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Lymphoma and COVID-19: Management guidelines

Mar 9, 2021
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Throughout the COVID-19 pandemic, healthcare has faced a myriad of challenges, including restrictions on cancer therapies and other medical resources. Physicians treating patients with lymphoma have been confronted with a difficult task when considering the inter-patient heterogeneity, variable treatment goals, and spectrum of treatment approaches in this disease setting.

Noemie Lang and John Kuruvilla have published a review of the considerations relevant to the treatment and management of patients with lymphoma during the COVID-19 pandemic. The overview collates guidelines from several medical groups, including the American Society of Hematology (ASH), European Hematology Association, American Society for Transplantation and Cellular Therapy, and European Society for Blood and Marrow Transplantation (EBMT).1 The Lymphoma Hub is happy to provide a comprehensive yet concise summary.

Hematological malignancies and COVID-191

Increasing evidence suggests that patients with hematological malignancies are more susceptible to severe disease, complications following infection with coronavirus, and lower survival rates. This is due to the underlying disease- and treatment-related immunosuppression observed in this patient population. The ASH Research Collaborative COVID-19 registry reported that 18% of Hodgkin lymphoma (HL) and 21% of non-Hodgkin lymphoma patients admitted with COVID-19 required assistance in intensive care units, translating to mortality rates of 17% and 21%, respectively.

Below is a summary of the efforts being made to minimize risk of infection in patients with lymphoma, while maintaining effective treatment regimens. Despite extensive collaboration between a number of reputable organizations, it must be noted that these guidelines are not evidence based and instead have been compiled from expert opinions.

Overview

Patients with lymphoma may be particularly susceptible to coronavirus infection, as well as the social and emotional effects of the pandemic. Guidelines should be put in place to minimize the risk of exposure to COVID-19 and infection. The below points provide guidelines for physicians treating patients with lymphoma throughout the COVID-19 outbreak.

  • Patients should be advised to follow the general COVID-19 hygiene and social distancing measures and are encouraged to adopt a well-balanced lifestyle.
  • The goal of care is to be determined, i.e., curative vs palliative, following risk-benefit analysis.
  • All essential cancer care should continue, but changes to reduce potential exposure to COVID-19 infection might include:
    • Reducing hospital/outpatient clinic visits.
    • Replacing face-to-face appointments with telemedicine where possible.
    • Encouraging oral and subcutaneous regimens that can be taken on an outpatient basis where possible.
  • Replace immunosuppressive regimens with effective alternatives where possible.
  • COVID-19 tests should be made available, particularly when patients are to undergo high-risk procedures such as hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapies.

Aggressive lymphomas

For effective management of aggressive B-cell lymphomas, standard frontline therapy remains the optimal route. However, certain aspects of treatment and management can be adjusted to provide the safest treatment approach for patients with aggressive disease, which are summarized in Table 1.  

Generally, in the frontline setting, the risks and benefits of intensified therapies that require frequent laboratory monitoring must be identified and discussed with the patient. For patients with relapsed or refractory (R/R) disease, there are a number of salvage therapies with similar outcomes, and so fewer toxic regimens can be utilized prior to consolidative autologous hematopoietic stem cell transplantation (auto-HSCT). Where possible, CAR T-cell therapy should be indicated as a potentially curative approach for patients with R/R disease.

Table 1. Modifications to the care of patients with aggressive B- and T-cell lymphomas throughout the COVID-19 pandemic (adapted from Lang and Kuruvilla1)

Line of therapy

SoC

Considerations

DLBCL and high-grade BCL

First line

Curative: Immunochemotherapy ± RT for advanced disease

• Early stage: consider shortening to four cycles if aaIPI 0, age < 60 years, and if CMR achieved
• Outpatient regimens if possible
• Consider to omit/delay:
              – CNS prophylaxis at the end of therapy
              – RT if CMR for bulky/extranodal disease

Relapsed/
progressive

Curative: Salvage chemotherapy regimen followed by auto-HSCT, CAR-T cell therapy, allo-HSCT

• Outpatient salvage regimen if possible, prioritize patients achieving CMR for auto-HSCT
• For CAR-T, strategize to minimize toxicity/ICU stay:
              – patient selection
              – disease control
              – choice of product
• Advise CAR-T over allo-HSCT whenever possible
• Consider dose reduction of chemotherapy
• Consider hypofractionation of RT

Palliative: Outpatient chemotherapy regimen, RT

Burkitt and lymphoblastic lymphoma

First line

Curative: Intensive immunochemotherapy regimen

 

Relapsed/
progressive

Curative (transplant eligible): Salvage chemotherapy plus auto-HSCT or CAR T-cell therapy/allo-HSCT

• Outpatient salvage regimen if possible, prioritize patients achieving CMR for auto-HSCT
• Advise CAR-T over allo-HSCT whenever possible
• For CAR-T, strategize to minimize toxicity/ICU stay:
              – patient selection
              – disease control
              – choice of product
• Consider hypofractionation of RT

Palliative: Outpatient chemotherapy or RT

T-cell lymphoma

First line

Curative: Chemotherapy ± novel agent ± auto-HSCT

• Outpatient chemotherapy if possible
• Omit or defer auto-HSCT in first line if CR is achieved

Palliative: Chemotherapy, novel agent, RT

Relapsed/
progressive

Curative: Salvage chemotherapy or auto-HSCT/allo-HSCT

• Outpatient salvage regimen if possible
• Consider dose reduction of chemotherapy e.g., bendamustine
• Consider spaced infusion intervals if disease control is achieved
• Choice of novel agent should minimize need for hospital visits and the degree of immunosuppression

Palliative: Chemotherapy, novel agent, RT

aaIPI, age adjusted International Prognostic Index; allo-HSCT, allogeneic hematopoietic stem cell transplantation; auto-HSCT, autologous hematopoietic stem cell transplantation; CAR, chimeric antigen receptor; CMR, complete metabolic response; CNS, central nervous system; CR, complete response; ICU, intensive care unit; MTX, methotrexate; RT, radiotherapy; SoC, standard of care.

Hodgkin lymphoma

Therapeutic approaches to HL demonstrate high cure rates and therefore the treatment of patients with HL should not be deferred if possible.

Radiotherapy (RT) following chemotherapy has been associated with favorable disease control in patients with HL, and so the risks of both undergoing RT and omitting RT must be discussed with the patient. Following negative interim fluorodeoxyglucose positron emission tomography (PET) scan, a large proportion of physicians have adopted omitting bleomycin to reduce the risks associated with its use, such as lung injury.2 For the suggested adaptations in the management of patients with HL, see Table 2.

Table 2. Modifications to the care of patients with HL throughout the COVID-19 pandemic (adapted from Lang and Kuruvilla1)

Stage

SoC

Considerations

Early

Curative:
(Favorable) short course chemotherapy ± RT
(Unfavorable) chemotherapy ± RT

• Omit RT if CMR for early-stage disease and consider hypofractionation
• Advise PET-guided strategies and regimens with less infectious toxicity
              – ABVD over escalated BEACOPP
• When possible omit bleomycin
              – following ABVD if CMR after Cycle 2
              – from the onset for elderly patients or those with significant smoking history/underlying lung disease.

Advanced

Curative: (Immuno-)
chemotherapy ± brentuximab maintenance*

Relapsed/
progressive

Curative: Salvage chemotherapy plus auto-HSCT

• Outpatient chemotherapy/novel agents salvage regimen if possible
• Prioritize patients achieving CMR for auto-HSCT
• Space ICB infusion to four or six weekly intervals

Palliative: Novel agents, chemotherapy, RT

auto-HSCT, autologous stem cell transplantation; allo-HSCT, allogeneic hematopoietic stem cell transplantation; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; CMR, complete metabolic response; ICB, immune checkpoint blockade; RT, radiotherapy; SoC, standard of care.
*If indicated.

Cutaneous lymphomas

Guidelines for managing patients with cutaneous lymphomas depend on a number of unique factors, including disease stage and risk factors, which are illustrated in Table 3.

Table 3. Modifications to the care of patients with cutaneous lymphomas throughout the COVID-19 pandemic (adapted from Lang and Kuruvilla1)

Risk

SoC

Considerations

Low to
low–intermediate

• Topic therapies
• Phototherapy (UVA, UVB)
• Heliotherapy
• Oral therapies (antibiotics, antipruritics, retinoids, methotrexate, steroids, vorinostat, interferons alpha or gamma)
• TSEBT
• Aggressive moisturization

• Advise home-based therapies over those requiring hospitalization
• Advise short-term topic therapies over oral
• Advise less immunosuppressive oral therapies over steroids (e.g., retinoids, interferons)
• Consider dose adjustments on an individual basis.

High–intermediate to high

• IV chemotherapies
• Antibodies
• Skin RT
• Photopheresis
• Office-based UV therapy
• Allo-HSCT

• Consider dose adjustments and spaced intervals on an individual basis
• Avoid polychemotherapy and fludarabine-based regimens if possible
• Consider allo-HSCT only for very highly selected cases.

allo-HSCT, allogeneic hematopoietic stem cell transplantation; IV, intravenous; RT, radiotherapy; SoC, standard of care; TSEBT, total skin electron beam therapy; UVA, ultraviolet light A; UVB, ultraviolet light B.

Indolent lymphomas

The initial management approach for patients with indolent lymphomas who present with few or no symptoms involves watchful waiting. Nevertheless, early therapeutic intervention can result in favorable overall survival and long-term disease control. In the context of the COVID-19 pandemic, it becomes ever more crucial to assess the risks and benefits of treatment vs no treatment for each patient.

A transition from intravenous therapies to subcutaneous and oral administrations is being observed in the indolent lymphoma setting in the hope to reduce hospital and outpatient clinic exposure. Additionally, concerns surrounding the immunosuppressive nature of bendamustine and anti–B-cell monoclonal antibodies have been raised, and it has been advised that anti-CD20 maintenance be delayed or omitted, and bendamustine doses reduced, during periods of severe COVID outbreak.

Mantle cell lymphoma

Patients with mantle cell lymphoma (MCL) represent a highly heterogeneous population, and treatment approaches within the MCL setting vary greatly. Throughout the COVID-19 pandemic, however, there have been general guidelines that can be followed for the management of patients with MCL.

For asymptomatic patients, and those with non-nodal leukemic MCL, the advised approach is watchful waiting. However, in patients who require intensive therapy, physicians should not deviate from standard of care, which consists mainly of cytarabine-based induction followed by auto-HSCT. Where available, targeted agents can be used as a replacement for intensive chemotherapy.

Chronic lymphocytic leukemia

Continued use of targeted therapies have been recommended in the frontline CLL setting whenever possible; this is particularly applicable to elderly patients and those with progressive disease. There is conflicting evidence surrounding the protective role of BTK inhibitors with respect to COVID-19. This, alongside the negative impact of abrupt omission of BTK inhibitor therapy, and the potential pulmonary side effects associated with the use of BTK inhibitors, means that it is crucial to monitor each patient individually over the course of the treatment, particularly if they contract COVID-19.

Changes to specific therapeutics

In the allogeneic (allo)-/auto-HSCT setting, patients are urged to follow the 14-day home isolation advice prior to undergoing transplant induction regimens. In addition, patients should have a negative COVID-19 test prior to conditioning. For HSCT to go ahead, stringent patient selection should consider patient fitness level and the potential impact of deferring treatment. This guidance comes following the EBMT-reported figures of 19% and 21% 6-week mortality rates amongst patients receiving auto- and allo-HSCT, respectively.

In the case of allogeneic cell products, including stem cells and CAR T cells, both the donor and recipient should provide a negative COVID-19 test result prior to collection/transfusion, and conditioning should not begin until the products are on site. Extensive guidelines for the use of CAR T-cell products throughout the COVID-19 pandemic have recently been published by the CAR T-cell Consortium and can be viewed here. Notably, tocilizumab should be accessible for the management of CAR T-associated adverse events.

Should a patient contract COVID-19 prior to transplant, the European Center for Disease Prevention and Control recommendations outline that, where feasible, the procedure should be postponed by at least 3 months. However, these decisions must consider patient-specific variables.

The International Lymphoma Radiation Oncology Group have recently published advice for RT procedures, which highlight the potential benefit of RT hypofractionation. RT may also provide a suitable alternative to systemic palliative treatment options, but the risk of frequent clinic visits must be assessed for these patients, as well as in the R/R consolidative setting.

Conclusions

The COVID-19 pandemic has impacted the day-to-day practice of physicians worldwide, including those dedicated to treating patients with lymphoma. Where cure is a possibility, patients should be treated appropriately without deferral. However, non-curative treatment decisions are to be made with haste following stringent risk-benefit assessment. Each treatment decision should be made on an individual case basis, with the aim to minimize the risk and severity of infection with COVID-19, while maintaining suitable disease control and honoring the patient’s wish.

  1. Lang N and Kuruvilla J. Evolving management strategies for lymphomas during the COVID-19 pandemic. Leuk Lymphoma. 2020. Online ahead of print. DOI: 1080/10428194.2020.1861277
  2. Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clin Chest Med. 1990 Mar;11(1):1–20

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