Managing Patients With Myeloid Malignancies During and After the Global COVID-19 Pandemic

Claire Harrison, MD

The rapid spread of the coronavirus disease 2019 (COVID-19) led to the declaration of a global pandemic from the World Health Organization. After a large spike in the incidence of COVID-19 cases has begun to pass in many countries around the world, little data remains available regarding the risk of COVID-19 infection among patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML).

This infection has impacted 188 territories around the globe. Causes of COVID-19 range from the common cold to more severe diseases, such as the Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome. COVID-19 is associated with complications by bilateral interstitial alveolar pneumonia and respiratory insufficiency whose pathogenesis is sustained by a marked cytokine release syndrome.¹

During the Virtual 25th Congress of the European Hematology Association (EHA), a group of physicians described their experiences and recommendations for managing patients with myeloid malignancies during the COVID-19 pandemic and after.²

“One of the things that is important that we found in managing the pandemic is to understand your local data,” said Claire Harrison, MD, Guy’s and St. Tomas’ NHS Foundation Trust, United Kingdom, during the presentation. London appears to be just coming out of a peak in COVID-19 cases, which is important for physicians to be aware of as they are seeing and treating patients. Harrison notes that it is important to continue encouraging the use of telemedicine, as well as other precautions and procedures that have been adopted during the pandemic.

Patients with blood cancers are considered vulnerable to COVID-19 infection in the United Kingdom, but Harrison notes many physicians debate whether an MPN is a blood cancer. However, telemedicine has played a crucial role in the outpatient treatment of these patients during the pandemic. Managing these patients via telemedicine requires very clear documentation from the team for each patient, which ultimately helped free up the capacity of her team in London so that appointments could be moved up to 6 weeks ahead. Another requirement for managing patients with MPNs during the pandemic is having the ability to send medications to patients.

Managing Patients With MPNs During COVID-19 Pandemic

According to experts, there is not enough information on COVID-19 in patients with MPNs to determine a potential higher risk for infection among this patient population. However, it is understood that patients with intermediate-2 or high-risk myelofibrosis (MF) and those with MF being treated with JAK inhibitors are likely to have a higher risk of infection. Certain treatments for MPNs as well as some co-morbid cardiovascular, thrombotic, or hematologic disorders may put patients with MPNs at a higher risk for COVID-19 infection as well, and they may also be less able to recover from the infection.¹

The literature describes an increasing frequency of COVID-19 among patients with thromboembolic events, particularly in advanced stages of disease, and this raises concerns for patients who are prone to disease-associated thrombotic or hemorrhagic complications. However, there is still no data demonstrating this correlation.

Patients with MPNs who do not have a documented COVID-19 diagnosis or symptoms should continue adhering to current treatment guidelines for MPNs that decrease the risk of thrombosis. Patients who have a confirmed or suspected COVID-19 infection should receive, at a minimum, prophylactic doses of low molecular weight heparin (LMWH) if they are in the ICU or are mechanically ventilated. Additionally, some centers are administering intermediate dosing regimens of LMWH in patients who are considered to be at high risk for COVID-19 without observing a thromboembolic event, and this is recommended to COVID-19 patients with MPNs as well, though physicians should monitor closely for bleeding.

A pulmonary embolism (PE) diagnosis should be suspected in the event of respiratory deterioration either with or without clinical signs of deep venous thrombosis together with a sudden increase of D-Dimer, which has been successfully treated with thrombolysis in many patients.

The risk of bleeding is higher among patients with MPNs who have had prior hemorrhages or extreme thrombocytosis or thrombocytopenia, and the risk is even higher among those with hepatic failure or severe renal failure. In these cases, it is recommended to collaborate with hematologists for the appropriate management of these scenarios.

No existing data suggest that cytoreductive agents, such as hydroxyurea, increase the risk of developing COVID-19 infection.

JAK inhibitors have not been shown to impact the development or worsening of COVID-19, but JAK inhibitors like ruxolitinib (Jakafi) have been suggested as a potential treatment for cytokine storm in critically-ill patients with COVID-19. According to experts, JAK inhibitors should not be abruptly halted among patients with MPNs as it could result in debilitation, progressive splenomegaly, or cytokine storm in rare cases, which all could potentially worsen COVID-19 infections. Use of JAK inhibitors should continue among patients already receiving the treatment, but new patients should not begin this therapy during the pandemic. For patients in which ruxolitinib must be stopped, twice-daily doses of 5 mg or more should be cautiously tapered before treatment is stopped.

For newly diagnosed patients with PV and a hematocrit > 48% to 50%, physicians can initiate phlebotomy and use aspirin as appropriate. The risks and benefits of cytoreductive therapy should be weighed carefully against phlebotomy alone for newly diagnosed patients with PV. Patients who are newly diagnosed with essential thrombocytopenia should also weigh the risks and benefits of cytoreductive therapy before initiating treatment, but physicians can move forward with initiation for those with clear indications for cytoreductive therapy, such as active or previous thrombohemorrhagic events and otherwise delay treatment based on age or cardiovascular risk.

Among patients with MF who are newly diagnosed, prognosis should be determined by MIPSS or DIPSS-Plus, or an equivalent test to provide adequate supportive care while weighing the risks and benefits of administering a JAK inhibitor. Stem cell transplants in this patient population can be conducted, but it is best to delay in patients with COVID-19 infection until the virus has significantly decreased.

For patients with MPNs that are ambulatory or in the inpatient setting, it is important to maintain a clean COVID-19 unit and test patients often for the infection, particularly if they have a high index of suspicion. Masks and other protective equipment should be used when seeing these patients, as well as social distancing measures.

Therapies being used in patients who are diagnosed with COVID-19 should not be adjusted or stopped unless there are drug-drug interactions between their MPN and COVID-19 treatments. A dose modification of ruxolitinib may be considered among patients who are also receiving medication for COVID-19 infection. Cytoreductive therapy does not need to be adjusted should the patient develop COVID-19.

For patients with MPNs who are already receiving an anticoagulation and develop COVID-19, an LMWH should be used instead, but patients taking aspirin can continue treatment, according to these recommendations. There has been no documented evidence of an association between aspirin and COVID-19 complications.

Treatment Recommendations for AML in COVID-19–Positive Patients

Felicetto Ferrara, MD

Patients with AML who are diagnosed with COVID-19 require isolation and collaboration with pneumonologists and intensivists. There may be problems in administering treatment for AML, including treatment delays or dose reductions. Similar to treatments for MPNs, drug interactions must also be analyzed when using treatments for both AML and COVID-19.

All patients should be tested for COVID-19 prior to admission to the hospital, and they should be retested during the course of their disease, especially before each treatment cycle, according to experts. Induction and consolidation regimens for patients should be evaluated and modified as needed as these can increase the risk for infectious complications. Severe and prolonged neutropenia with neutrophil counts below 500/μl or in some cases 100/μl can increase the risk of febrile complications.

Respiratory virus infections may also be observed in patients with AML, particularly during outbreak seasons, with incidences of this varying between 1% and 50%. However, this is often controlled by the widespread use of molecular microbiologic testing. The progression of an upper respiratory tract infection to a lower respiratory tract infection has been associated with an increased likelihood of death. The most common respiratory viruses observed include influenza, parainfluenza, respiratory syncytial virus, adenovirus, and human metapneumovirus, and COVID-19 has not been determined to be as aggressive as most respiratory viruses.

“We know from different studies that no cases of AML are a medical emergency, therefore we can wait for the resolution of symptoms at the least, not the negativity of the test,” said Felicetto Ferrara, MD, Cardarelli Hospital, Italy, during the presentation.² “However, in the few cases in which immediate treatment is needed, treatment should be performed in a dedicated [COVID-19] unit in strict collaboration with pneumonologists and intensivists.”

“This is very important…because we are talking about a curable disease. [AML is] curable in more than 90% of patients,” said Harrison. “We have to distinguish between symptomatic and asymptomatic patients.”

Symptomatic young or adult patients can receive hydroxyurea until their symptoms resolve, but a significant number of these patients do not require immediate treatment at diagnosis. Elderly patients, however, are at a greater risk for COVID-19 and related complications. Because the virus can be particularly aggressive in this patient population, physicians should modify their treatment regimens accordingly for each patient and pay particularly close attention to the elderly patients with AML who are diagnosed with COVID-19. For elderly patients who are symptomatic with AML and require immediate treatment, they can receive hydroxyurea until symptoms resolve.

If possible, treatments should be postponed until the patient tests negative for COVID-19 for patients in the relapsed setting. High-dose chemotherapy should be avoided, so targeted treatments including gilteritinib (Xospata) for FLT3-positive patients and ivosidenib (Tibsovo) and enasidenib (Idhifa) for patients with IDH1and IDH2 mutations, respectively, are recommended for eligible patients.¹

Standard induction therapy can be performed on young, asymptomatic patients who have tested positive for COVID-19. For patients 65 years or older who are asymptomatic and eligible for conventional chemotherapy, they could receive standard induction therapy, but patients who have molecular markers for high-risk disease, the combination of venetoclax (Venclexta) and hypomethylating agents are the preferred treatment if they are eligible to receive this therapy. Patients should be stratified based on their molecular characteristics.

For patients requiring transplant for their AML, allogeneic transplantations should be delayed up to at least 1 month from obtaining negative test results for COVID-19. It is important to evaluate the risks and benefits of transplant and discuss this with the patient, as well as the undetermined impact of COVID-19 on outcomes.

It is recommended that consolidation therapy be postponed in patients with a CR who are positive for COVID-19 until the virus has cleared, which includes high-dose cytarabine-based therapy. Intermediate dosing of cytarabine, however, is recommended for patients with COVID-19 who require consolidation therapy. Studies have demonstrated no differences in outcomes when treated with either intermediate or high-dose cytarabine, so the preferred dosing schedule would be days 1, 3, and 5 as opposed to 1, 2, and 3.

Managing COVID-19 Among Patients With CML

Delphine Rea, MD, PhD

Most patients with CML, particularly those in chronic phase who are well-controlled, are not at a higher risk of developing COVID-19, and the tyrosine kinase inhibitor (TKI) therapies used in these patients are not immunosuppressive drugs, so the CML patient population is not at a higher risk because of their treatment. However, certain comorbidities may put select patients at a higher risk, such as pulmonary toxicities.¹

“There is a specific warning we should however take into account, which is in those with ongoing preliminary toxicity [from a] TKI, these patients present a group with a question mark that may be at a higher risk of COVID-19 or lung damage,” said Delphine Rea, MD, PhD, Saint-Louis University Hospital APHP, in Paris France, during the presentation. It is unknown whether this population of patients are at a higher risk of infection.²

For newly diagnosed patients with CML, those who have progressive disease, or those with severe toxicity from treatment, the management of these patients should not be delayed due to COVID-19. Treatment cannot be delayed, including the introduction of a new treatment, says Rea. However, 1 problem with this is that patients may require treatment in the hospital, but some patients are afraid to travel to the hospital for fear of becoming infected with COVID-19 during travel.¹

Delayed introduction of TKI treatment may lead to worsening of lung damage or gas exchanges by uncontrolled leukocytosis or increased risk of CML progression to advanced phases. During the first 3 months of treatment with a TKI, physicians should use extreme caution as severe cytopenia can occur, which increases the risk of severe COVID-19 infection.

Prophylactic interruption of a TKI is also not recommended as this can cause loss of response or disease relapse/progression, and this is particularly important if access to regular monitoring of CBC counts and BCR-ABL transcripts are altered. Outcomes may be jeopardized if patients experiencing resistance or intolerance to the TKI if treatment is delayed or changed.

Another challenge in treating patients with CML during the COVID-19 pandemic is required access to BCR-ABL monitoring PCR tests as physicians need to monitor the residual disease in patients with CML. Patients are well-controlled with TKI therapy so the tests could be delayed without jeopardizing their outcomes, and telehealth visits are recommended, especially for those who just entered treatment.

Patients with CML in treatment-free remission (TFR) who discontinue TKI treatment for less than 6 to 12 months and do not have access to regular monitoring/testing should speak with their physicians right away about the possibility of restarting TKI therapy or postponing it at the of the COVID-19 pandemic. Patients entering TFR should also wait to halt treatments until after the pandemic.

Patients who are in TFR and develop COVID-19 can be managed in the same manner as the general population as no data suggests these patients with chronic phase CML are at a higher risk of COVID-19 infection. The only exceptions to this include the onset of severe cytopenia on TKI treatment during early stages and active TKI-induced hypersensitivity pneumonitis or other forms of lung damage.

Rea highlighted cases of COVID-19 among patients with CML from personal experience at her institution in France. Although there were many cases of COVID-19 in her country and her demographic area, she only experienced 7 cases of COVID-19 among patients with CML.

“I was surprised not to have more phone calls. In my institution, we have several hundred patients that are outpatients, almost thousands, and only 7 [patients with CML] called for suspicion or confirmed COVID-19 infection,” said Rea.² “This seems to be very little. We currently do not know why, but this may be [because] these patients are very careful in following the hygiene rules. However, there may be other things we do not understand.”

There was a wide range of ages among the 7 patients from 36 to 81 years. Patients were treated with different TKI agents. For the 7 patients, all symptoms were benign, but there were no significant signs of similarity between these different patients. All patients had a fever. None of these patients had their TKI treatment modified, and none of them required hospitalization and were able to recover at home with either no treatments for the infection or paracetamol to treat fever.

The International CML Foundation is currently performing a survey for patients with CML who are either confirmed with or suspected of a COVID-19 infection. Updates from this survey are shared weekly, Rea said, to continue evaluating whether these patients may be at a greater risk of developing the virus and to modify recommendations accordingly.

Recommendations for the treatment of patients with myeloid malignancies during the COVID-19 pandemic will continue to be updated.

_Reference

1. _{COVID-19 & Hematology Information Center. Recommendations for specific hematologic malignancies. European Hematology Association. Accessed June 23, 2020. https://bit.ly/37Z1yTt}
2. _{Harrison C, Ferrara F, Rea D. COVID-19 and myeloid malignancies: Managing patients during the pandemic. Presented at: Virtual 25th EHA Congress; June 11, 2020.}