The co-opting and weakening of the immune system by hematologic malignancies and many of their treatments – and the blunting of the immune system’s response to vaccines – may be more salient during the COVID-19 pandemic than ever before.
Courtesy NIAID
Hematologic malignancies have been associated in large cancer-and-COVID-19 registries with more severe COVID-19 outcomes than solid tumors, and COVID-19 mRNA vaccines have yielded suboptimal responses across multiple studies. Clinicians and researchers have no shortage of questions, like what is the optimal timing of vaccines relative to cancer-directed therapy? What is the durability and impact of the immune response? What is the status of the immune system in patients who do not produce antispike antibodies after COVID-19 vaccination?
Moreover, will there be novel nonvaccine strategies – such as antibody cocktails or convalescent plasma – to ensure protection against COVID-19 and other future viral threats? And what really defines immunocompromise today and moving forward?
“We don’t know what we don’t know,” said Jeremy L. Warner, MD, associate professor of medicine (hematology/oncology) and biomedical informatics at Vanderbilt University, Nashville, Tenn., and cofounder of the international COVID-19 and Cancer Consortium. “The immune system is incredibly complex and there are numerous defenses, in addition to the humoral response that we routinely measure.”
Another of the pressing pandemic-time questions for infectious disease specialists working in cancer centers concerns a different infectious threat: measles. “There is a lot of concern in this space about the reported drop in childhood vaccinations and the possibility of measles outbreaks as a follow-up to COVID-19,” said Steven A. Pergam, MD, MPH, associate professor in the vaccine and infectious disease division and the clinical research division of the Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance.
Whether recipients of hematopoietic cell transplantation (HCT) and cellular therapy should be revaccinated earlier than 2 years post treatment is a question worthy of preemptive discussion, he said.
What about timing?
“A silver lining of the pandemic is that it’s improving our understanding of response to vaccinations and outcomes with respiratory viruses in patients with hematologic malignancies,” said Samuel Rubinstein, MD, of the division of hematology at the University of North Carolina at Chapel Hill. “We’re going to learn a lot more about how to ensure that our patients are optimally protected from respiratory viruses.”
Dr. Rubinstein focuses on plasma cell disorders, mostly multiple myeloma, and routinely explains to patients consenting to use daratumumab, an anti-CD38 monoclonal antibody, or a BCMA-directed therapy, that these therapies “in particular probably do impair vaccine immune response.”
He has handled the timing of the COVID-19 vaccines – currently boosters, in most cases – as he has with influenza and other immunizations such as the pneumococcal vaccine, administering the vaccines agnostic to therapy unless the patient is about to start daratumumab or a BCMA-directed therapy. In this case, he considers vaccinating and waiting 2 weeks (for an immune response to occur) before starting therapy.
However, “if I have any concern that a delay will result in suboptimal cancer control, then I don’t wait,” Dr. Rubinstein said. Poor control of a primary malignancy has been consistently associated with worse COVID-19–specific outcomes in cancer–COVID-19 studies, he said, including an analysis of almost 5,000 patients recorded to the COVID-19 and Cancer Consortium .1
(The analysis also documented that patients with a hematologic malignancy had an odds ratio of higher COVID-19 severity of 1.7, compared with patients with a solid tumor, and an odds ratio of 30-day mortality of 1.44.)
Ideally, said Dr. Warner, patients will get vaccinated with the COVID-19 vaccines or others, “before starting on any cytotoxic chemotherapy and when they do not have low blood counts or perhaps autoimmune complications of immunotherapy.” However, “perfect being the enemy of good, it’s better to get vaccinated than to wait for the exact ideal time.”
Peter Paul Yu, MD, physician-in-chief at Hartford (Conn.) Healthcare Cancer Institute, said that for most patients, there’s no evidence to support an optimal timing of vaccine administration during the chemotherapy cycle. “We looked into that [to guide administration of the COVID-19 vaccines], thinking there might be some data about influenza vaccination,” he said. “But there isn’t much. … And if we make things more complicated than the evidence suggests, we may have fewer people getting vaccinations.”
The National Comprehensive Cancer Network offered several timing recommendations in its August 2021 COVID-19 vaccination guidance – mainly that patients receiving intensive cytotoxic chemotherapy (such as those on cytarabine/anthracycline-based induction regimens for acute myeloid leukemia) delay COVID-19 vaccination until absolute neutrophil count recovery, and that patients on long-term maintenance therapy (for instance, targeted agents for chronic lymphocytic leukemia or myeloproliferative neoplasms) be vaccinated as soon as possible.
Vaccination should be delayed for at least 3 months, the NCCN noted, following HCT or engineered cell therapy (for example, chimeric antigen receptor [CAR] T cells) “in order to maximize vaccine efficacy.”