Is Immune Impairment a Potential Benefit?

One of the key questions to come from this study is whether the immune suppression that typically increases susceptibility to infections may reduce the risk of developing a cytokine storm, one of the most common ways that patients with COVID-19 die from the disease. Given the findings, “their hypothesis that perhaps the immune dysregulation of CLL prevents severe cytokine storm is good,” Dr Rogers said.

Dr Montserrat called their hypothesis speculative and provocative as he described the potential mechanism: “In short, the accepted paradigm is that infection by SARS-Cov-2 (affecting primarily T lymphocytes, particularly CD4+ and CD8+ T cells), is followed by a rapid viral replication (first “viral wave”) that, unless controlled by an efficient immune system, results in further viral replication.” That second “viral wave” might then lead to “a skewed and exaggerated immune reaction, leading to a cytokine and inflammatory storm,” he said. “Because of this, not having a totally efficient immune system could be an advantage rather than a problem.”

The paper also brings up questions about whether certain immune-suppressing therapies that treat CLL could have benefits with COVID-19, Dr Spurgeon said. He noted that ibrutinib, widely used to treat CLL, is effective as an inhibitor of Bruton’s tyrosine kinase (BTK) but has off-target effects too.


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“One of those effects postulated is against HCK, a protein that can, when it’s overexpressed, lead to increased pulmonary inflammation and enhanced innate immune responses in mouse models,” he said. “We don’t know exactly what that means clinically in our CLL patients or Waldenström [macroglobulinemia] patients or lymphoma patients treated ibrutinib in general, but it’s a particular interest in COVID[-19] patients.”

Overall, these findings from Barcelona are intriguing, Dr Spurgeon said, and open up the possibility that patients with impaired immune function don’t mount the immune response that can lead to a cytokine storm.

“Ultimately, it’s about the balance between controlling an overactive immune system but ideally maintaining or developing humoral immunity,” he said.

Like any good hypothesis-generating study, this publication raises far more questions than it answers, Dr Rogers said. She went on to explain that“people with CLL have impaired humoral immunity, so we don’t know if that will affect how long they shed the virus, if antibody testing in CLL patients works, if different CLL features affect outcomes,” and how various CLL treatments might affect a COVID-19 disease course. Dr Rogers also noted that ibrutinib is under exploration as a COVID-19 treatment, raising the question of whether it may help CLL patients who develop COVID-19.

Findings Do Not Change Practice

“While we are looking for more data, it makes sense to manage CLL patients as at high-risk for COVID-19. Prudence does not harm,” Dr Montserrat said. “But I would not recommend measures beyond those we apply to the general population.”

Dr Spurgeon expressed more concern about whether patients were continuing to receive therapy they need.

“Some people may be deferring therapy” out of fear during the pandemic, but “it’s important to understand that patients who need treatment, need treatment,” Dr Spurgeon stated. “We shouldn’t always make assumptions that the therapy given for a certain disease, with CLL might have harm. It speaks to the importance of following outcomes in real time.”

One important takeaway from the study for patients, however, is the cautious optimism that might ease a bit of anxiety for CLL patients right now, Dr Rogers said.

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“Our CLL patients are terrified of getting COVID-19 and becoming severely ill or dying from it.” Letting them know about CLL patients in Spain who survived the disease without needing the ICU “does offer some much needed hope to both patients and clinicians at a time when people are really terrified of this pandemic virus,” she said.

It’s important for patients with CLL to continue following public health recommendations to reduce their risk of exposure to the virus, but at the least, Dr Rogers concluded, this study lets people know that getting COVID-19 while living with CLL is not a “death sentence.” 

Disclosures: The study did not use external funding, and the authors had no disclosures. Dr Spurgeon has received research funding from Janssen, BMS, Genentech, Velos-Bio, Sutro Pharma, Acerta, Gilead Sciences, and Beigene, and has consulted for Janssen. Dr Rogers has received research funding from Genentech, AbbVie, and Janssen; has received travel support from AstraZeneca; and has served on advisory boards for Acerta Pharma, AstraZeneca, and Pharmacyclics.

References

  1. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21(3):335‐337. doi:10.1016/S1470-2045(20)30096-6
  2. Baumann T, Delgado J, Montserrat E. CLL and COVID-19 at the Hospital Clinic of Barcelona: an interim report. 2020 May 19. Leukemia. 2020;1‐3. doi:10.1038/s41375-020-0870-5
  3. SEER Cancer Stat Facts: Chronic Lymphocytic Leukemia. National Cancer Institute. https://seer.cancer.gov/statfacts/html/clyl.html. Accessed June 18, 2020.