The Case

A 66-year-old woman with stage IV follicular lymphoma (FL) on observation since 2017 calls to report an uncomfortable mass in her left axilla. She has no fevers, sweats, or weight loss. At the time of her call, there is a moderate but increasing level of COVID-19 in your area. The reproductive (R) value is 1.1, and COVID-19 hospitalizations are increasing. The local health care system is not overwhelmed, and the hospital-based cancer clinic where you work has been able to maintain access to diagnostic tests and treatments. The patient expresses reluctance to come into the hospital due to a fear of COVID-19.

Questions

What is the impact of the COVID-19 pandemic on delayed diagnoses and treatment? How should this patient be counselled?

Response

There is mounting evidence that during the COVID-19 pandemic, patients are experiencing delayed diagnosis and treatment for non–COVID-19–related illnesses1-3 ; fear of contracting COVID-19 and subsequent care avoidance likely contributes to this pattern.4  Delays result in preventable morbidity and mortality for patients with cancer.5,6  In this case, the presentation is suspicious for transformed lymphoma versus progressive FL, both of which require prompt investigation and treatment.7,8 

Except for health care systems in crisis or experiencing recurrent COVID-19 outbreaks, the anticipated benefits of timely diagnosis and treatment likely outweigh the risk of contracting COVID-19 in a health care setting. Clinicians can help address patient fears by advocating for modified clinic operations including telemedicine, social distancing, masking, vaccination of health care staff, and testing for COVID-19 where appropriate.9,10  It is critically important that we maintain safe access to cancer care and that patients are aware that in most cases they can safely visit their cancer team.

The Case, Continued

The patient agrees to visit the hospital for further investigation. Lactate dehydrogenase is mildly elevated; complete blood cell count, creatinine, extended electrolytes, and liver enzymes are all normal. Positron emission tomography/computed tomography demonstrates FDG-avid nodes above and below the diaphragm, with the largest nodal mass in the left axilla at 5.5 cm. Biopsy of the axillary mass demonstrates FL, grade 2, with no evidence of transformation. The patient remains concerned about the possibility of dying from COVID-19 but is also increasingly uncomfortable from her axillary mass.

Question

What is this patient’s risk of dying from COVID-19?

Response

An individual patient’s risk of dying from COVID-19 is impacted by their risk of exposure to the virus, the nature of their exposure (prolonged, masked vs. unmasked, etc.), and their individual risk of infection and serious sequelae. At the time of writing, it is not known whether having a hematologic malignancy independently increases the risk of contracting COVID-19. We do know that patients with hematologic malignancy have a higher risk of COVID-19 mortality than patients without hematologic malignancy. A cohort study of over 17 million Britons reported that patients diagnosed with a hematologic malignancy in the previous year had a higher risk of dying from COVID-19 (adjusted HR 2.80) compared to those without hematologic malignancy.11  A meta-analysis of patients with COVID-19 and hematologic malignancy found a risk of death of 34 percent in a mainly hospitalized sample.12 

There are important limitations to reports of high COVID-19 mortality in patients with blood cancer. First, many published reports of COVID-19 in patients with blood cancer are heavily enriched with hospitalized patients12 ; thus, mortality risk estimates may not be accurate for all-comers. Second, most published reports of COVID-19 in patients with blood cancer are based on data from early in the pandemic, and COVID-19 outcomes are improving.13  Third, while the attributable COVID-19 mortality risk from hematologic malignancy is substantial, it is much lower than the impact of advanced age (adjusted HR for age over 80 years, 20.6, compared to age of 50-59).11  A validated COVID-19 mortality risk predictor is available, incorporating regional COVID-19 risks with a patient’s demographics and comorbidities.14  However, factors such as protective behaviors, disease-specific information, and the impact of systemic cancer treatment are beyond the scope of this calculator.

Question

Does systemic cancer treatment increase the risk of COVID-19 mortality? How should this patient be treated?

Response

Infections are widely recognized as occurring more frequently and with greater severity in patients with hematologic malignancy and among those receiving systemic cancer therapy. However, data specifically addressing the risk of cancer treatment on COVID-19 mortality are sparse, of low quality, and inconsistent.12,15,16  In the face of this uncertainty, hematologists must weigh the competing risks of mortality and morbidity from untreated blood cancers against an uncertain but possibly increased risk of mortality in the event of COVID-19 infection. Expert groups have advised that in the context of high COVID-19 prevalence and/or health system capacity challenges, it may be appropriate to modify or delay cancer treatment, particularly for low-grade disease.17 

In this case, the patient was treated with low-dose radiation to the left axilla, and close follow-up. Chemoimmunotherapy was deferred. This decision was influenced by the recognized radiosensitivity of low-grade lymphoma,18  a rising local prevalence of COVID-19, a lack of immediate access to COVID-19 vaccination but anticipation of access within six months, and patient preference. These factors were balanced against a high probability of achieving prolonged disease control with chemoimmunotherapy,19  and a risk that radiation treatment might minimally delay time to systemic treatment given that the patient had multiple sites of disease.

In this case, treating with chemoimmunotherapy such as bendamustine plus rituximab (BR) would also have been reasonable. During the pandemic, we have continued to recommend maintenance rituximab (MR) following chemoimmunotherapy given improvements in progression-free survival with this approach.20  However, as there are no randomized data supporting MR after BR, and there are some reports suggesting increased infectious risk,21  it would also be reasonable to defer MR.

Question

Should this patient be vaccinated against COVID-19 if available?

Response

There are limited data on the safety and efficacy of the COVID-19 vaccines in patients with hematologic malignancy. However, safety data from other non-live vaccines are reassuring, and based on these data, it seems unlikely that unique safety concerns will arise for our population. However, the existing vaccination literature does raise potential concerns about vaccine effectiveness in patients with blood cancers, particularly those receiving anti-CD20 agents.22  Anti-CD20 therapy appears to have a prolonged and powerful negative impact on vaccine responses which can last for more than a year beyond the last dose of anti-CD20.23-25  It is unknown if this negative immune response will affect COVID-19 vaccines. We also don’t know if different types of COVID-19 vaccines will differ in their ability to stimulate immunity in our patient population, what vaccination schedule will be optimal, or if booster doses of vaccine will be helpful. Collaborative research in this area is urgently needed. In the absence of data, our approach is to encourage COVID-19 vaccination among our patients, and when feasible, to vaccinate before starting systemic cancer treatment. Because we anticipate impaired vaccine responses in our patients, we also encourage their caregivers and household contacts to be vaccinated against COVID-19 if possible and recommend continued infection control measures such as masking and social distancing.

References

References
1.
Czeisler
,
Marynak
K
,
Clarke
KEN
, et al
.
Delay or avoidance of medical care because of COVID-19–related concerns – United States, June 2020
.
MMWR Morb Mortal Wkly Rep
.
2020
;
69
:
1250
-
1257
.
2.
Dinmohamed
AG
,
Visser
O
,
Verhoeven
RHA
, et al
.
Fewer cancer diagnoses during the COVID-19 epidemic in the Netherlands
.
Lancet Oncol
.
2020
;
21
:
750
-
751
.
3.
Zheng
NS
,
Warner
JL
,
Osterman
TJ
, et al
.
A retrospective approach to evaluating potential adverse outcomes associated with delay of procedures for cardiovascular and cancer-related diagnoses in the context of COVID-19
.
J Biomed Inform
.
2021
;
113
:
103657
.
4.
Lou
E
,
Teoh
D
,
Brown
K
, et al
.
Perspectives of cancer patients and their health during the COVID-19 pandemic
.
PLoS One
.
2020
;
15
:
e0241741
.
5.
Sud
A
,
Jones
ME
,
Broggio
J
, et al
.
Collateral damage: the impact on outcomes from cancer surgery of the COVID-19 pandemic
.
Ann Oncol
.
2020
;
31
:
1065
-
1074
.
6.
Lai
AG
,
Pasea
L
,
Banerjee
A
, et al
.
Estimated impact of the COVID-19 pandemic on cancer services and excess 1-year mortality in people with cancer and multimorbidity: near real-time data on cancer care, cancer deaths and a population-based cohort study
.
BMJ Open
.
2020
;
10
:
e043828
.
7.
Wagner-Johnston
ND
,
Link
BK
,
Byrtek
M
, et al
.
Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS)
.
Blood
.
2015
;
126
:
851
-
857
.
8.
Freedman
A.
Follicular lymphoma: 2018 update on diagnosis and management
.
Am J Hematol
.
2018
;
93
:
296
-
305
.
9.
Healthcare facilities: Managing operations during the COVID-19 pandemic
.
Centers for Disease Control and Prevention
.
Updated Dec. 22, 2020. Accessed Jan 2021. Access via https://pubmed.ncbi.nlm.nih.gov/29314206/
.
10.
Al-Shamsi
HO
,
Alhazzani
W
,
Alhuraiji
A
, et al
.
A practical approach to the management of cancer patients during the novel coronavirus disease 2019 (COVID-19) pandemic: An international collaborative group
.
Oncologist
.
2020
;
25
:
e936
-
e945
.
11.
Williamson
EJ
,
Walker
AJ
,
Bhaskaran
K
, et al
.
Factors associated with COVID-19–related death using OpenSAFELY
.
Nature
.
2020
;
584
:
430
-
436
.
12.
Vijenthira
A
,
Gong
IY
,
Fox
TA
, et al
.
Outcomes of patients with hematologic malignancies and COVID-19: A systematic review and meta-analysis of 3377 patients
.
Blood
.
2020
;
136
:
2881
-
2892
.
13.
Horwitz
LI
,
Jones
SA
,
Cerfolio
RJ
, et al
.
Trends in COVID-19 risk-adjusted mortality rates
.
J Hosp Med
.
2020
; doi:
10.12788/jhm.3552. [Epub ahead of print]
.
14.
Jin
J
,
Agarwala
N
,
Kundu
P
, et al
.
Individual and community-level risk for COVID-19 mortality in the United States
.
Nat Med
.
2020
; doi:
10.1038/s41591-020-01191-8
.
[Epub ahead of print]
.
15.
Liu
H
,
Yang
D
,
Chen
X
, et al
.
The effect of anticancer treatment on cancer patients with COVID-19: A systematic review and meta-analysis
.
Cancer Med
.
2020
; doi:
10.1002/cam4.3692. [Epub ahead of print]
.
16.
Wang
B
,
Huang
Y
.
Immunotherapy or other anti-cancer treatments and risk of exacerbation and mortality in cancer patients with COVID-19: a systematic review and meta-analysis
.
Oncoimmunology
.
2020
;
9
:
1824646
.
17.
Advani
R
,
Bartlett
N
,
Gordon
L
, et al
.
COVID-19 and indolent lymphomas: Frequently asked questions
.
Am Soc of Hematology
.
2020
. .
18.
Yahalom
J
,
Dabaja
BS
,
Ricardi
U
, et al
.
ILROG emergency guidelines for radiation therapy of hematological malignancies during the COVID-19 pandemic
.
Blood
.
2020
;
135
:
1829
-
1832
.
19.
Rummel
MJ
,
Niederle
N
,
Maschmeyer
G
, et al
.
Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial
.
Lancet
.
2013
;
381
:
1203
-
1210
.
20.
Bachy
E
,
Seymour
JF
,
Feugier
P
, et al
.
Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: Long-term results of the PRIMA study
.
J Clin Oncol
.
2029
;
37
:
2815
-
2824
.
21.
Hiddemann
W
,
Barbui
AM
,
Canales
MA
, et al
.
Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: Influence of chemotherapy on efficacy and safety
.
J Clin Oncol
.
2018
;
36
:
2395
-
2404
.
22.
van Aalst
M
,
Langedijk
AC
,
Spijker
R
, et al
.
The effect of immunosuppressive agents on immunogenicity of pneumococcal vaccination: A systematic review and meta-analysis
.
Vaccine
.
2018
;
36
:
5832
-
5845
.
23.
Issa
NC
,
Marty
FM
,
Gagne
LS
, et al
.
Seroprotective titers against 2009 H1N1 influenza A virus after vaccination in allogeneic hematopoietic stem cell transplantation recipients
.
Biol Blood Marrow Transplant
.
2011
;
17
:
434
-
438
.
24.
Nazi
I
,
Kelton
JG
,
Larché
M
, et al
.
The effect of rituximab on vaccine responses in patients with immune thrombocytopenia
.
Blood
.
2013
;
122
:
1946
-
1953
.
25.
de Lavallede
H
,
Garland
P
,
Sekine
T
, et al
.
Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host
.
Haematologica
.
2011
;
96
:
307
-
314
.

Competing Interests

Dr. Hicks and Dr. Vijenthira indicated no relevant conflicts of interest.