 2021 were included. The cohort from a previously published multi-center study that included 42 MPN cases with CVT, which were not included in the current study, was used for comparison of observations. Diagnosis of CVT was established with computed tomography or magnetic resonance imaging with venography. Results Patient characteristics at time of CVT Among 74 patients with CVT and MPN (median age 44 years, range 15-85;61% females);disease-specific frequencies were 1.3% (39/2,893), 1.2% (21/1,811) and 0.2% (3/1,888) for essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), respectively. CVT occurred prior to (n=20, 27%, median time to MPN diagnosis 16.5 months), at (n=32, 44%) or after (n=21, 29%, median time to CVT 26 months) MPN diagnosis. 72% of patients presented with headaches, 22% visual changes, 12% nausea/vomiting, 8% neurological deficits, and 6% seizures. Transverse (51%), sagittal (43%) and sigmoid (35%) sinuses were involved with central nervous system hemorrhage in 10 (14%) patients. MPN phenotype included ET (n=39, 53%), PV (n=21, 28%), pre-fibrotic MF (n=6, 8%), MPN-unclassified (n=4, 5%), PMF (n=3, 4%) and post-PV MF (n=1, 1%). Driver mutation testing was performed in 65 patients: 91% harbored JAK2V617F, 3% CALR type 1, 2% MPL, 5% triple negative;moreover, JAK2V617F was mutated in 27/33 (82%) ET patients. An underlying thrombophilia was identified in 19 (31%) cases. No patient had thrombocytopenia. (Table 1). Notably, one patient received the Ad26.COV2.S vaccine, five days prior to presenting with CVT, not associated with thrombosis in other sites, thrombocytopenia or platelet factor 4 antibodies. A history of thrombosis was documented in 10 (14%) patients with three splanchnic venous events. These observations were similar to those noted in our comparative group from a previously published report that included 42 cases;(ET (n=25, 60%), PV (n=11, 26%), PMF (n=5, 12%);median age 51 years, range 16-84;55% females;81% JAK2V617F mutated). Prior thrombosis occurred in 8(19%) patients with four splanchnic venous events. Treatment for CVT included systemic anticoagulation alone in 27 (36%) patients or in conjunction with aspirin (n=24, 32%), cytoreductive therapy (n=14, 19%), or both aspirin and cytoreduction (n=9, 12%). 5/21 (24%) patients with CVT post MPN diagnosis, were on anticoagulation at the time of CVT. 1. Outcome following CVT At a median follow-up of 5.1 years (range;0.1-28.6), recurrent CVT was documented in 3 (4%) patients;incidence rates for other arterial and venous thromboses and hemorrhage were 11% (2 per 100 patient-years), 9% (1.9 per 100 patient-years) and 14% (3 per 100 patient-years), respectively. 3 of 7 (43%) venous thromboses were splanchnic events. Antithrombotic therapy was ongoing in 53% and 80% of patients with thrombotic recurrences and hemorrhage, respectively. A higher incidence of venous thrombosis was noted in the aforementioned previously published cohort (12 (29%) vs 7 (9%), p=0.01);with 5/12 (42%) splanchnic events. Incidence rates for arterial thrombosis and major hemorrhage were similar. Fibrotic and leukemic transformation occurred in 5 (8%) and 1(1%) patient, respectively, with five (7%) deaths unrelated to CVT. Conclusions The current study highlights close association of CVT w th JAK2V617F, younger age, and female gender. Clinical features distinguishing COVID vaccine-related from MPN-associated CVT include lower likelihood of concomitant non-CVT venous thromboses with the latter;moreover, the absence of thrombocytopenia resulted in a lower rate of intracerebral hemorrhage in MPN cases;as a result, MPN-CVT was not fatal. (Figure Presented).

Should be a Third Dose of BNT162b2 mRNA COVID-19-Vaccine Administered in Patients with Myelofibrosis Under Ruxolitinib?

[Formula presented] Introduction. Patients with Myelofibrosis (MF) are considered fragile and thus eligible in Italy for COVID-19 BNT162b2 mRNA vaccination. According to the International Prognostic Scoring System (IPSS), patients with intermediate and high MF, may receive clinical benefits from ruxolitinib, the first approved JAK1/JAK2 inhibitor. Given the potent anti-inflammatory properties of ruxolitinib against immunocompetent cells, we previously reported a lower but non-statistically absolute IgG anti-Spike humoral response in vaccinated MF patients treated with ruxolitinib. In the present report we extended the cohort of MF patients. Methods. All MF patients received 2 injections of 30 ug per dose of BNT162b2 mRNA COVID-19 vaccine 3 weeks apart, according to the standard protocol. After injection, mild pain at the injection site was frequently reported. No serious adverse events were registered. The serum level of IgG anti-Spike glycoprotein was tested after a median time of 45 days (range 40-60) from the second vaccine dose, using the approved anti-SARS-CoV-2 IgG CLIA (LIAISON® SARS-CoV-2 TrimericS IgG assay, Diasorin, Saluggia, Italy). An Arbitrary Units per milliliter (AU/mL) ratio of <12.0 was considered to be negative, 12.0-15.0 AU/mL to be borderline and >15 AU/mL to be positive. A conversion of AU/mL to binding antibody units (BAU/mL) as recommended by the World Health Organization (WHO) guidelines was achieved considering the following equation: BAU/mL = 2.6*AU/mL. Results. Overall, 30 MF patients (median age 65 years, range 48-83) were vaccinated. A diagnosis of primary MF was reported in 21 cases (70%), post essential thrombocythemia-MF in 6 (20%) patients and post polycythemia vera-MF in 3 (10%) patients;23 out of 30 patients (76.6%) were positive for the JAK2V617F, 5 (16.6%) for CALR mutation, 1 (3.3%) for MPL mutation and 1 patient (3.3%) resulted triple negative. Splenomegaly was observed in 14 patients (46%) and 19 (63.3%) reported comorbidities. Nineteen patients (63.3%) were classified as DIPSS low or intermediate-1 risk, and 11 (36.6%) as intermediate-2 or high risk. Fifteen patients (50%) were receiving ruxolitinib, at a median total dose of 20 mg/die (range 20-40 mg) and the remaining 15 patients other treatments (8 patients hydroxyurea and 7 only supportive therapy). None of the patients reported COVID-19 infection neither previous nor subsequently to vaccination. Overall, a positive immune response against COVID-19 was observed in 8 out of 15 patients (53.3%) in the ruxolitinib group, in comparison with 13 out 15 patients (86.6%) in the other treatment group (p=0,046). The absolute IgG anti-Spike value was lower in the ruxolitinib group (median 35.2±49.81) in comparison with the other group (median 226.1±163.9;p=<0.001), Figure 1. In univariate analysis, only ruxolitinib treatment was found associated with a lower humoral immune response to the vaccine. Conclusions. MF patients under ruxolitinib achieved a lower humoral immune response in comparison with MF patients who underwent other treatments. No COVID-19 infection was observed in both groups after vaccination, after a median follow up of 3 months since the second dose. Whether patients with a potential insufficient humoral response to vaccine will benefit from a third dose of BNT162b2 mRNA COVID-19 vaccine is a matter of further investigation. Our preliminary data need to be confirmed in larger cohort of MF patients. [Formula presented] Disclosures: Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation;Janssen: Consultancy, Honoraria.

COVID-19 Infection in Vaccinated Adult Patients with Hematological Malignancies. Preliminary Results from Epicovideha (Epidemiology of COVID-19 infection in patients with hematological malignancies: A European Haematology Association Survey)

Introduction Coronavirus disease 2019 (COVID-19) is a life-threatening condition of high relevance for co-morbid patients, such as those with baseline hematological malignancies (HM). One year after the diagnosis of the first COVID-19 case, at the end of 2020, the first vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were administered to the population, starting with individuals at highest risk of infection. EPICOVIDEHA aims to describe the epidemiology, vaccination strategies and mortality rates from HM patients at risk. Methods We collected clinical and epidemiological data from patients with laboratory-based diagnosis of SARS-CoV-2 infection after partial or complete vaccination. The study was sponsored by the European Hematology Association - Infectious Diseases Working Party. Patients were registered in the EPICOVIDEHA online survey between January 1, 2021 and July 31, 2021 from Europe and United States. Data captured included underlying conditions prior to SARS-CoV-2, HM status and management prior to SARS-CoV-2, SARS-CoV-2 vaccination and infection details and mortality. The survey will continue until December 31, 2021. Results Overall, 40 patients have been so far registered, 24 male and 16 females, the vast majority of them aged over 50 years (N=38, 95%). Three quarters of patients were affected by lymphoproliferative malignancies (chronic lymphoid leukemia [CLL] N=14 and non-Hodgkin lymphoma [NHL] and multiple myeloma [MM] N=8, each), followed by myelodysplastic syndrome (MDS) (N=4), acute myeloid leukemia (AML) (N=2) and others (chronic myeloid leukemia [CML], acute lymphoid leukemia [ALL], polycythemia vera [PV] and aggressive mastocytosis one of each). Thirty-one patients (77.5%) were receiving active treatment for underlying HM at the time of SARS-CoV-2 infection, with 16 of them being on chemotherapy in the month prior to infection. All patients were vaccinated with a median time from vaccine to SARS-CoV-2 infection of 45.5 days (IRQ 19-67.5). Twenty-nine patients received a mRNA vaccine (BioNTech/Pfizer N=28, Moderna COVE N=1), whereas the remaining 11 an inactivated vaccine (Sinovac CoronaVac N=6) and vector-based vaccine (AstraZeneca Oxford N=5). Twenty-three patients were completely vaccinated, of which 22 (97.5%) patients were immunized (a minimum of 15 days following second dose). On the contrary, among 17 patients partially vaccinated, none was immunized. In 9 cases, viral genomes were analyzed (English variant N=7, South Africa variant N=1, Indian variant N=1). Overall, 25/40 patients presented with a severe/critical infection (62.5%), 13 of which (52%) were fully vaccinated and immunized, whereas only 15 (37.5%) were asymptomatic or mildly symptomatic. Twenty-seven (92.5%) patients were admitted to hospital, 5/27 (18.5%) to ICU, all requiring mechanical ventilation. After a follow-up of 30 day from SARS-CoV-2 infection, 8 patients died (20%), with 7/8 deaths (87.5%) attributable to SARS-CoV-2. There was no difference in overall survival between those patients that received 2 doses of vaccine or 1 dose (figure 1a), as well as no difference being observed between patients with and without lymphoproliferative malignancies (figure 1b), patients that receiving/not receiving active treatment in the last month (figure 1c), or the type of vaccine injected (figure 1d). Conclusions Our survey, involving over 150 Hematology Departments around the world, provides some preliminary insights. The majority of patients who do not respond to vaccination are patients with lymphoproliferative diseases, as can also be observed for other types of vaccination (e.g., flu-vaccination). Dramatically the mortality observed in all patients, although lower than that observed in the pre-vaccination period which in our experience was around 31%, still remains high (20%). Recruitment to this survey continues, and we hope that with larger numbers of cases, more definitive conclusions can be drawn to develop strategies to keep these complex patients safe. [Formula presented] Disclosures: Lop z-Garcia: Celgene: Other: Speaker Honoraria;Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants;Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding;Roche: Other: Speaker Honoraria, Travel and accommodation grants;Novonordisk: Other: Speaker Honoraria;Fresenius: Other: Speaker Honoraria. Glenthoej: Novo Nordisk: Honoraria;Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees;Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Alexion: Research Funding. Mikulska: Biotest: Speakers Bureau;Janssen: Speakers Bureau;MSD: Speakers Bureau;Gilead: Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Busca: Gilead Sciences: Other: Lecture Honoraria;Merck: Other: Lecture Honoraria;Pfizer Pharmaceuticals: Other: Lecture Honoraria;Basilea: Other: Lecture Honoraria;Biotest: Other: Lecture Honoraria;Jazz Pharmaceuticals: Other: Lecture Honoraria;Takeda: Membership on an entity's Board of Directors or advisory committees. Corradini: KiowaKirin;Incyte;Daiichi Sankyo;Janssen;F. Hoffman-La Roche;Kite;Servier: Consultancy;AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria;AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy;Amgen;Takeda;AbbVie: Consultancy, Honoraria, Other: Travel and accommodations;Novartis;Gilead;Celgene: Consultancy, Other: Travel and accommodations;BMS: Other: Travel and accommodation;Sanofi: Consultancy, Honoraria;Incyte: Consultancy;Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Hoenigl: Gilead, Pfizer, Astellas, Scynexis, and NIH: Research Funding. Klimko: Gilead Science, MSD, Pfizer: Membership on an entity's Board of Directors or advisory committees;Gilead Sciences, MSD, Pfizer Pharmaceuticals, and Astellas Pharma: Speakers Bureau. Pagliuca: Gentium/Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Gilead, Pfizer, and MSD: Research Funding. Passamonti: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AbbVie: Speakers Bureau;BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Köhler: German Federal Ministry of Research and Education and the State of North Rhine-Westphalia, Germany: Other: Support;Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany: Other: Non-financial grants;Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, MSD Sharp & Dohme GmbH, Noxxon N.V., and University Hospital, LMU Munich: Consultancy, Honoraria. Cornely: Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis: Other: Grants or Contracts. Pagano: Gilead Science, MSD, Pfizer, Basilea, Janssen, Novartis, Jazz Pharmaceutical, Cidara: Membership on an entity's Board of Directors or advisory committees;Gilead Sciences, MSD, Pfizer Pharmaceuticals, Astellas Pharma: Speakers Bureau;Menarini: Consultancy.

Multi-Arm Trial of Inflammatory Signal Inhibitors (MATIS) for Hospitalised Patients with Mild or Moderate COVID-19 Pneumonia: A Structured Summary of a Study Protocol for a Randomised Controlled Trial

Introduction: Severe COVID-19 pneumonia is characterised by respiratory and multi-organ failure in the context of marked systemic inflammation. This hyperinflammatory syndrome is reflected by the elevation of several inflammatory molecules, such as C-reactive protein (CRP), ferritin, IL-6, troponin, and D-dimer. In a subset of patients, early intervention with signal inhibitors may treat the Covid-19 hyperinflammatory syndrome before the development of acute lung injury and organ failure. We present a summary of a study protocol for a randomised controlled, multi-arm trial with two novel inflammatory signal inhibitors;Ruxolitinib (RUX) and Fostamatinib (FOS) for the treatment of Covid-19 pneumonia. RUX is an oral Janus Associated Kinase (JAK1/JAK2) inhibitor approved for the treatment of splenomegaly, myelofibrosis and polycythaemia vera. Inhibition of STAT3 downregulates IL-6 and IL-23, which are important for the inflammatory effects of Th17 cells. Further, JAK2 inhibition has been shown to reduce levels of TNFa and CRP, as well as reducing viral cellular entry and assembly. FOS is an oral spleen tyrosine kinase (SYK) inhibitor approved for the treatment of chronic immune thrombocytopenia. Studies of severe acute respiratory distress syndrome (ARDS) suggest that the pathogenesis relies on a series of SYK events leading to cytokine and chemokine release. FOS acts by inhibiting SYK activity, blocking the production and release of cytokines induced via C-lectin receptors and Fc receptor activation, ameliorating the cytokine storm which precedes ARDS. Primary Objective: The primary objective of MATIS is to determine the efficacy of RUX or FOS compared to standard of care (SOC) to reduce the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia at 14 days from baseline. Secondary objectives at 7, 14 and 28 days: - Determine the efficacy of RUX or FOS to reduce mortality - Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO - Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation - Determine the efficacy of RUX or FOS to reduce the proportion of patients suffering significant oxygen desaturation - Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy - Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism COVID-19 pneumonia - Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a modified WHO Ordinal Scale] - Determine the efficacy of RUX or FOS to reduce the level of inflammatory biomarkers - Determine the efficacy of RUX or FOS to reduce the duration of hospital admission - Evaluate the safety of RUX and FOS for COVID-19 pneumonia Study Design: This is a multi-arm, two-stage, open-label, randomised (1:1:1) controlled trial. Participants will be recruited during hospitalisation for COVID-19 in multiple centres in the UK. Eligible participants (table 1) are randomised to one of the three interventions (RUX, FOS, SOC) by a central web-based randomisation service. This uses randomisation sequences with random block sizes, stratified by age (<65 and ≥65 years) and site. The treatment duration is 14 days from baseline. Patients receiving RUX will be administered 10mg BD for Day 1-7 and 5mg BD for Day 8-14. FOS will be administered as 150mg BD day 1-7 and 100mg BD day 8-14. Participants receive follow up assessments on days 7, 14 and 28 after the first dose. Outcomes: Primary endpoints will be assessed with a pairwise comparison (FOS vs SOC and RUX vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a modified WHO COVID-19 Ordinal Score 5, comprising the following indicators of disease severity: - Death - Requirement for invasive ventilation - Requirement for non-invasive ventilation including CPAP or high flow oxygen - O2 saturation < 90% on 60% inspired oxygen Samples size: In stage 1 of this multi-arm study, 171 parti ipants will be randomised (57 per arm). Following an interim analysis, if either intervention shows a signal of efficacy, stage 2 will recruit a further 95 participants per arm (Fig 1). Trial Status: Recruitment is ongoing and commenced 2nd October 2020. Currently 127 patients are recruited and stage 1 is projected to be completed by 1st September 2021. The full protocol can be accessed via the trial's website. [Formula presented] Disclosures: Milojkovic: Novartis: Honoraria, Speakers Bureau;Incyte: Honoraria, Speakers Bureau;Bristol-Myers Squibb: Honoraria, Speakers Bureau;Pfizer: Honoraria, Speakers Bureau. Cooper: Principia and Sanofi: Consultancy;Sanofi and Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations expenses. OffLabel Disclosure: Fostamatanib - is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase (SYK). In the context of treating COVID-19, Fostamatanib acts by inhibiting SYK activist, blocking the production and release of cytokines induced via C-lectin receptors and Fc receptor activation, ameliorating the cytokine storm which precedes ARDS. Studies of severe acute respiratory syndrome induced by coronavirus, suggest that pathogenesis relies on a series of SYK events. SYK medicates ctuokine and chemokine release, induced by the activation of C-lectin receptors and immunoglobulin Fc receptors, resulting in neutrophil and monocyte lung ingress, sequential activation of neutrophil extracellular traps and activation of lung epithelium and multiple myeloid cell. This is followed by inflammation and tissue destruction that contribute to ARDS. Ruxolitinib - A JAK1/JAK2 inhibitor. JAK and STAT molecules are proteins that trance extracellular stimulation into intracellular signalling, leading to expression of host inflammatory cytokines and a variety of immune cells. In the context of MATIS, we use low dose ruxolitinib to treat COVID-19 by targeting key signalling pathways implicated in the hyper-inflammatory response of patients with COVID-19 infection. The mechanisms of Ruxolitinib to act in COVID-19 is through inhibition of STAT3 activation, down regulating IL-6 and IL-23, signalling important for the inflammatory effects of Th17 cells. Furthermore it leads to reductions of TNFa and CRP.

Autoantibodies Against Type I IFNs in Patients with Ph-Negative Myeloproliferative Neoplasms

Background. The classic Ph-negative myeloproliferative neoplasms (MPN) are a group of clonal haematopoietic disorders, including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), whose shared and diverse phenotypic signatures are caused by a dysregulated JAK/STAT signal transduction because of acquired somatic mutations. It has been demonstrated that autoimmune diseases and MPN can be associated (Kristinsson et al., Haematologica. 2010 Jul;95(7):1216-20.), suggesting a common background of immune dysregulation (Barosi, Curr Hematol Malig Rep. 2014 Dec;9(4):331-9). SARS-CoV-2 infection displays extreme inter-individual clinical variability, ranging from silent infection to lethal disease. It has been described that at least 10% of patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia have neutralizing autoantibodies (AAbs) against type I IFNs, that precede SARS-CoV-2 infection (Bastard et al., Science. 2020 Oct 23;370(6515):eabd4585). In this study we searched for AAbs against type I IFNs in a cohort of MPN patients to evaluate the prevalence of these AAbs in the MPN population and to check for clinical correlations, including severity of COVID-19. Methods. Plasma samples from consecutively referred MPN patients were prospectively collected between November 2020 and June 2021 and frozen at -30°C immediately after collection. Levels of AAbs against type I IFN subtypes including IFNs alpha, beta and omega were measured using the enzyme-linked immunosorbent assay (ELISA) and a neutralization assay, as previously reported (Bastard et al., Science. 2020 Oct 23;370(6515):eabd4585;Moreews et al., Sci Immunol. 2021 May 25;6(59):eabh1516). Results. We included a total of 219 MPN patients (101 ET, 76 PV, 36 MF and 6 MPN unclassificable). Neutralizing AAbs to type I IFNs were detected in 29 patients (13.2%, 95%CI: 9.1% - 18.5%). Comparing patients with and without AAbs we observed a significant difference in terms of distribution of MPN diagnosis (P = 0.029) and driver mutations (P = 0.019), while we did not observe a difference in terms of age, sex, and treatment (Table 1). Overall, 29 patients (13%) got SARS-CoV-2 infection and 8 of them (28%) required hospitalization due to severe COVID-19. AAbs against type I IFNs were detected in 4 of the 29 SARS-CoV-2 infected patients. A higher rate of hospitalization for severe COVID-19 was observed in patients with AAbs to type I IFNs (2 of 4 patients, 50%) compared to those without these AAbs (6 of 25 patients, 24%), although the difference did not reach a statistical significance (P = 0.300). Conclusions. In this study, we detected a prevalence of AAbs against type I IFNs which is much higher in our MPN cohort (13%) than in the general population (2-3%). We also found a correlation between the presence of AAbs to type I IFNs and both the hematological diagnosis and the driver mutation. Despite a comparable prevalence of SARS-CoV-2 infection between MPN patients with or without AAbs to type I IFNs, we observed a different rate of hospitalization due to severe COVID-19 which is almost twice in those with AAbs against type I IFNs compared to those without these AAbs. However, this difference did not reach a statistical significance, probably because of the low number of SARS-CoV-2 infection in the subgroup of patients with AAbs against type I IFNs. Thus, further studies to analyse the prevalence of AAbs against type I IFNs in patients with MPN, their association with other forms of auto-immunity and severe COVID-19 are warranted. [Formula presented] Disclosures: Arcaini: Gilead Sciences: Research Funding;Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy;Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses;Celgene: Speakers Bureau. Rumi: Novartis, Abbvie: Consultancy.

A Survey Conducted during COVID-19 Pandemic Among Brazilian Chronic Myeloid Leukemia and Philadelphia-Negative Myeloproliferative Neoplasms Patients

Introduction: COVID-19 has severely affected the Brazilian population. By July 2021, the incidence was 19,9 million cases and 556.000 deaths. Recent studies suggest that patients with MPN have higher infection and death rates than the general population. Older age and comorbidities are risk factors for severe COVID-19 in CML and MPN. Objectives This study aimed to evaluate the incidence and clinical evolution of COVID-19 in a cohort of CML and MPN Brazilian patients. Methods This is a prospective, observational, ongoing study. All patients signed informed consent and answered two structured questionnaires within a six months interval. The questionnaire included questions about patient's behavior during pandemic, symptoms, contacts, COVID-19 infection, and vaccination data in the last six months. In addition, demographic data, CML and NMP treatment, comorbidities, laboratory tests, COVID severity, and outcome were collected from the medical records. Results From September 2020 to July 2021, 370 patients answered the first questionnaire, and 153 answered the second: 225 with CML and 145 with MPN (45% essential thrombocythemia, 27.6%, polycythemia vera, 23% myelofibrosis, and 4.8% not classified). In the CML population, the median age was 56 (19-90). Most were receiving tyrosine kinase inhibitors (88,5%) and 26 (11,5%) no treatment, in treatment-free remission (TFR). 80% of the patients were practicing social distancing, and 30% had at least one family member or close contact diagnosed with COVID-19. Comorbidities: hypertension (35%), diabetes (14%), pulmonary disease (6%), cardiac disease (16%), renal disease (7%), other (18%). A total of 28/225 (12.4%) patients had confirmed COVID-19 diagnosis (by serology or PCR), while 10 were suspect. The median age was 47 years, 68% were male, and 41% were not respecting social distancing. Thirty-five percent had comorbidities: 25% hypertension;68% had a history of close contact with an infected person. One patient was in the accelerated phase, and 27 were in the chronic phase;4 had a complete cytogenetic response, 13 major molecular response (MMR), 3 MR4.0, and 7 MR4.5. COVID-19 was mild/moderate in 27 and in severe in one case, resulting in death. This patient was a male, 71-year-old, with hypertension, in MMR with nilotinib. At COVID-19 onset, 16 pts were receiving imatinib, five dasatinib;five nilotinib e 2 were in TFR. There was one reinfection, in a 54 years old male patient, with no comorbidities. To date, 84 (37%) patients (pts) have received vaccines against COVID-19: 32 CORONAVAC (Sinovac/Butantan), 51 ChAdOx1nCov-19-Covishield (Astrazeneca/Oxford), and one BNT162 (Pfizer). All COVID-19 cases occurred before vaccination. Among the 145 MPN pts, the median age was 67 years (29-90), and 86% had comorbidities (52% hypertension, 17.5% diabetes, and 13% cardiac diseases). Social distancing was 83%. Nine out of 145 (6.2%) had confirmed COVID-19 diagnosis, and 3% suspect. The median age of these pts was 43 years (28-80). Seven patients had ET and 2 PV. Seven were female. Four pts received Hydroxyurea (HU) and aspirin, four aspirin, one HU, and one no treatment. There were seven mild and two moderate cases requiring hospitalization, none requiring oxygen or mechanical ventilation, none with thrombosis. Two COVID cases occurred after the first dose of vaccines (CORONAVAC and Covishield). In the whole MPN group, 11% have received two doses (57% CORONAVAC, 40% Covishield, and 3.6% BNT 162). Conclusions COVID-19 cases occurred more frequently in younger patients. COVID-19 incidence was higher in the CML than in the MPN population, probably because MPN patients were less exposed, and the older pts were the first to receive vaccines. The impact of the vaccination on the prevention of new cases will be evaluated during the follow-up. Disclosures: Bortolini: Novartis: Speakers Bureau. Pagnano: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;intpharma: Other: Lecture;EMS: Other: Lecture;Jansenn: Other: Lecture.

Increased Risk of Thrombosis in Patients with Myeloproliferative Neoplasms Compared with the General Population Hospitalized with COVID-19

[Formula presented] Background: Coronavirus disease-2019 (COVID-19) is an inflammatory, multisystem infectious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2) and is associated with increased risk of thrombosis, particularly among critically ill patients. The myeloproliferative neoplasms (MPNs) include Philadelphia chromosome-negative (Ph-negative) MPNs polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), and Philadelphia-chromosome positive chronic myeloid leukemia (CML). Patients with MPNs, especially PH-negative, have increased risk of thrombotic complications. Given the increased propensity of thrombosis and prognostic significance of thrombosis in both COVID and MPNs, defining the risk of thrombotic complications in this patient population compared to the general population is important. Methods: Using an institutional database within the Mass General Brigham integrated health network, we retrospectively analyzed 63 consecutive patients with MPN who were ≥ 18 years old and tested positive for SARS-COV-2 infection based on polymerase chain reaction (PCR) testing from March 1, 2020 to January 1, 2021. We compared patients admitted to the hospital in our “MPN cohort” with patients admitted to the hospital from a separate COVID-19 (non-MPN cohort) Mass General Brigham registry of 1114 consecutive patients who tested positive for SARS-COV-2 infection based on PCR testing from March 13, 2020 to April 3, 2020. Care was taken to ensure the cohorts were mutually exclusive. The 90-day primary outcome for MPN cohort was a composite of all-cause death, any thrombosis (composite of arterial and venous thromboembolism [VTE]), International Society on Thrombosis and Haemostasis (ISTH) defined major and clinically relevant non-major bleeding. To identify risk factors for primary outcome in MPN cohort we used a multivariable logistic regression using age, sex, hospital admission status, MPN type, cytoreduction for MPN, hypertension, smoking status, baseline anticoagulation (AC), prior thrombosis (stroke, myocardial infarction or VTE) as co-variables. The 90-day outcomes of interest in our MPN vs non-MPN cohort analysis were any thrombosis, death, ISTH major and clinically relevant non-major bleeding and readmission for any reason. To assess impact of MPN status in hospitalized patients in our MPN vs non-MPN comparison, we used a multivariable logistic regression using age, sex, race, Hispanic ethnicity, ICU admission, treatment with steroids and/or Remdesivir, baseline AC and aspirin use, prior thrombosis (stroke, myocardial infarction or VTE), diabetes, heart failure, admission hematocrit, platelet count and D-dimer as co-variables. Continuous variables were compared using student t-test and categorical variables were compared using Fischer's Exact Test with a p value of < 0.05 considered significant. Results: Of the 63 patients with MPN (23 with PV, 17 ET, 4 PMF, 15 CML, 4 other), 27 (43%) were admitted to the hospital for COVID-19 and 5 (8%) required ICU admission. The mean age of all MPN patients was 66, 84% were White, 8% Black and 10% Hispanic. Primary 90-day outcome occurred in 12 (19%) of MPN patients. In multivariable analysis, only admission to hospital was associated with increased odds of composite (aOR 21.11, 95% CI 2.38 - 546.40), Figure 1A. In patients with (n = 27) and without MPN (n = 399) who were admitted to the hospital, patients with MPN were older (mean age 70 vs 61, p = 0.0076), more likely to be White (89% vs 54%, p = 0.0004) and less likely to be Hispanic (7% vs 29%, p = 0.0158), less likely to be admitted to the ICU (19% vs 43%, p = 0.0138), and more likely to be treated with corticosteroids (30% vs 14%, p = 0.025) or remdesivir (41% vs 13%, p < 0.0001). After multivariable logistic regression, diagnosis of MPN was significantly associated with increased odds of thrombosis (aOR 5.38, 95% CI 1.15-25.38) and readmission (aOR 6.28, 95% CI 1.60-24.88), but not bleeding (aOR 3.51, 95% CI 0.62-18.87) or death (aOR 4.29, 95% CI 0.95-18.9 ), Figure 1B. Conclusions: Thrombotic complications are common in patients with MPN and COVID-19, particularly if hospitalized for COVID-19. After multivariable analysis, MPN patients admitted for COVID-19 had a significantly increased risk of thrombotic complications compared with non-MPN patients. [Formula presented] Disclosures: Al-Samkari: Dova/Sobi: Consultancy, Research Funding;Novartis: Consultancy;Argenx: Consultancy;Rigel: Consultancy;Amgen: Research Funding;Agios: Consultancy, Research Funding;Moderna: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding;BMS: Consultancy, Research Funding;Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees;Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fathi: Agios/Servier: Consultancy, Other: Clinical Trial Support;BMS: Consultancy, Other: Clinical Trial Support;AbbVie: Consultancy, Other: Clinical Trial Support;Pfizer: Consultancy;Trillium: Consultancy;Kura: Consultancy;Blueprint Medicines Corporation: Consultancy;Genentech: Consultancy;Novartis: Consultancy;Trovagene: Consultancy;Daiichi Sankyo: Consultancy;Novartis: Consultancy;Morphosys: Consultancy;Kite: Consultancy;Foghorn: Consultancy;Takeda: Consultancy;Amgen: Consultancy;Seattle Genetics: Consultancy;NewLink Genetics: Consultancy;Forty Seven: Consultancy;Ipsen: Consultancy. Goldhaber: Bayer: Consultancy, Research Funding;Boehringer-Ingelheim: Consultancy, Research Funding;BMS: Research Funding;Boston Scientific BTG EKOS: Research Funding;Daiichi: Research Funding;Janssen: Research Funding;Pfizer: Consultancy, Research Funding;Agile: Consultancy. Piazza: Portola: Research Funding;Bayer: Research Funding;Amgen: Research Funding;BMS: Research Funding;Janssen: Research Funding;BSC: Research Funding. Hobbs: Celgene/Bristol Myers Squibb: Consultancy;Novartis: Consultancy;Merck: Research Funding;Constellation Pharmaceuticals: Consultancy, Research Funding;Bayer: Research Funding;Incyte Corporation: Research Funding;AbbVie.: Consultancy.

COVID Vaccine Antibody Responses in Patients with Hematologic Malignancies in a Myeloid Enriched Cohort: A Better Antibody Response in Patients with Myeloid Malignancies Than B-Cell Malignancies

Background: The risk of severe COVID-19 is increased in patients (pts) with hematologic malignancies, with a reported risk of death of 34% (Vijenthira et al, 2020). The ASH-ASTCT COVID-19 vaccine guidelines indicate that certain immunocompromised patient populations could have an attenuated response to the SARS-CoV-2 vaccine. However, most SARS-CoV-2 vaccine trials required pts to be off immune suppression to be eligible and therefore excluded most pts with hematologic malignancies. Little is known about the efficacy of SARS-CoV-2 vaccines in pts with hematologic malignancies. In this study, we aimed to evaluate the serological response of Pfizer and Moderna vaccination after two doses given in pts with hematologic malignancies with a focus on pts with myeloid malignancies. Methods: Patients with a history of hematologic malignancies treated at the University of Texas Southwestern Medical Center and received two doses of vaccination with quantitative measurement of SARS-CoV-2 IgG Spike antibody to assess vaccination response were included in this study. Baseline patient and disease characteristics including disease status and therapy given at the time of vaccination were collected. Time to vaccine response was defined as having a positive quantifiable spike IgG antibody titer per the lab reference range. The development of COVID-19 infection as well as antibody titer levels were collected. Categorical variables were compared using Chi-square and Fisher's exact tests and student t-test and ANOVA test were used to compare continuous variables. Results: A total of 61 pts with hematologic malignancies had spike IgG antibody testing after receiving 2 doses of the vaccine were included in this study. The median age at the time of vaccination was 72 (22-85) and 46% of pts were female. Eighty five percent of pts were Caucasian. The majority of pts (67.3%) had a myeloid malignancy (MDS/CMML 29.5%, AML 14.8%, myelofibrosis 16.4%, CML 6.6%), followed by chronic lymphocytic leukemia (16.4%), and others (6.6%). The median time from hematologic malignancy diagnosis to the first vaccine dose was 51 months (0.4-337 months). At the time of vaccine administration, 46 (75%) of pts were on active therapy and 39 (64%) of pts had active disease. Median time from the second vaccine dose to IgG spike antibody testing was 64 days (26-268 days). Most pts (75%) mounted a serological response with quantifiable COVID-IgG spike antibodies, 85% and 56% in myeloid and lymphoid malignancy, respectively. All pts with MDS/CMML/CCUS and CML mounted an immune response (100%), followed by acute myeloid leukemia (n: 7/9, 78%) and myelofibrosis (n: 6/10, 60%). Eight (13%) of pts were receiving hypomethylating agent therapy at the time of vaccination and all (100%) had a positive IgG response. Only one patient developed COVID-19 infection post vaccination with a documented IgG response and 2 pts had COVID-19 infection prior to the first dose of vaccination, both of these pts had IgG titers >10,000. Sixty percent of pts (9/15) with negative IgG response received treatment with either CD20 monoclonal antibodies or BTK inhibitors within 12 months of the first vaccine dose. Two out of three pts (67%) receiving Ruxolitinib had negative serology. Seven pts were on treatment with hydroxyurea, interestingly, all but the 2 pts with polycythemia vera had a negative antibody titer while on treatment with hydroxyurea. There was a strong positive correlation between vaccine titer and absolute lymphocyte count (r 2=0.27, p<0.001) (Figure). Conclusions: In this retrospective study, we demonstrate a higher rate of COVID-19 vaccine efficacy in pts with myeloid malignancy with varying responses per treatment and disease subtype compared to pts with B-cell malignancy with variable anti-CD20 or BTK inhibitor therapy. Pts with myelodysplastic syndromes, overlap syndromes of clonal cytopenia of undetermined significance all developed spike antibodies irrespective of hypomethylating therapy or Hydrea as did pts with chronic myeloid leukemia. However, pts with polycythemia vera nd those on treatment with Ruxolitinib had an attenuated response to the vaccine. Albeit this single center study, pts with myelodysplastic syndromes should be offered COVID vaccines irrespective of their blood counts or ongoing treatment. Our findings should be validated in a larger group of patients. [Formula presented] Disclosures: Patel: Agios: Membership on an entity's Board of Directors or advisory committees;Celgene-BMS: Membership on an entity's Board of Directors or advisory committees;PVI: Honoraria. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan: Cardinal Health: Consultancy;BMS: Consultancy;Dava Oncology: Consultancy;Karyopharm: Consultancy;Merck: Consultancy;Johnson and Johnson: Consultancy;Incyte: Consultancy;Beigene: Consultancy;Verastem: Consultancy;MEI Pharma: Consultancy;Celgene: Consultancy;Kite pharma: Consultancy;Gilead sciences: Consultancy;Pharmacyclics: Consultancy;Janssen: Consultancy;Abbvie: Consultancy;ADCT therapeutics: Consultancy;Astrazeneca: Consultancy;Genentech: Consultancy. Madanat: Blue Print Pharmaceutical: Honoraria;Onc Live: Honoraria;Stem line pharmaceutical: Honoraria;Geron Pharmaceutical: Consultancy.

Hydroxyurea-induced genital ulcers and erosions: Two case reports.

Hydroxyurea is a chemotherapeutic agent used for myeloproliferative disorders and sickle cell anemia that is well known to cause painful mucocutaneous ulcers, typically involving the legs or mouth. However, genital ulcerations due to hydroxyurea therapy are a rare, and likely underrecognized, adverse effect with only a few cases reported in the literature to date. Ulcers of the lower legs caused by hydroxyurea are associated with a diagnostic delay, and this is likely exacerbated in cases of genital ulceration due to a lack of awareness. Herein we present two cases of painful genital ulceration in patients on hydroxyurea therapy. In the first Case, an 87 year-old male with polycythemia vera developed an ulcer on the scrotum, which was assessed initially through virtual visits during the COVID-19 pandemic, and was refractory to topical and oral antibiotic treatments. The second case was a 79 year-old male with essential thrombocythemia and a history of persistent leg ulcers who developed erosions of the glans penis. Both patients experienced complete resolution within weeks of discontinuing hydroxyurea therapy. In conclusion, genital ulcers and erosions induced by hydroxyrea may be underrecognized in clinical practice, but if identified, withdrawal of hydroxyurea leads to quick resolution of these lesions and the associated pain.

Ruxolitinib-Associated Infections in Polycythemia Vera: Review of the Literature, Clinical Significance, and Recommendations.

Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, is approved for second-line therapy in patients with polycythemia vera (PV) who are resistant or intolerant to hydroxyurea. Due to the immunomodulatory and immunosuppressive effect of RUX, there is an increased susceptibility to infections. However, an increased risk of infection is inherent to even untreated myeloproliferative neoplasms (MPN). To obtain more information on the clinical significance of RUX-associated infections in PV, we reviewed the available literature. There is no evidence-based approach to managing infection risks. Most data on RUX-associated infections are available for MF. In all studies, the infection rates in the RUX and control groups were fairly similar, with the exception of infections with the varicella zoster virus (VZV). However, individual cases of bilateral toxoplasmosis retinitis, disseminated molluscum contagiosum, or a mycobacterium tuberculosis infection or a hepatitis B reactivation are reported. A careful assessment of the risk of infection for PV patients is required at the initial presentation and before the start of RUX. Screening for hepatitis B is recommended in all patients. The risk of RUX-associated infections is lower with PV than with MF, but compared to a normal population there is an increased risk of VZV infection. However, primary VZV prophylaxis for PV patients is not recommended, while secondary prophylaxis can be considered individually. As early treatment is most effective for VZV, patients should be properly informed and trained to seek medical advice immediately if cutaneous signs of VZV develop. Vaccination against influenza, herpes zoster, and pneumococci should be considered in all PV patients at risk of infection, especially if RUX treatment is planned. Current recommendations do not support adjusting or discontinuing JAK inhibition in MPN patients to reduce the risk of COVID-19.

Thrombosis and Bleeding as Presentation of COVID-19 Infection with Polycythemia Vera. A Case Report.

Coronavirus disease (COVID-19) has a wide spectrum of clinical manifestations. In this case report, we describe our first case of COVID-19 pneumonia that was complicated by cerebral venous thrombosis and bleeding in a patient with polycythemia vera. Madam A, a 72-year-old lady with polycythemia vera, ischemic stroke, hemorrhoids, diabetes mellitus, hypertension, and dyslipidemia was admitted to the hospital for COVID-19 pneumonia. She was treated with hydroxychloroquine and lopinavir/ritonavir as per hospital protocol. She continued taking hydroxyurea and aspirin for her treatment of polycythemia vera. Subsequently, she developed rectal bleeding when her platelet count was 1247 × 103/µl, even though she was not on an anticoagulant. Her aspirin was withheld. One week later, she was readmitted to the hospital for cerebral venous thrombosis and her D-dimer was 2.02 µg/ml. She was commenced on a therapeutic dose of low molecular weight heparin. Following that, her D-dimer level showed a decreasing trend and normalized upon her discharge. Patients with polycythemia vera are prone to develop thrombotic and bleeding complications. Management of this group of patients has become more complex with COVID-19 infection. It is crucial for us to decide when to start an anticoagulant especially when there is a history of recent bleeding. We need to balance the risks of further bleeding versus potentially fatal thrombotic events. Studies have shown that D-dimer can be used as a clinical marker to predict thrombotic events in COVID-19 infection. Patients with COVID-19 infection and polycythemia vera will benefit from both pharmacological thromboprophylaxis and close monitoring for bleeding.