Table 4.
Outcomes of the included studies.
| Name of Study | Method for Measurement and Cutoff for Seropositivity | Seropositive Rate | Antibody Levels | Adverse Effects | Other Reported Outcomes |
|---|---|---|---|---|---|
| Parry et al. (23) | Roche Elecsys anti-SARS-CoV-2 immunoassay to detect IgG against Spike protein (receptor binding domain) with seropositivity cutoff of ≥ 0.8 U/mL | Spike-specific antibody responses were detectable in 34% of CLL patients after one vaccine (29/86) compared to 94% in age-matched healthy donors. Antibody responses increased to 75% after the second vaccine (9/12), compared to 100% in healthy donors (59/59); patients with CLL received an equivalent proportionate antibody response after the second vaccine (although titers remained lower than those of the control group) | After the first dose: (0.4 vs. 41.6 U/mL, respectively; P<0.0001); antibody titers 104 times lower in the patient group compared to the AEs group. Second dose: 53 U/mL vs. 3900 U/mL; P<0.0001); Antibody titers 74-fold lower in CLL patients compared to healthy age-matched groups. | N/A | Previous natural SARS-CoV-2 infection exhibited stronger immune responses after COVID-19 vaccination in both the patient and control groups. Responses were found to be lower in groups on active therapy (especially on BTKi therapy) or who were due to start therapy soon. Serum concentrations of IgG, IgA, or IgM showed positive correlations with antibody response (but only for IgA were statistically significant). |
| Tzarfati et al. (24) | Liaison chemiluminescence immunoassay method to detect anti-S1 and S2 specific IgG with seropositivity cutoff of >12 AU/mL | The seropositivity in the cohort of hematological malignancies reached 235/315 (75%) vs. the AEs cohort 107/108 (99%) after two doses of vaccination (P<0.001)In a matched analysis (n=69 with paired age, sex, comorbidities, and time from vaccination to serology assay): 52/69 (75%) vs. 68/69 (99%) in AEs. | Median antibody titer of the cohort of hematologic malignancies 85 AU/mL (IQR 11-172) vs. AEs 157 AU/mL (IQR 130-221) with P<0.001. On matched analysis (n=69): 90 AU/mL (IQR 12-185) vs. 173 AU/mL (IQR 133-232) in AEs. | N/A | Seropositive patients had significantly higher absolute lymphocyte count (median [IQR]=1.5 [1.1–2.1] compared to 1 [0.6–1.88] × 103/μl; P<0.001), total globulin levels (29 [26–31] compared to 26 [22–30] g/L; P=0.003) and lower LDH (378 [316–444] compared to 427 [325–574] U/L; P=0.015) compared to seronegative patients. Patients who had never received treatment were more likely to obtain seropositivity, and patients who received treatment 0-6 months before vaccination had the lowest seropositivity rate (66%). The type of treatment also had a significant effect on the seropositivity rate. |
| Claudiani et al. (25) | Imperial double antigen binding ELISA method to detect IgG against Spike protein (receptor binding domain) with seropositivity cutoff of >1.8 BAU/mL | CML vs. HS; T1 = 48/50 (96%) vs. 25/26 (96.1%); T2 = 31/39 (79.5%, decreased P=0.019 vs. T1) vs. 25/27 (100%, P=0.99 vs. T1); T3 = 51/52 (98%) vs. 29/29 (100%); T4 = 45/46 vs. 26/26 | Median CML vs. HS in Binding antibody units (BAU)/mL; T1 = 16.6 vs. 27.4 (P=0.8); T2 = 6.6 vs. 10 (P=0.2); T3 = 1867 vs. 2452 (P=0.29); T4 = 534.1 vs. 695.6 (P=0.25) | N/A | In univariate analysis, response status and TKI were not associated with anti-RBD levels in patients with CML (P=0.74 and 0.5 respectively); Age was inversely correlated with antibody responses only for HS (p 0.048); BNT162b2 was associated with higher anti-RBD responses (P<0.0001) |
| Perry et al. (23) | Roche Elecsys anti-SARS-CoV-2 immunoassay to detect IgG against Spike protein (receptor binding domain) with seropositivity cutoff of ≥ 0.8 U/mL | The Ab response to the COVID-19 vaccine was achieved in 73 of 149 (49%) patients with B-NHL included in our cohort, compared to 64 of 65 (98.5%) age-compatible AEs (P <.001). | Healthy controls had statistically significant higher Ab titers compared with the entire B-NHL patient cohort (mean titer, 1332 ± 1111 U/mL vs. 440 ± 1124 U/mL, respectively; P <.001), as well as when compared with each group of patients, separately (mean 1008 ± 1345 U/mL, 13.7 ± 98.5 U/mL, and 555 ± 1347 U/mL, in patients who were treatment-naïve, actively treated, or >6 months from last anti-CD20 Ab, respectively; P <.001). | Sixty of 118 evaluable patients (51%) reported AEs. The most common local AE reported in 44 (37.3%) patients was pain at the injection site. The most common systemic AE was fatigue (n=23; 19.5%), followed by muscle pain (n=11; 9.3%). Three (2.5%) patients reported transient lymph node enlargement. All AEs were mild and resolved spontaneously. There were no statistically significant differences in the types and severity of AEs between patients with B-NHL and AEs, except for pain at the injection site, which was reported to be more severe by patients with B-NHL. | Response rates in patients receiving an active anti-CD20 Ab–containing treatment regimen (chemoimmunotherapy or immune monotherapy) and in patients currently treated with R/Obi maintenance were 10.3% and 0%, respectively (P=.24), both significantly lower than in AEs (P <.001); Univariate analysis of the entire cohort of patients showed treatment status (current R/Obi treatment vs. therapy completed >6 months before vaccination vs. treatment-naïve; P <.001), ALC ≤.0.9 × 103/µL vs. ALC >.0.9 × 103/µL (P=.002), and any exposure to R/Obi (P <.001) since diagnosis to be significantly associated with lower response rates to the COVID-19 vaccine; Multivariate analysis, including age, ALC, disease type (i-B-NHL vs. a-B-NHL), and prior exposure to anti-CD20 Abs, confirmed that ALC ≤0.9 × 103/µL vs. higher ALC counts and any exposure to anti-CD20 therapy were independent predictors of negative serology |
| Herishanu et al. (27) | Roche Elecsys anti-SARS-CoV-2 immunoassay to detect IgG against Spike protein (receptor binding domain) with seropositivity cutoff of ≥ 0.8 U/mL | Antibody-mediated response in the CLL group (66/167 or 39.5%); analysis with 52 HS matched showed a significant reduction in the response rate 52% vs. 100% (adjusted OR 0.010, 95%CI 0.001-0.162; P<.001) | CLL median 0.824 U/mL (IQR 0.4-167.3 U/mL); 155 U/mL (IQR 7.6-490.3 U/mL) in responding patients with CLL; 1084 U/mL (IQR 128.9 -1879 U/mL) in HS with P<.001 | The first dose=52 (31.1%) reported a mild local reaction and the second dose=56 (33.5%) reported a mild local reaction (pain at the injection site, local erythema or swelling) without statistically significant differences in local reaction rates between 2 dose; systemic 1st dose=21 (12.5%; weakness 11, headache 9, fever 4, muscle pain 3) and second dose=39 (23.4%) (weakness 14, fever 11, chills 10, headache 10, muscle pain 8) so more frequent after the second dose (P=.005) and all were mild; no significant correlation between local or systemic reactions and a positive serologic response to the vaccine; no correlation between AEs and active treatment; no correlation between AEs and active treatment | Univariate analysis variables were found to be significant: younger age, female, early stage of disease (Binet stage A), mutated IGHV, beta2-microglobulin <3.5 mg/L, untreated or off therapy >12 months, high levels of IgG, IgM and IgA levels; Multivariate analysis independent predictors of response=age <65 years OR 3.17, female sex OR 3.66, lack of active therapy OR 6.59, IgG levels >550 mg/dL OR 3.70, and IgM levels >40 mg/dL OR 2.92; Treatment naive had a higher response rate (55.2% vs. 16%, OR 0.16 95%CI 0.07-0.35) and a higher antibody level (median 1.7 U/mL vs. 0.4 U/mL, P<.001); no significant differences between patients receiving BTKis or venetoclax + anti-CD20 antibodies; high response rate (79.2%) and antibody levels (median 297.6 U/mL) were observed among 24 patients who completed treatment and maintained their response (CR/PR) |
| Pimpinelli et al. (28) | Liaison XL chemiluminescence immunoassay method to detect anti-S1 and S2 specific IgG with seropositivity cutoff of 15 AU/mL | TP1 (p vs. HC)=MM 9/42 (21.4%, P=0.005), MPM 26/50 (52.0%, P=1), HC 19/36 (52.8%); TP2 (p vs. HC)=MM 33/42 (78.6%, P=0.03), MPM 44/50 (88.0%, P=0.038), HC 36/36 (100%) | TP1 (p vs. HC)=HC 17.1 AU/mL, MM 7.5 AU/mL (P<.001), MPM 16.2 AU/mL (P=0.837); TP2 (p vs. HC)=HC 353.3 AU/mL, MM 106.7 AU/mL (P=0.003), MPM 172.9 AU/mL (P=0.049) | After the first dose=mild (20% pain, 10% tenderness, 1% headache, 3% malaise, 1% myalgia) and moderate (2% malaise); after the second dose=mild (13% pain, 7% tenderness, 3% fever, 2% headache, 1% malaise, 1% chills), moderate (3% pain, 1% tenderness, 1% fever, 1% myalgia, 1% chills), and severe (2% pain) | No sex effect (P=0.913); there was a significant trend to a lower response according to age increase in age (P<0.001) and for the disease cohort (both MM and MPM P<0.001); in MM cohort, patients on active treatment with proteasome inhibitors-based and IMID-based therapies (alone or in combo) without daratumumab had a higher likelihood of response compared to those on daratumumab (92.9% vs. 50%, P=0.003) |
| Avivi et al. (29) | Roche Elecsys anti-SARS-CoV-2 immunoassay to detect IgG against Spike protein (receptor binding domain) with seropositivity cutoff of ≥ 0.8 U/mL | MM=133/181 (78%); HC=63/64 (98%) P=0.00013; active MM=121/159 (76%); all patients with SMM had a serological response. | Median active MM=91 U/mL (0–4875); SMM 822 U/mL (5-2878); HC=992 U/mL (0.4-5,000) | For MM=any AEs 53%, pain injection site 44%, fatigue 15%, muscle pain 14%, headache 14%, fever 6%, dizziness 4%, rash 2%, chills 2%, lymphadenopathy 1%; for HC=any AEs 55%, pain injection site 43%, fatigue 19%, muscle pain 6%, headache 8%, fever 4%, arthralgia 2% | Univariate analysis of active (comparing responder vs. non)=older age (above 65), high risk cytogenetics, lower level of level of polyclonal globulins, lower lymphocyte count, advanced treatment line (second or third line), greater number of new drugs the patient was exposed to before vaccination and depth of response to anti-myeloma therapy at vaccination time were associated with a lower response rate; Daratumumab-containing regimens trended towards a lower response rate; Multivariate analysis revealed older age (P=0·009), exposure to 4 new antimyeloma drugs (P=0·02) and hypogammaglobulinemia (P=0·002) were associated with lower response rates. |
| Gavriatopoulou et al. (30) | GenScript ELISA cPass SARS-CoV-2 NAbs detection kit to detect NAbs with seropositivity cutoff of ≥ 30% | After the first dose: WM 34% (36/106) vs. HC 65% (138/212) with P<.001; After the second dose: WM 60.8% (45/74) vs. HC 92.5% (196/212) with P<.001 | After the first dose: WM median Nab inhibition titer 20.5% (IQR 10-37%) vs. HC 39.8% (IQR 21.9-53.4%) with P<.001. After the second dose: WM 36% (IQR 18-78%) vs. HC 92% (IQR 70-96%) with P<.001 | There were no differences between mild reactions (37% after the first dose vs. 38% after the second dose). Thirteen percent (after first dose) and 24% (after second dose) of patients developed systemic adverse reactions such as fatigue, fever, lymphadenopathy, muscle pain, arthralgia, headache. | BNT162b2 produced higher NAb compared to AZD1222 (median NAb 52% vs. 21.8% with P=.02). The asymptomatic subgroups had a higher median NAbs titer (52.9% vs. 44.3% for the symptomatic). Symptomatic patients who received Rituximab-based or Bruton tyrosine kinase as therapy showed suboptimal antibody response after vaccination. |
| Stampfer et al. (31) | Sino biological ELISA to detect IgG against Spike protein with seropositivity cutoff of ≥ 250 IU/mL | Using the 250 IU/mL cutoff, 45% of the MM patients responded, 22% partially (above 50 IU/mL), and 33% did not responded; all 7 patients with smoldering MM responded to vaccination; 2/31 HC had partial response and 29/21 fully responded | Active MM median IgG spike antibody 173.7 IU/mL (range 0.1 - 8215.9 IU/mL); Smoldering MM median 555.8 IU/mL (range 283.1 - 3162.9 IU/mL); HC median 893.6 IU/mL (range 116.7 - 6006.4 IU/mL) | N/A | Younger patients (<68 years) developed higher anti-spike IgG levels. Neither sex nor race were correlated with vaccine response. Patients with low lymphocyte counts had inferior responses. Patients who received steroids as treatment had reduced antibody levels. More advanced disease and worse disease status were indicative of a poorer response to mRNA vaccination. |
| Bergman et al. (32) | Roche Elecsys anti-SARS-CoV-2 immunoassay to detect IgG against Spike protein (receptor binding domain) with seropositivity cutoff of ≥ 0.8 U/mL | Lower in CLL (50/79) compared to controls (78/78) with P<0.01 | N/A | More severe AEs in the CLL group (6 severe adverse reactions in 3 patients) than in the control group (n=0); all 6 were classified as moderate, were unlikely to be related to vaccination, and 5 of them resolved. | Ongoing treatment with mycophenolate mofetil and ibrutinib is noted to dampen the seroconversion process. Patients with a history of ibrutinib or anti-CD20 treatment had a higher seroconversion rate (55.6% and 88.9%, respectively). |
| Monin et al. (33) | Using the ELISA method to detect IgG against Spike protein with seropositivity cutoff of >70 EC50 dilution units OR EC50 was reached at 1:25 OR OD at 405 nm was 4 times higher than background | After the first dose for the hematological cancer cohort, the anti-SARS-CoV-2 IgG response was lower was lower (8/44 or 18% (95%CI 10-32) vs. HC (32/34 or 94% (95%CI 81-98) and after the second dose at day 21 for the hematological cancer cohort (3/5 or 60% (95%CI 23-88) vs. HC (12/12 or 100% (95%CI 76-100) | N/A | After the first dose, 65/140 cancer patients reported side effects (vs. 25/40 in the AEs group). After the second dose, 9/31 cancer patients reported side effects (vs. 9/16 in AEs). Injection-site pain was the most common local reaction (23/65 patients with cancer), others included injection-site erythema, swelling, fatigue, headaches, arthralgia, etc.) | Patients with hematological malignancies also showed a poorer response to T cell vaccine (measured as T cells producing IFN gamma or IL-2 producing T cells) compared to AEs and the cancer cohort sold (9/18 or 50% vs. 14/17 or 82% and 22/31 or 71%, respectively). There were no differences in the safety profiles between patients with solid and hematological cancer. |
| Malard et al. (34) | Using Abbott automated chemiluminescence assay method to detect IgG against Spike protein with seropositivity cutoff of ≥ 3100 UA/mL OR equal to NAbs ≥ 30% | After first dose: only 1.5% (3/195) patients seroconverted. After second dose: only 47% (91/196) of the patients achieved an anti-S IgG d42 level ≥3100 UA/mL after the two BNT162b2 inocula, compared to 87% (26/30) of AEs. | N/A | The most common were injection site pain (42.9%), fatigue (20.1%), and myalgia (10.4%). After the second injection of BNT162b2, 34.4% of the patients showed AEs (grade 1 to 2, 26%; grade 3, 8.4%; grade 4, 0%), with the most common types: injection site pain (grade 1 to 2, 23.4%; grade 3, 1.9%), fatigue (grade 1 to 2, 13%; grade 3, 5.8%), and myalgia (grade 1 to 2, 13%; grade 3, 3.9%) | Male sex, older patients, ongoing chemotherapy, and history of anti-B-cell treatment within the previous 12 months had significantly lower anti-S IgG after two doses of vaccination. Among patients without pathological B-cells, there was a strong positive correlation between the number of CD19+ B-cells with anti-S IgG antibody titers. T cell responses were detected in 53% (36/68) patients and were negatively affected by the active treatment received. |
| Tvito et al. (35) | Using the Abbott immunoassay method to detect IgG against the Spike protein with seropositivity cutoff of ≥ 150 UA/mL | Only one of 28 lymphoma patients (3.6%) developed a seropositive response, compared to 100% (28/28) of healthy volunteers. | N/A | N/A | Low levels of at least one immunoglobulin class were observed in 16 patients in the lymphoma group. CD19 + lymphocytes were not detected in 27 of 28 patients. All lymphoma patients treated with anti-CD20 mAb alone or in combination with chemotherapy did not exhibit a seropositive response after vaccination. |
| Cavanna et al. (15) | Using Liaison XL chemiluminescence immunoassay method to detect anti-S1 and S2 specific IgG with seropositivity cutoff of ≥ 15 AU/mL | Seropositivity in hematological malignancies: 9/21 (42.86%), whereas the control group was 100% (58/58) | The median IgG value at T1 was significantly higher in the seroconverted group (189 (IQR: 60–280) AU/mL vs. 3.8 (IQR: 3.80–5.55) AU/mL, p-value < 0.01) | N/A | There were no significant differences in seroconversion when comparing treatment status and received treatment (except for lower rates in patients treated with anti-CD20). Multivariate analysis showed a higher probability of seroconversion after vaccination (OR 3.30 with a 95% confidence interval (CI) of 1.23–8.87, p-value 0.02) for solid tumors compared to patients with hematological malignancies. |
| Marasco et al. (36) | Using Roche Elecsys anti-SARS-CoV-2 immunoassay to detect IgG against Spike protein (receptor binding domain) with seropositivity cutoff of ≥ 0.8 U/mL | From 263 subjects in the hematological malignancies cohort, 131 (49.8%; 95% CI 43.6%–56.0%) patients seroconverted four weeks after the first dose and 39 [14.8%; 95% confidence interval (CI) 11.0%–19.6%] two weeks after the second one, for a total of 170 (64.6%; 95% CI 58.5%–70.4%). Comparison with matched AEs also showed a lower rate of rate of rate of seroconversion in the cohort of cohort of cohort of hematological malignancies [64.1% (95%CI 56.3%-71.3%) vs. 99.4% (95%CI 96.7%-100%) with P<0.001]. | The median antibody titer at two weeks after the second dose was 175 U/mL [interquartile range (IQR) 0.44–2.600]. Comparison with matched AEs showed lower antibody titers in the hematological malignancies cohort [median 207.5 U/mL (IQR 0.44-3,062) vs. 1,078 U/mL (IQR 643-1,841) with P<0.001]. | N/A | Variables significantly associated with the lack of serological response included treatment in the last 12 months (especially for anti-CD20 antibody plus chemotherapy), type of malignancies, lymphopenia (<800 cell/uL), and low IgM levels. A total of 48 patients with malignancies on active treatment (out of 99 patients) showed the immune response (through assessing IFN-gamma, IL-2, TNF-alpha) two weeks after the second dose (vs. 99/99 in the matched AEs group). |
Ig, immunoglobulin; CLL, chronic lymphocytic leukemia; BTKi, Bruton’s tyrosine kinase inhibitor; IQR, interquartile range; LDH, lactate dehydrogenase; ELISA, enzyme-linked immunosorbent assay; RBD, receptor binding domain; CML, chronic myeloid leukemia; HS, healthy subjects; HC, healthy control; TKI, tyrosine kinase inhibitors; AE, adverse effects; NHL, non-Hodgkin lymphoma; R/Obi, rituximab/obinutuzumab; ALC, absolute lymphocyte count; OR, odd ratio; CR, complete response; PR, partial response; TP, time point; MM, multiple myeloma; SMM, smoldering multiple myeloma; MPM, myeloproliferative malignancies; IGHV, immunoglobulin heavy chain variable region; NAb, neutralizing antibody titer; WM, Waldenstrom macroglobulinemia; OD, optical density; IFN, interferon; CI, confidence interval; IL, interleukin; TNF, tumor necrosis factor; N/A, not available.