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COVID-19 severity, mortality, and mRNA vaccine responses in patients with CLL

Jan 6, 2022

Since the first cases of coronavirus disease 2019 (COVID-19) were reported in December 2019, more than 3 million people have died of the disease worldwide. Disease severity varies widely, with certain factors (including age and certain comorbidities) conferring a worse prognosis. Patients with hematologic malignancies generally have more severe disease with higher mortality rates compared to the general population: a meta-analysis of 3,240 adult patients with hematologic malignancies reported a 34% risk of death associated with COVID-19.1 This is multifactorial but is thought to be due largely to impaired humoral immune response due to both the underlying malignancy and anticancer therapy.

Following is a summary of recent data from published studies as well as from abstracts presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition regarding COVID-19 severity, mortality, and mRNA vaccine responses in patients with chronic lymphocytic leukemia (CLL).

Update of COVID-19 severity and mortality in patients with CLL: ERIC and Campus CLL

Patients with CLL are likely to be more susceptible to severe COVID-19 and increased risk of death associated with COVID-19 due to age, disease, and impaired immune function. Chatzikonstantinou, et al. recently published in Leukemia a retrospective review of data from the European Research Initiative on CLL (ERIC) and Campus CLL to determine severity and mortality of COVID-19 in patients with CLL.2  


Data were collected from 91 centers from the beginning of the pandemic until March 16, 2021, and case fatality rate, disease severity, and overall survival (OS) were analyzed. The OS analysis was limited to patients with severe COVID-19 (defined by hospitalization and requirement of supplemental oxygen or admission into an intensive care unit).2


Most patients were diagnosed with CLL (94.3%; Table 1) and had a median of two comorbidities, with a median age of 69 years. Most patients were treated with Bruton’s tyrosine kinase (BTK) inhibitors (56.3%), venetoclax monotherapy (10.7%), or chemoimmunotherapy (9.1%).

Table 1. Patient Characteristics*

Patient characteristics, % (unless otherwise stated)


Age at COVID-19 (median, IQR), years

69 (61–77)










Obesity (BMI >30)



              Current smoker




              Never smoker


Hypogammaglobulinemia (IgG <550 mg/dL)



CIRS score (range)


N of comorbidities (median, range), n

2 (0–11)

Other respiratory






Cardiac Failure




Coronary artery disease


Other cardiovascular






Chronic renal disease


Other hematologic malignancies


Other non-hematologic malignancies (excluding skin)


CIRS, cumulative illness rating scale; COPD, chronic obstructive pulmonary disease; CLL, chronic lymphocytic leukemia; IQR, interquartile range; MBL, monoclonal B lymphocytosis; SLL, small lymphocytic lymphoma.
*Adapted from Chatzikonstantinou, et al.2


The case fatality rate in patients with severe COVID-19 was 38.4%, and untreated patients had a greater OS than those on treatment or recently treated (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.41–0.72; p < 0.001). The authors also assessed the impact of specific treatments on COVID-19 outcome in two comparisons:

  • First, they compared patients receiving BTK inhibitors at the time of SARS-CoV-2 infection (n = 169) with patients receiving venetoclax at the time of SARS-CoV-2 infection (n = 31) and patients who had received chemoimmunotherapy in the last 12 months (n = 128). There was no statistically significant difference between the groups.
  • The second analysis replaced the third group (patients who had received chemoimmunotherapy in the last 12 months) with patients who had received any anti-CD20-based therapy (alone or in combination) in the last 12 months (n = 128). As in the first comparison, there was no statistically significant difference between the groups.

On multivariate analysis, statistically significant risk factors for mortality included older age (p < 0.001), cardiac failure (p = 0.035), and treatment status (p < 0.001) (Table 2).

A subanalysis of patients with severe COVID-19 found age ≥75 (compared with age <75, p < 0.001) and CLL treatment status (treated vs untreated, p < 0.001; treated at the time of COVID-19 infection vs untreated, p < 0.001; treated in the last 12 months yes vs no, p = 0.002) to be the most statistically significant risk factors of infection outcome in this population.

Table 2. Risk factors for OS*

Risk factor

p value

Age (≥65 vs <65)


Age (≥75 vs <75)


IGHV gene somatic hypermutation status (unmutated vs mutated)


del(17p) (last assessment) (positive vs negative)


CIRS score (> 6 vs ≤6)


Cardiac Failure (yes vs no)


Chronic renal disease (yes vs no)


Hypogammaglobulinemia (IgG <550 mg/dL) (present vs absent)


CLL treatment status (untreated vs treated)


CLL treatment during COVID-19 (treated vs untreated)


Treated in last 12 months (treated vs untreated)


CIRS, cumulative illness rating scale; CLL, chronic lymphocytic leukemia; COVID-19, coronavirus disease 2019; IGHV, immunoglobulin heavy chain variable.
*Adapted from
Chatzikonstantinou, et al.2

COVID-19 outcomes in patients with lymphoid malignancies

During the 63rd ASH Annual Meeting and Exposition, Yun Choi, et al. reported data from a multicenter retrospective review of COVID-19 outcomes in 519 patients with lymphoid malignancies, including CLL; the review aimed to determine the odds ratio (OR) of deaths, severe events, and hospital admissions in patients with lymphoid malignancies diagnosed with COVID-19.3


The median age of patients in this study was 61.9 years, and the risks of death, severe event, and hospital admission increased with age: for each 10 years of age increase, the ORs were 1.78, 1.58, and 1.65, respectively. Patients with CLL had a greater risk of severe events (OR, 4.64), mortality (OR, 4.65) and hospital admission (OR, 5.93) compared with patients with HL.3

Patients who were in remission at the time of COVID-19 infection had a reduced risk of severe events (OR, 0.42), mortality (OR, 0.36), and hospital admission (OR, 0.40) compared to with active disease, while patients who were administered cytotoxic chemotherapy within 28 days of COVID-19 infection had a higher risk of severe events (OR, 2.54), mortality (OR, 2.79), and hospital admission (OR, 2.31). Patients who were administered an anti-CD20 monoclonal antibody within six months of COVID-19 infection also had a greater risk of severe events (OR, 2.60), mortality (OR, 2.17), and hospital admission (OR, 3.28) compared to those who did not.3

Humoral and cellular responses to mRNA vaccines in patients with CLL

Patients with CLL may have suboptimal response after two COVID-19 vaccine doses. While the novel BNT162b2 mRNA COVID-19 vaccine was introduced with 95% efficacy in the immunocompetent, approximately 50% of patients with CLL are unable to achieve a humoral response to the vaccine, as detected by low anti-spike antibodies. Information regarding T-cell immune responses to the COVID-19 vaccines, however, is sparse. During the 63rd ASH Annual Meeting and Exposition, Cristina Bagacean, et al.4 and Gilad Itchaki, et al.5 presented data regarding the humoral and cellular responses, respectively, to COVID-19 vaccination in patients with CLL.

Humoral responses (Bagacean, et al.)

Bagacean, et al. investigated humoral responses in 530 patients with CLL (and 14 controls) following the first, second and third doses of the NBT162b2 and mRNA-1273 vaccines. The median age of the CLL patients was 71 years.4

Following the first dose, the global response rate was 27% (43/158).

  • Patients who were treatment-naïve (TN) had a response rate of 34% (23/67), similar to those who had prior CLL treatment (33%, 12/36).
  • Patients currently receiving therapy had a response rate of only 15% (8/55; p = 0.02).

Following the second dose, the global response rate was 52% (256/506).

  • TN patients had a response rate of 72% (151/210) in comparison to previously treated patients (mostly treated with immunochemotherapy), who had a response rate of 60% (78/130; p = 0.02).
  • Patients who were receiving venetoclax monotherapy at the time of the second dose had a significantly higher response rate (52%, 12/23) than those who were receiving BTK inhibitors (22%, 23/104; p < 0.001).
  • Patients who were treated with venetoclax in combination with anti-CD20 therapy (n = 19) or in combination with a BTK inhibitor (n = 6) were seronegative following the second dose.
    • Age >65 years (p = 0.02), ongoing CLL treatment (p < 0.001), and gamma-globulins ≤6 g/L (p = 0.03) were significantly associated with seroconversion rate on multivariate analysis.

Patients who were seronegative following the second dose were allowed a third dose, after which the response rate was 42% (28/66).

  • TN patients and previously treated patients had a significantly better response rate (57%, 16/28) compared to patients who were receiving treatment (32%, 12/38; p = 0.03).
  • Patients who seroconverted after the third dose were found to have had significantly higher titres after the second dose compared with those who remained seronegative (though the median values are considered by the manufacturer to be below the threshold).

There were 40 patients who had SARS-CoV-2 infection prior to vaccination, and these patients were analyzed independently. Interestingly, all 40 patients achieved seroconversion after infection and a single dose of the vaccine, despite 30% of patients having ongoing CLL treatment.

Cellular responses (Itchaki, et al.)

Gilad Itchaki and colleagues investigated T-cell responses in 83 patients with CLL at 139 days post administration of the second dose of vaccine; of these, 68 patients were eligible for the analysis. The median age was 68 years, and 65% of the patients were male. Most patients were Binet stage A or B and were TN (28%); 46% of patients were on therapy with either a BTK inhibitor (n = 17) or a venetoclax-based regimen (n = 13). In the 12-month period prior to vaccination, 13 patients had been treated with an anti-CD20 monoclonal antibody; 29 patients (42%) had received prior anti-CD20 therapy at any time.5

A total of 32% of patients (22/68) had a T-cell immune response to the vaccine which was highly correlated to the detection of anti-spike IgG antibodies at the time of the second dose (p = 0.0239) and at the time of T-cell testing (p = 0.048).

  • 50% of patients who were positive for anti-spike IgG antibodies also developed a positive T-cell response.
  • 17% of patients who did not develop a T-cell response were positive for anti-spike IgG antibodies.
  • 24% of the patients who tested negative for anti-spike IgG antibodies developed a positive T-cell response.

A cumulative illness rating score >6, and hypertension specifically, were significantly associated with a lower T-cell response on univariate analysis (p < 0.05). No significant differences were seen regarding age, gender, treatment, of T-cell subpopulation distribution according to flow cytometry.


In summary, the findings of Chatzikonstantinou, et al. suggest age, CLL-directed treatment, and cardiac failure were significant risk factors for OS and confer a worse prognosis. Untreated patients had a better chance of survival than those on treatment or recently treated. However, there were limitations in this study, including missing asymptomatic patients and the increased likelihood of capturing data from hospitalized and/or symptomatic patients.

Choi et al. found that patients with CLL and patients who received cytotoxic chemotherapy within 6 months or anti-CD20 monoclonal antibodies at any time are likely to have poor COVID-19 outcomes. Patients at a high risk for poor prognosis should be prioritized for studies that offer monoclonal antibody prophylaxis. Further studies are needed to deduce if a deficit in humoral immunity may lead to poor response to vaccination and a poor outcome. 

Bagacean, et al. showed a double-dose mRNA vaccination had a humoral response in 52% of patients with CLL and concluded that the best immune response booster in this population was SARS-CoV-2 infection. This was due to the significant increase in anti-spike antibodies that was seen in all patients with CLL that had previous infection, after receiving a single dose of the vaccine. Similarly, Gilad Itchaki, et al. showed that the BNT162b2 mRNA COVID-19 vaccine can illicit an immune response in patients with CLL. However, all three trials concluded that larger studies are warranted to validate these results.

  1. 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(25):2881-92. DOI: 1182/blood.2020008824
  2. Chatzikonstantinou T, Kapetanakis A, Lydia Scarfò, et al. COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study. 2021;35(12):3444-3454. DOI: 10.1038/s41375-021-01450-8
  3. Choi Y, Caro J, Li X, et al. A multi-center retrospective review of COVID-19 outcomes in patients with lymphoid malignancy. Poster Abstracts 184. 63rd American Society of Hematology Annual Meeting & Exposition; December 11, 2021; Virtual.
  4. Bagacean C, Letestu R, Al Nawakil C, et al. Humoral response to mRNA vaccines BNT162b2 and mRNA-1273 COVID-19 in chronic lymphocytic leukemia patients. Poster Abstracts 637. 63rd American Society of Hematology Annual Meeting & Exposition; December 13, 2021; Virtual.
  5. Itchaki G, Rokach L, Benjamini O, et al. Cellular immune responses to BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Poster Abstracts 638. 63rd American Society of Hematology Annual Meeting & Exposition; December 13, 2021; Virtual.

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