Managing blood disorders during the Covid-19 pandemic: current pharmacological insights

KEYWORDS:

• Hematology
• malignant
• benign
• COVID-19
• pharmacology

1. Introduction

The COVID-19 disease, which was declared as a pandemic by WHO on the 11^th of March 2020 has to date, infected over 38 million people worldwide. The medical community was mostly unprepared for the impact of this pandemic and is now gradually learning to live with the pandemic. Hematology practice is complex as it includes using immunosuppressive therapy in both benign and malignant diseases. There is a lack of published literature on how COVID-19 affects patients with blood disorders and therapeutic guidelines are being formulated based on both expert opinion and limited available evidence.

In general, the knowledge of which aspect of immunity is affected by the therapy is utilized to differentiate immunosuppressive therapy into more dangerous and less dangerous. As lymphocytes play a vital role in the immune response to viral infections – some guidelines advocate avoiding therapeutic modalities which predominantly affect the lymphocyte lineage and cause severe lymphopenia (<0.2 × 10⁹/L) [1]. Since COVID-19 is known to be pro-thrombotic – efforts are made to avoid medications that are associated with an increased risk of thrombosis [1].

The following are disease-specific practice recommendations used widely during the pandemic situation.

2. Malignant blood disorders

In the case of therapy for Acute Myeloid Leukemia (AML) in the time of the pandemic, the standard 7 + 3 induction regimen is still recommended. It causes prolonged neutropenia and is associated with an increased incidence of predominantly bacterial and fungal infections. For post-remission consolidation, high dose cytarabine can be still be administered, possibly at a reduced dose. The combination of hypomethylating agents with venetoclax is also associated with prolonged bone marrow aplasia and therefore, cannot be considered safer than the 7 + 3 regimen. The use of molecularly targeted therapies such as gilterinitib for FLT3+ patients, ivosidenib, and enasidenib for IDH1 and IDH2 mutant AML are not to be excluded if part of the treatment algorithm [2].

The use of high dose steroids in Acute Lymphoblastic Leukemia (ALL) during the COVID-19 pandemic is a double-edged sword. While the use of steroids has shown to be protective during the SARS-COV2 infection – it is also associated with prolonged virus shedding and increased overall mortality [3]. Currently, experts do not recommend any steroid dose modification during the initial intensive phase in patients with ALL. During the post-induction phase and maintenance phase – a reduction in dose and/or duration of steroids may be considered. Pegylated L-asparaginase is associated with an increased risk of thrombosis and therefore, some experts advocate dose reduction while using the same [3].

Prolonged therapy with tyrosine kinase inhibitors (TKI) in patients with Chronic Myeloid Leukemia (CML) is not associated with any clinically significant immunosuppression. Alternatively, its discontinuation can be associated with loss of disease control and leukocytosis – which can aggravate pulmonary injury if the patient contracts a SARS-COV2 infection [2]. Extreme caution is advocated during the initial 3 months of treatment in patients with CML during the pandemic, as there is a heightened risk of developing therapy-related cytopenia. Dasatinib is known to cause complications like pleural effusion, pulmonary infiltrates, and pulmonary artery hypertension. While per se they do not constitute a contraindication – they can be additional contributors to complications and have to be considered when prescribing a second line TKI. Additionally, TKI’s may prolong QTc, and caution with ECG monitoring is advised if the patient is planned for COVID-19 prophylaxis with chloroquine or azithromycin [2].

Myeloproliferative neoplasms (MPN) are innately prone for thrombosis. The use of twice-daily low dose aspirin, instead of once-daily aspirin has been recently proven to be more effective and is recommended even during COVID-19 [4]. Strict leukocyte count control with hydroxyurea is recommended as it will also help in decreasing the risk of thrombosis. JAK pathway inhibitors, like Ruxolitinib, which are part of the therapeutic armamentarium of MPN have also been used to treat COVID-19 [4]. Besides, their abrupt termination during therapy of MPN can lead to a devastating rebound of symptoms as well as an increase in blood counts and hence is not advised [1].

For aggressive lymphomas like Diffuse Large B-cell lymphoma, the treatment approach during the COVID-19 pandemic remains largely the same. As far as the treatment for indolent lymphomas during the COVID-19 pandemic is concerned, there have been concerns regarding the use of Bendamustine, since it causes severe and prolonged lymphocyte depletion. Some experts, therefore, recommend that regimens excluding Bendamustine (like R-CVP or R-CHOP) should be considered for the first-line treatment in these indolent diseases. It is well known that the use of anti-CD20 monoclonal antibodies (Rituximab, Ofatumumab, and Obinutuzumab) result in prolonged B lymphocyte depletion. Thus, the concern with the use of these drugs is the prevention of the production of protective antibodies [5]. Despite the concerns, current recommendations advocate no change in therapy during the initial phase of chemotherapy in indolent lymphomas. Although experts had recommended avoiding the usage of Anti CD20 antibodies as remission maintenance therapy, recent data from Italy suggest that Rituximab is safe when administered a single agent [6,7]. In the therapy for Chronic Lymphocytic Leukemia (CLL) during the pandemic – Ibrutinib has been proven to be safe to be continued during COVID-19. Additionally, Ibrutinib has been shown to protect the lungs from injury with improved pulmonary function in those with severe COVID-19. Thus, the continuation of Ibrutinib therapy is advised if the CLL patient contracts a SARS-COV2 infection [8].

In the management of patients with Hodgkin’s lymphoma during the pandemic – ABVD continues to be the preferred frontline regimen. However, experts advocate omitting bleomycin if there is a good clinical response after the initial 2 months of therapy, given the concerns of Bleomycin induced lung injury. Replacing brentuximab with bleomycin may alleviate pulmonary toxicity, but it comes at an increased risk of myelosuppression and neurotoxicity [6].

All the frontline agents in the treatment of multiple myeloma – proteasome inhibitors, lenalidomide, the anti-CD38 monoclonal antibodies, and high dose dexamethasone – are associated with increased risk of viral infections. No COVID-19 specific change in therapy is yet recommended, although experts advocate a preference for home-based administration and all-oral regimens [6].

Across diseases, considerations are made for shifting intravenous therapeutics like Rituximab, Daratumumab to subcutaneous administration to keep hospital exposure to the minimum. Although G-CSF is a standard component of febrile neutropenia management, it has the potential to aggravate pulmonary inflammation in the setting of COVID-19. However, the benefits of its use clearly outweigh the risks involved, and guidelines thus advice a liberal use of G-CSF to prevent and treat neutropenia [9].

3. Benign blood disorders

Any viral infection can trigger the onset of Immune Thrombocytopenia (ITP) or be the cause for exacerbation of preexisting ITP and COVID-19 is no exception. The use of high-dose corticosteroids, which are the standard frontline therapy in ITP, may be avoided during the pandemic. Thrombopoietin receptor agonists (TPO-RA) are thus, the preferred drugs in this setting. Since the onset of action of TPO-RA takes around 2–3 weeks, Intravenous Immunoglobulin (IVIg) is the preferred choice if there is a need to raise platelet counts rapidly. It has to be kept in mind that the IVIg does not contain antibodies against SARS-CoV-2 and won’t be protective against COVID-19. TPO-RA’s have a slightly increased risk of venous thrombosis. Among the TPO-RA’s, Eltrombopag has a higher risk of venous thrombosis but Romiplostim has the disadvantage of being a subcutaneous agent. These considerations may be used when deciding therapy for acute ITP in the time of the COVID-19 pandemic. The fibrinolysis inhibitor tranexamic acid (TXA) is frequently used as prophylaxis against bleeding in ITP and other bleeding disorders. The drug is contraindicated in overt DIC and hence there are concerns about its use in patients with COVID-19. However, studies have also shown that TXA can reduce the infectivity of SARS-CoV2 by blocking the action of plasmin, which cleaves the furin site in the S protein of SARS-CoV-2 and thus, blunt severity of COVID-19 [5].

Regarding the treatment of aplastic anemia in the time of the pandemic, although Anti-thymocyte globulin (ATG) is an intensely lympho-cytotoxic regimen, the effect of the same is short-lived. Cyclosporine does not affect viral infections and thus it can be safely used. In the treatment of mild disease – an oral combination of Eltrombopag with Cyclosporine is preferred [8].

In the management of the most common hemoglobinopathy – thalassemia, there is no major change during the time of the pandemic. The erythroid maturation agent luspatercept is considered safe to be used [10]. Iron chelators have immunomodulatory and antiviral properties and are also considered safe to use [11].

For sickle cell disease (SCD) regular exchange blood transfusion is the preferred therapy, especially for secondary prophylaxis against complications like acute chest syndrome and stroke [12]. Unfortunately, the pandemic has led to critical shortages in the availability of blood products [13]. A low dose of hydroxyurea may be added, which can reduce transfusion requirements while avoiding cytopenia’s [14]. The routine prescription of non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors should be tempered against their possible harmful effects in COVID-19. There is no contraindication for continuing the use of the newer agents voxelotor or crizanlizumab [10].

In hemophilia, patients on recombinant factor product replacement are considered safe during the pandemic and no change in the therapeutic regimen is required. However, if they contract a SARS-CoV2 infection – a higher factor level has to be maintained in the blood – due to an overall increased risk of bleeding [15].

Covid-19 infection is associated with an increased risk of thrombosis and thrombo-prophylaxis for hospitalized is considered essential. Direct Oral Anticoagulants are not recommended due to potential drug interactions, especially with anti-viral agents, and the potential for wide fluctuation in plasma levels. Low molecular weight heparin is therefore considered the standard of care. Heparin has the added benefit of having anti-inflammatory properties and reducing the infectivity of the virus. The increased incidence of thrombosis despite adequate thromboprophylaxis is concerning and has led to suggestions that the high-risk population requires a higher dose of anticoagulation, although this view is not widely accepted [16,17].

4. Conclusion

The SARS-COV2 infection has affected all corners of the world but has surprisingly shown a difference in its impact in different countries or even regions within a country. In the age of protocol-based management, COVID-19 presents a unique challenge where the therapy must be individualized to each patient and each treating center. The existing guidelines are based mostly on expert advice. Thus, there is a need for constant revision of these guidelines as more scientific evidence becomes available. It is essential that we remain consistent in our approach in these challenging times.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.