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Patients with chronic lymphocytic leukemia (CLL) can be expected to have a more severe course of SARS-CoV-2 infection and a higher mortality risk, research suggests. Investigators are analyzing existing cases for information and insights, and the American Society of Hematology (ASH) has offered guidance on managing patients with both CLL and COVID-19.

Two of the largest case studies to date have reported high mortality rates for these patients. The European Research Initiative on CLL (ERIC) examined with CLL and confirmed SARS-CoV-2 infection, mostly from Italy and Spain. Almost 80% of patients presented with a severe course of COVID-19, as defined by need of oxygen and/or intensive care admission. The mortality rate of hospitalized patients was 32.5%, and patients age 65 and older had nearly four times the risk for severe disease (HR 3.72, 95% CI 1.79-7.71).

Another that included 198 patients from the U.S., Europe, and South America reported similar outcomes. Anthony Mato, MD, of Memorial Sloan Kettering Cancer Cancer in New York City, and colleagues found that 90% of patients were hospitalized with oxygen support, and the overall case mortality rate was 33%. In multivariable analyses, significant predictors for adverse outcomes among CLL patients were increased age, comorbidity, asthma, and chronic renal disease.

The two studies differed on one point, however. The ERIC study found a protective effect for patients on the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica). The hospitalization rate for severe COVID-19 was lower for CLL patients on ibrutinib compared with patients receiving any other CLL-specific treatment, as well as those off treatment (OR 0.44, P<0.05).

Mato and co-authors, however, found no such protective effect. In their study, nearly half of the patients were receiving active CLL therapy at COVID-19 diagnosis, most commonly BTK inhibitors. Nevertheless, the watch-and-wait and treated cohorts had similar rates of hospital admission (89% vs 90%) and mortality (37% vs 32%). More specifically, CLL-directed treatment with BTK inhibitors at COVID-19 diagnosis did not affect survival (case fatality rate of 34% vs 35%), the study found.

As for why the two studies differed, Mato told 乌鸦传媒: "This is a hard question to answer. In our study a very high proportion of patients discontinued the BTK inhibitor at the time of COVID diagnosis, and so it was very hard to judge if continuing the BTK inhibitor would have helped," he noted via email, adding that randomized clinical trials have not yet shown that BTK inhibitors minimize the pulmonary complications of COVID.

Guidance from ASH

Mato was part of a panel that provided guidance in the form of on the ASH website. "Recently published reports suggest a possible benefit from the BTKis [BTK inhibitors] (ibrutinib and acalabrutinib [Calquence]) in the setting of severe COVID-19 infection," the guidance states. "While controlled studies are needed to confirm those results, it is our practice to continue BTKis in patients with CLL diagnosed with COVID-19 ... There is general agreement on holding monoclonal antibodies for COVID-positive patients ... It is also our practice to hold venetoclax [Venclexta] in patients diagnosed with COVID-19."

The lead author of the ASH guidance, Mazyar Shadman, MD, of Fred Hutchinson Cancer Research Center in Seattle, explained further: "In a patient who is on active treatment and tests positive for COVID, in general, in principle in oncology, we stop cancer therapy because of any type of infection and wait until recovery," he told 乌鸦传媒.

"Now something that's a little bit different, and may be an exception here, is that over the course of the past year we've learned that BTK inhibitors, like ibrutinib, acalabrutinib, and zanubrutinib [Brukinsa], may have a protective impact with the COVID-19 infection. So, based on studies that have been published, the practice now is to continue patients on BTK inhibitors. Of course everything needs to be assessed case-by-case, but in general we do tend to keep patients on those agents," Shadman said.

"But other drugs, such as chemotherapy, which is not very common these days, or monoclonal antibodies, or even venetoclax, we would stop the drug and wait until they recover," he advised.

Mato noted that the severity of the COVID infection is a key consideration. "When a patient is diagnosed with COVID we are balancing the goal to minimize the risks of the viral infection and at the same time keep the CLL under good control," he explained. "In the setting of severe COVID (hospitalized, high oxygen need) I tend to hold any of the CLL-directed drugs including BTKi. In the setting of less severe disease I tend to continue them."

CLL and COVID Vaccination

As for vaccination, a recent study called into question the effectiveness of vaccinating patients with CLL against COVID-19. In 167 CLL patients who were given two doses of the Pfizer/BioNTech COVID-19 vaccine 21 days apart, the antibody response rate was just 39.5%, researchers led by Yair Herishanu, MD, of Tel Aviv University in Israel, reported in .

In a matched comparison analysis, all healthy individuals responded to the vaccine, but only 52% of CLL patients did. Response rates were highest at 79.2% for CLL patients in clinical remission after treatment, followed by 55.2% for treatment-naïve patients and just 16% for patients on active treatment. Response rates were low in patients being treated with BTK inhibitors (16%) and venetoclax (13.6%), the study found.

Shadman said ASH is studying the data but is not ready to change its recommendation that CLL patients get the vaccine on the basis of a single study.

"The hot topic with CLL and COVID now is the vaccine, and the effectiveness of the COVID vaccine in CLL patients," he said. "There is a paper that came out from Israel that showed some concerning data, and there are more studies that are being presented and will be published soon. I can tell you there is no agreement or consensus on what to do with that data. We have to be careful -- we don't want to make recommendations based on one small study."

"It's true we may not have seen the same antibody response to the vaccine in CLL patients, but another important way that our body responds to the vaccine is the cellular response, the T-cell response, and we don't have any data on that," Shadman continued. Future studies might show that CLL patients have a cellular response to the vaccine and make antibodies eventually, and in studies that show a weaker response to the vaccine, the actual COVID infection rate in CLL patients is still low, he added.

"To be honest, everybody needs to get the vaccine regardless," Shadman emphasized. "We should hope for the best, hope that they get a response, and if they don't maybe they get the T-cell response. And even if the response rates or antibodies are low, we are still hoping that the actual rate of infection remains low, and if they get the infection it's not as severe as someone who is not vaccinated. So the absolute message should be very clear that patients should get vaccinated."

Mato agreed: "All patients with CLL should be vaccinated with the first available vaccine," he said. "Please follow the ASH guidelines, which continue to evolve as we have more information available to guide decision-making."

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