COVID-19 and Indolent Lymphomas: Frequently Asked Questions

(Version 6.0; last updated April 1, 2022)

Input from Ranjana Advani, MD; Nancy Bartlett, MD; Ann LaCasce, MD, MSc; Leo Gordon, MD; Peter Johnson, MD, FRCP; Kerry Joanne Savage, BSc, MD, MSc; Laurie Sehn, MD, MPH; Jane Winter, MD.

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

Whereas treatment for indolent lymphomas and mantle cell lymphoma is not curative, there is more flexibility in approach with a key focus on safety in the setting of COVID-19. The International Lymphoma Radiation Oncology Group (ILROG) has published emergency guidelines for radiation therapy of hematologic malignancies that may be helpful when considering radiotherapy.

Most centers screen patients beginning therapy in the outpatient clinic or even monthly for SARS-CoV-2 on an ongoing basis or on admission to the hospital for treatment. Practices differ depending on the prevalence of COVID-19. The decision on when and how to treat indolent lymphoma in the face of a positive result must be individualized. The degree to which ongoing chemotherapy affects the outcome of patients with COVID-19 remains controversial, but at least one large study shows that individuals with hematologic malignancies undergoing treatment when diagnosed with COVID-19 are at high risk of severe complications. According to one report, the more intensive the therapy, the greater the impact on clinical outcomes from COVID-19.

Patients, their families, and caregivers should be encouraged to be vaccinated against influenza and SARS-CoV-2 and cautioned to follow recommendations for reducing the risk of contracting COVID-19. The high morbidity and mortality rates reported in patients with hematologic malignancies underscore the vulnerability of this patient population. Special considerations are noted below and in the ASH FAQ on this topic.

Patients undergoing treatment should be encouraged to alert their physicians to new symptoms that could represent SAR-CoV-2 infection so that testing and treatment for COVID-19 with oral antiviral therapy or antibodies can be initiated promptly.

Are you changing your indications for therapy?

Given COVID-19, the threshold for initiating treatment should be high, and watchful waiting should be the preferred strategy whenever possible. Treatment is recommended in symptomatic patients, but if the indication for therapy is borderline, (e.g., if the patient meets GELF criteria but is asymptomatic) treatment deferral and close monitoring with repeat imaging may be prudent. Treatment for asymptomatic patients with rituximab monotherapy is not recommended. Vaccination against SARS-CoV-2 is recommended prior to initiating treatment when feasible. Based on results in immunocompetent patients immunized with the mRNA vaccines, rituximab-containing therapy should be delayed two weeks from the second vaccination (for two-dose vaccines), or third or fourth dose to allow for the development of neutralizing antibodies and T-cell responses.

Are you changing your approach to initial therapy?

When treatment is indicated, rituximab monotherapy rather than R-chemotherapy may be a consideration. If a single disease site is of concern, localized radiotherapy is an effective option (see ILROG Emergency Guidelines). Many experts have concerns about the immunosuppressive properties of bendamustine and are recommending R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with growth factor support as alternatives, without rituximab maintenance. Others continue to prescribe R-bendamustine sometimes followed by maintenance but changes in practice continue to evolve. The availability of vaccines against SARS-CoV-2 is altering practice and leading many experts to avoid the most immunosuppressive therapies.

For those who tolerate the first dose of rituximab given intravenously, subcutaneous administration is an option going forward that reduces time spent in the clinic.

Ibrutinib and other Bruton’s tyrosine kinase (BTK) inhibitors continue to be prescribed for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Waldenström macroglobulinemia, and are options for relapsed mantle cell lymphoma. Ibrutinib is approved for relapsed marginal-zone lymphoma in the United States. Consolidation with high-dose chemotherapy and HCT in mantle cell lymphoma continues to be controversial.

Are you changing therapy to minimize visits? For example, changing to oral or less frequent regimens?

In many regions, both physicians and patients have become more comfortable visiting the medical center wearing masks and socially distancing. Overall, telemedicine visits have declined but do help to reduce crowding in the outpatient clinic and opportunities for infection with the very infectious new variants.

Some experts continue to prefer oral options rather than intravenous chemotherapy in CLL/SLL, marginal zone lymphoma, or mantle cell lymphoma, in an effort to reduce the risk of infection and to reduce crowding in the outpatient clinic. Some patients may be eligible to receive up to a three-month supply of their oral medications; this approach, with labs obtained locally and telehealth visits may allow patients to stay at home for the time being. Patients who are on “watchful waiting” may have visits delayed with telemedicine alternatives, with lab work obtained locally or delayed if risk is low.

Are you changing your approach to supportive care?

Growth factor support is recommended by some for patients receiving R-CHOP regardless of age, hoping to prevent trips to the emergency department during the pandemic and may be helpful in selecting patients who are receiving bendamustine. Patients with comorbidities, recurrent infections, and low IgG levels, including those who have received rituximab, may benefit from monthly immunoglobulin supplementation if available.

Are you changing your treatment recommendations for relapsed/refractory disease?

Management of relapsed/refractory indolent lymphoma should be based on symptoms and indications for treatment as for previously untreated patients. When possible, experts recommend delaying treatment. When choice of therapy is available, options that minimize clinic/chemotherapy unit visits are preferred. Use of bendamustine, given its immunosuppressive properties, is discouraged by some experts. Oral agents such as BTK inhibitors and lenalidomide with rituximab are options that should be considered. Radioimmunotherapy, where available, is an underutilized option for relapsed/refractory follicular lymphoma available at some centers.

Should patients with indolent lymphoma receive a vaccine for SARS-CoV-2?

Patients with indolent lymphoma should be encouraged to receive the SARS-CoV-2 vaccines. Specific to SARS-CoV-2, data regarding the safety and efficacy of vaccines in immunocompromised patients are evolving, but thus far there do not appear to be any specific concerns for toxicity for this patient population. As a general statement, we recommend that patients with indolent lymphoma be vaccinated against SARS-CoV-2, though they may not mount an effective immune response. For patients not yet vaccinated who are receiving rituximab monotherapy or rituximab-containing regimens, decisions regarding the timing of vaccination must be individualized based on the prevalence of COVID-19 in the community, the patient’s capacity to self-isolate and that of their family members and caregivers, and the expected duration of treatment.

A primary series consisting of three doses of mRNA vaccine is recommended for immunocompromised patients with a fourth dose three months from the third. Although, rituximab therapy is expected to blunt or entirely eliminate a humoral response to vaccination for at least nine to twelve months from last exposure, or longer, T-cell responses may provide some degree of protection or reduce severity of infection, justifying vaccination during or soon after completion of therapy. Recent data show that antibody responses achieved prior to treatment can endure through anti-CD20–containing treatment (Shree et al). Prophylaxis with long-acting antibodies where available provide an additional level of protection for patients requiring treatment. For more information about SARS-CoV-2 vaccines and immunocompromised patients, prophylaxis and treatment, see the ASH FAQs on this topic.

Resources

Yahalom J, Dabaja BS, Ricardi U, et al. ILROG emergency guidelines for radiation therapy of hematological malignancies during the COVID-19 pandemic. Blood. 2020 May 21;135(21):1829-1832. doi: 10.1182/blood.2020006028. PMID: 32275740; PMCID: PMC7243146.

Lee, Lennard Y WGault, Abigails et al. COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study. The Lancet Oncology. 2020; Volume 21, Issue 10, 1309 - 1316. Published 2020 Aug 24. DOI: https://doi.org/10.1016/S1470-2045(20)30442-3.

Clift AK, Coupland CAC, Keogh RH, et al. Living risk prediction algorithm (QCOVID) for risk of hospital admission and mortality from coronavirus 19 in adults: national derivation and validation cohort study. BMJ. 2020 Oct 20;371:m3731. doi: 10.1136/bmj.m3731.

Shree T, Shankar V, Lohmeyer JJK, et al. CD20-targeted therapy ablates de novo antibody response to vaccination but spares preestablished immunity. Blood Cancer Discov. 2022;3(2): 95-102..

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