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(Version 6.1; last updated September 3, 2021)

Input from Ruben Mesa, MD; Alberto Alvarez-Larran, MD; Claire Harrison, MD; Jean-Jacques Kiladjian, MD, PhD; Alessandro Rambaldi, MD; Ayalew Tefferi, MD; Alessandro Vannucchi, MD; Srdan Verstovsek, MD; Valerio De Stefano, MD; and Tiziano Barbui, MD.

Note: Please review ASH's disclaimer regarding the use of the following information.

Are MPN patients at high risk for COVID-19?

To date, there is too little known about the clinical outcomes of individuals with MPN who are infected with COVID-19. It is felt that patients with intermediate 2 or high-risk myelofibrosis may have a higher risk of adverse outcomes if they become infected with COVID-19. Additionally, recent analysis of MPN experiences from a European retrospective study () suggests patients with ET having higher rates of thrombotic complications with COVID19 infection, and a sharp drop in platelet counts post COVID19 diagnosis may be associated with worse outcomes.

Thrombosis is a concern in COVID19 patients; what are the implications for MPN patients who also are predisposed to thrombosis and implications in management?

Thromboembolic (TE) complications are described with increasing frequency in COVID-19 especially in advanced stages of the disease. Increased risk of TE with COVID-19 may be of particular concern for MPN patients due to the pre-existing risk for disease-associated thrombotic and/or hemorrhagic complications. Additionally, recent analysis of MPN experiences from a European retrospective study () suggests patients with ET having higher rates of thrombotic complications with COVID-19 infection and a sharp drop in platelet counts post–COVID-19 diagnosis may be associated with worse outcomes. Although there is not yet robust data showing an increase in COVID-19 related TE in the global population of MPN patients, the following approach is our current consensus while awaiting more relevant information from MPN patients.

In MPN patients without documented COVID-19 infection or symptoms: Given the baseline increased risk of thrombosis in MPN patients, and the real possibility of asymptomatic COVID-19 infection, we suggest strict adherence to current treatment goals aimed at decreasing the risk of thrombosis (HCT<45% in PV, anti-platelet therapy in all PV and ET patients with an indication, cytoreduction with a goal of achieving European Leukemia Net levels of control (HCT<45%, leukocytes <10 x 10(⁹)/L, platelets < 400 x 10(⁹)/L).

In MPN patients with known or suspected COVID-19 infection:  The approach to all serious or critical COVID-19 patients regarding prevention of TE is rapidly evolving and under intense study. All hospitalized patients should receive prophylactic doses of LMWH/heparin. Since the onset of the pandemic, some centers have been administering intermediate or double-dose regimens of LMWH in high risk COVID-19 patients without known TE events, either empirically or in the context of a clinical trial. In late December 2020, a multigroup trial of empiric full dose anticoagulation was stopped for those with already critical illness, due to both futility and safety signals (see COVID-19 and VTE/Anticoagulation FAQ). This trial did not enroll those with pre-existing known hypercoagulability such as MPN patients, thus extrapolation is challenging, but at present, patients without a known clot should not be fully anticoagulated outside a clinical trial. Diagnosis of pulmonary embolism (PE) should be suspected in case of respiratory deterioration with or without other clinical evidence of deep venous thrombosis together with a sudden increase of D-Dimer (see PE FAQ). Anecdotally, cases of massive and sub-massive PE in COVID-19 MPN patients have been successfully treated with thrombolysis.

Patients with MPNs receiving therapeutic anticoagulation with a vitamin K antagonist or direct oral anticoagulant for venous thromboembolism or atrial fibrillation stroke prevention should continue treatment or shift to LMWH/heparin according to drug-drug interactions (see COVID-19 and VTE/Anticoagulation FAQ). In patients with MPN who have pre–COVID-19 arterial thrombosis or recent percutaneous coronary intervention (within ≤ 3 months), it is strongly recommended not to discontinue antiplatelet drugs.

The risks of bleeding on anticoagulation are higher in MPN patients, particularly in those with prior hemorrhages or extreme thrombocytosis or thrombocytopenia. The risk is even higher in MPN patients with hepatic failure (INR >1.5) or severe renal failure (filtration rate < 30ml/min per m2). We strongly recommend that COVID-19 infected and hospitalized MPN patients have input from a hematologist for management of the complex scenarios around thrombosis and bleeding risks.

Should cytoreduction be adjusted to decrease the risk of developing serious COVID-19 disease in established MPN Patients?

No. Currently, we have no data suggesting that non-immunosuppressive drugs (ie hydroxyurea, IFNa, anagrelide) increase the risk of COVID-19 infection or severe disease. Therefore, we are not recommending adjustments to these therapies. Good disease control is likely important to avoid a further increase in thrombosis risk should someone with a MPN become infected (see Question 2). Patients who are stable should be converted to telemedicine visits and local labs if feasible and especially if community infection is widespread. Patients maintained on phlebotomy for polycythemia vera (PV) may skip or decrease the frequency for a short period if they are stable, although increased fluid intake is recommended if tolerated to reduce blood viscosity.

Should JAK inhibition (ruxolitinib, fedratinib, other) be adjusted or stopped in MPN patients to decrease risk of COVID-19?

No. Data from the initial European experience with COVID-19 (Barbui et. Al. Leukemia in press 2020) strongly suggests that discontinuation of ruxolitinib in the setting of COVID-19 infection may be deleterious and should be avoided if clinically feasible. The abrupt cessation of JAK inhibitors (JAKi) in successfully controlled MPN patients may result in debilitation, progressive splenomegaly, or rarely cytokine storm, all of which could potentially worsen the clinical course of COVID-19. If JAKi with ruxolitinib needs to be stopped, patients on doses of 5mg or more twice daily should be tapered cautiously. The effect of JAKi on developing/worsening of COVID-19 is unknown and in fact, JAKi have been suggested as a possible therapy for cytokine storm in patients who are critically ill with COVID-19. It should be noted that favorable data on the use of ruxolitinib (as an anti-inflammatory/anti-cytokine) therapy in non-MPN COVID-19 patients has been seen in small clinical trials, reporting improved outcome and accelerated discharge in the setting of COVID-19 pneumonia. However, a large randomized commercial study (RUXCOVID) failed to show any benefit in the treatment of severe COVID-19 pneumonia, although in that particular study, low doses of ruxolitinib were used. It is unknown whether these latter observations impact patients on chronic ruxolitinib therapy with MPNs.

How would you manage a new MPN patient presenting for treatment in the current pandemic?

We are recommending that care of MPN patients proceed as normally, augmented with telemedicine visits where appropriate, during the pandemic. Earlier lessons have shown continued care of MPN patients, including the medical therapies, important to continue according to your current country guidelines.

In patients who have developed the COVID-19 infection, should their MPN therapy be adjusted or stopped?

No, except for drug-drug interactions. In patients who start coronavirus-directed medications and are on ruxolitinib, a dose modification of ruxolitinib (downward in particular if on lopinavir/ritonavir [Kaletra®]) can be considered, but abrupt cessation of ruxolitinib should be avoided (see above), otherwise there is a risk of sudden worsening of the cytokine reaction from myelofibrosis as well as from the COVID-19 infection. Cytoreductive therapy (hydroxyurea, anagrelide, interferon) does not need to be empirically adjusted in someone with COVID-19.

Should MPN patients receive a COVID-19 vaccine when available?

The The rapid approval and potential access of MPN patients to COVID-19 vaccines is a hopeful development. We advise patients to be vaccinated as soon as possible. It is important to stress that, at present, we have no indication that even in patients with an MPN with a history of thrombosis, vaccination for COVID-19 should be avoided or delayed. There is some evolving data that some patients treated with JAK inhibition (ruxolitinib, etc) might have less antibody response to the COVID-19 vaccine; however, we still believe that there will likely be a benefit to patients from receiving the vaccine. Similarly, where offered, booster doses of vaccines may be of benefit. Please refer to the COVID-19 and Vaccination for HCT and CAR T Cell Recipients FAQ regarding general considerations regarding immunocompromised hematology patients. Patients with MPN have a spectrum of immune function, from patients who are not or minimally immunocompromised (i.e., potentially ET/PV/ some MF) to those who might be significantly immunocompromised (advanced MF, post allogeneic transplantation, etc). There is likely no excess risk to MPN patients from either the mRNA vaccines or the replication-incompetent viral vaccines becoming available, with the degree of immunocompromise potentially impacting less the safety and more the efficacy of these vaccines in generating a protective immune response. Additionally, there have been reports of individuals with significant allergies having reactions which might be relevant (especially with patients with systemic mastocytosis/MPD overlap syndromes).We advise patients to connect with their hematologists as to any concerns regarding receipt of a COVID-19 vaccine.

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