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Humoral and cellular responses in patients with lymphoid malignancies receiving SARS-Cov-2 vaccination

Dec 9, 2021
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Factors that influence the efficacy of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) vaccination in patients with lymphoid malignancies are still not fully detailed. Immune dysregulation associated with active malignancies has proven to impair serological response, and concurrent anti-cancer treatment may also negatively influence humoral immune activity. Previous research has excluded the measurement of T-cell mediated immune responses following vaccination, which could play a protective role against infection irrespective of seropositivity.

Recent papers by Marasco, et al.1 published in BJH, and Liebers, et al.2 in Blood, examined both humoral and T-cell mediated responses in patients with lymphoid malignancies following two doses of SARS-CoV-2 vaccine. We summarize key results from both papers below.

Marasco, et al.1

This was a prospective study observing the efficacy of two doses of either mRNA-1273 or BNT162b2 vaccines administered 28 days apart in adult patients vaccinated at the Istituto Nazionale dei Tumori in Milan, Italy. The general study design is shown below.

Figure 1. Study design

BCL, B-cell lymphoma; HL, Hodgkin lymphoma; IMIDs, immunomodulatory imide drugs; LM, lymphoid malignant; MM, multiple myeloma; TCL, T-cell lymphoma.
*Adapted from Marasco, et al.1

Results

As reported in Table 1, a total of 131 (49.8%) patients achieved seroconversion 4 weeks following first dose while a further 39 patients achieved seroconversion 2 weeks after their second dose (14.8%), producing a total response rate of 64.6%. The median antibody titer at 2 weeks after the second dose was 175 U/ml.

Table 1. Patient characteristics and the associated seroconversion rate 4 weeks after a first vaccine dose and 2 weeks after a second dose*

Characteristic, %

N = 263

Seroconversion at 4 weeks

Seroconversion at 6 weeks

Overall population

100

49.8

64.6

Female

46.7

49.6

63.4

Diagnosis

              B-cell aggressive lymphomas

22.4

23.7

35.5

              B-cell indolent lymphomas

42.4

44.1

61.2

              Hodgkin lymphoma

12.6

54.5

78.8

              Multiple myeloma

19.8

88.4

94.2

              T-cell lymphomas

3

50

75

Active disease

68

51.9

66.4

Last therapy ≤12 months prior

64.2

39.6

55

<6 months prior to first vaccine

53.2

37.1

53.6

>6 to ≤12 months prior to first vaccine

11

51.7

62

Last type of therapy

              Patients receiving anti CD20 antibody +               chemotherapy

19.3

5.9

17.6

              Chemotherapy alone

13.6

47.2

69.4

              Received IMIDs

9.9

80.7

84.6

              Novel oral agents

8

23.8

52.3

              Receiving CAR-T cell therapy or HSCT

8

52.3

57.1

ALC, <800 cells/µl

18.6

22.4

42.8

ANC, <1500 cells/µl

7.6

35

60

IgG, <600 mg/dl

21.3

42.8

53.5

IgA, <80mg/dl

28.5

44

57.3

IgM, <40mg/dl

32.3

40

51.7

ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CAR-T, chimeric antigen receptor T-cell therapy; HSCT, hematopoietic stem cell transplantation; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; IMIDs, immunomodulatory imide drugs.
*Adapted from Marasco, et al.1

Patients receiving anti-CD20 treatment plus chemotherapy had the lowest seroconversion rate and median antibody titers 2 weeks after the second vaccine dose. This was significantly lower than patients who received other treatments (17.6% vs 71.2%; odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04–0.20; p < 0.001; median antibody titre, 0.44 U/ml vs 183 U/ml; p < 0.0001). Patients with multiple myeloma treated with immunomodulatory imide drugs, in contrast, had a higher seroconversion rate.

Another notable observation was the effect of the time interval between last treatment and first vaccine dose. Patients who received their last treatment within 6 months of vaccination had comparable seroconversion to those who received their last treatment >6 months to ≤12 months, suggesting long lasting immunosuppression.

A comparison of 167 patients with lymphoid malignancies with 167 healthy controls revealed significantly lower seroconversion (Figure 2) among the patients with lymphoid malignancies, as well as a lower antibody titer two weeks following a second dose of the COVID-19 vaccine (median, 1,078 U/ml vs 207.5 U/ml; p < 0.001).

Figure 2. Comparison of seroconversion between patients with lymphoid malignancies and healthy controls* 

HCWs, healthcare workers; LMs, lymphoid malignancies.
*Adapted from Marasco, et al.1

On multivariate analysis, independent predictors of serological conversion included the type of treatment, type of diagnosis, absolute lymphocyte count, and immunoglobulin M levels (Table 2).

Table 2. Rate of seroconversion and antibody titer at two weeks after second dose*

Variable

OR

95% CI

p value

Diagnosis

              Hodgkin lymphoma

1

<0.001

              Aggressive B-cell lymphomas

0.54

0.15–1.91

              Indolent B-cell lymphomas or B-cell
              chronic lymphocytic leukemia

1.33

0.36–4.93

              Multiple myeloma

28.15

4.43–178.95

              T-cell lymphoma

0.5

0.06–3.82

Type of treatment

              Other therapies

1

 

<0.001

              Anti-CD20 antibody plus chemotherapy

0.07

0.02–0.22

 

              Watch and wait or last therapy >12
              months prior

2.84

0.96–8.36

Absolute lymphocytic count

              <800 cells/µL

1

0.001

              ≥800 cells/µL

1.66

0.65–4.25

Immunoglobulin M

              <40mg/ dl

1

0.004

              ≥40 mg/dl

4.31

1.52–12.24

95% CI, 95% confidence interval; OR, odds ratio.

*Adapted from Marasco, et al.1

T-cell mediated immune response was assessed in 99 patients on active treatment and 99 healthy controls by measuring interferon-gamma (IFN-γ), interleukin-2 and tumor necrosis factor alpha levels (Table 3). A high proportion of patients with lymphoid malignancies achieved a T-cell mediated response, though it was lower than that of the healthcare worker control group. Patients with lymphoid malignancies also had a lower median level of IFN-γ and tumor necrosis factor alpha release compared with healthcare workers. In contrast, interleukin-2 levels were higher in patients with lymphoid malignancies compared with healthy controls.

Table 3. Comparison of T-cell mediated responses*

 

Patients with LMs
(n = 99)

HCWs (n = 99)

p value

T-cell mediated
response detected,
(IFN-γ > 12 pg/ml), %

86

100

<0.001

Median IFN-γ, U/ml

179.5

309

<0.0001

Median TNF-α, pg/ml

32.71

104.0

<0.0001

Median IL-2, pg/ml

553.6

196.0

<0.0001

HCW, healthcare worker; IFN-γ; interferon gamma; IL-2, interleukin-2; LM, lymphoid malignancy; TNF-α, tumor necrosis factor-alpha.
*Adapted from Marasco, et al.1

Notably, T-cell immune response was detectable in 47 (98%) seropositive patients and 38 (74%) seronegative patients. However, 13% of patients were defined as “double negative” with neither detection of a humoral or T-cell mediated response.

In summary, active lymphoid malignancies were confirmed to be a negative predictor of serological response to SARS-CoV-2 vaccination in line with previous research; however, a significantly increased serological response rate 2 weeks following the second dose emphasizes the importance of double dosing. Active treatment with anti-CD20 plus chemotherapy, CAR T-cell therapy, or novel oral agents in the 12 months prior to vaccination was associated with reduced serological response rates.

The use of B-cell depleting anti-CD20 agents produced an extremely low seroconversion rate, perhaps owing to the prolonged half-life of agents such as rituximab. Patients with multiple myeloma treated with immunomodulatory imide drugs had higher seroconversion (84%)—contradicting previous studies—which may be a result of a small cohort number and concomitant treatment.

Measurement of T helper cytokine release indicated alternative protection against infection, with cytokine release detected in 74% of seronegative patients; however, a notable fraction (13%) of patients had neither humoral or T-cell responses and may be at high risk for COVID-19 infection and related complications.

Liebers, et al.2

It has been demonstrated previously that patients treated with anti-CD20 plus chemotherapy had impaired humoral responses, and further data was published by Liebers, et al.2 who investigated seroconversion and T-cell mediated responses specifically for patients treated with these agents, either as a monotherapy or in combination with other agents.

The authors measured anti-SARS-CoV-2-S1 and anti-SARS-CoV-2-N antibody levels in patients without previous COVID-19 infection and assessed the T-cell response in a subset of patients. Patients with a known history of COVID-19, as well as those with detectable nucleocapsid protein antibodies (anti-SARS-CoV-2-N) were excluded.

Results

Patient characteristics are summarized in Table 4.

Table 4. Patient characteristics*

Characteristic, % (unless otherwise stated)

N = 80

Median age (range), years

66 (23–88)

Female

38

Diagnosis

 

              Aggressive lymphomas

40

              Indolent lymphoma

40

              Chronic lymphocytic leukemia

14

              Nodular lymphocyte-predominant Hodgkin lymphoma

5

              Hairy cell leukemia

1

Active treatment

31

Treatment <12 months

56

Last/current treatment

 

              Anti-CD20 + chemotherapy

41

              Anti-CD20 monotherapy

29

              Anti-CD20 + novel agents

15

              AutoHSCT following anti-C20 +
              Chemotherapy

8

              Novel agents following anti-CD20 failure

8

No prior alloHCT

100

Median interval between first and second vaccination (range),
days

42.0 (12.0–84.0)

No second vaccination until data cut-off

5

AlloHCT, allogeneic hematopoietic cell transplantation; AutoHCT, autologous hematopoietic cell transplantation; WBC, white blood cell count.
*Adapted from Liebers, et al.2

Following two vaccine doses, the overall seroconversion rate was 41%, a significant increase from the first dose (9%), confirming the importance of two doses in patients treated with immunosuppressive agents. Importantly, patients who had their last treatment >12 months prior to vaccination demonstrated higher seroconversion rates compared with those receiving last treatment within 3 to 12 months (p = 0.001) or <3 months (p < 0.001) (Figure 3).

Figure 3. Seroconversion rates dependent of the time interval of last anti-CD20 treatment to vaccination*

*Adapted from Liebers, et al.2

Notably, no statistically significant difference was reported when comparing seroconversion rates between patients receiving anti-C20 monotherapy or in combination with chemotherapy.

A multivariate analysis confirmed the interval from last anti-CD20 treatment to vaccination as an independent predictor of serological response (per 1 year; OR, 2.2; 95% CI, 1.3–4.7; p = 0.02) and revealed high CD4 cell counts (per 100 cells/µl; OR, 1.6; 95% CI, 1.2–2.3; p = 0.005) and age (per 10 years; OR, 0.5; 95% CI, 0.2–0.8; p = 0.008) as additional predictors.

T-cell responses were measured using IFN-γ levels in patients with available peripheral blood samples (n = 50), and these were compared with seven healthy vaccinated controls (Figure 4). The number of patients achieving seroconversion was comparable between patients and healthy controls. Half of the patients who did not seroconvert still had a positive T-cell response, providing further evidence of T-cell activity in patients with humoral suppression.

Figure 4. Percentage of patients achieving a T-cell response and T-cell response status in patients with or without seroconversion*


*Adapted from Liebers, et al.2

In contrast with serological response, T-cell mediated immune response was not affected by the time interval between last anti-CD20 treatment and first vaccine dose. When assessing T-cell responses following vaccination in patients with proven negative pre-vaccination T-cell responses (n = 20), the authors reported T-cell responses comparable to the entire cohort that were independent of seroconversion.

In summary:

  • This study confirmed that anti-CD20 treatment is associated with reduced serological response, and patients with treatment within 12 months had significantly impaired responses.
  • T-cell immunity was again demonstrated in a significant number of patients negative for serological response and was comparable with healthy controls.
  • T-cell response appeared dependent of vaccination, understating their importance for this vulnerable population.

The limitations of this study included an overall small cohort sample set, and a small number of healthy controls used for comparison.

Conclusion

Data from both studies confirm the significant impact of lymphoid malignancies on serological response. In addition, they demonstrated a negative association of anti-CD20 treatment, either in combination with chemotherapy or as a monotherapy. Furthermore, an independent negative predictor was the time interval of last anti-CD20 treatment to vaccination. Second doses appeared to improve the rate of seroconversion; however, further data is needed to evaluate whether a booster dose will further improve the seroconversion rate.

A key takeaway from these studies was the presence of T-cell immune responses in a significant number of patients with lymphoid malignancies who failed to seroconvert. Data from Liebers, et al.2 appeared to show that the T-cell response was dependent on vaccination, providing evidence for the importance of vaccination in this population, with T-cell mediated responses perhaps providing compensatory protection against infection in those lacking humoral activity.

  1. Marasco V, Carniti C, Guidetti A, et al. T‐cell immune response after mRNA SARS‐CoV‐2 vaccines is frequently detected also in the absence of seroconversion in patients with lymphoid malignancies. Br J Hematol. 2021. Online ahead of print. DOI:1111/bjh.17877
  2. Liebers N, Speer C, Benning L, et al. Humoral and cellular responses after COVID-19 vaccination in anti-CD20 treated lymphoma patients. Blood. 2021. Online ahead of print. DOI: 1182/blood.2021013445