Table 2. Literature summary: cellular... | American Society of Hematology

Table 2.

Literature summary: cellular responses

Study, year	Design	Location	Anti-CD20 drug	Population	N	Median age, y^*	Sex, % F	Interval between anti-CD20 and vaccination	Vaccine type	Measurement of T-cell response and outcomes
Arad et al, 2011³⁹	Cohort	Israel	RTX	RA	29	62	79	16 patients: <5 mo; 13 patients: >5 mo	Seasonal influenza	Measurement: Flow cytometry for activated CD4 T cells; influenza-specific cells were defined as the percentage of CD69⁺/IFN-γ–producing cells within the total CD4⁺ T-cell population in the antigen-stimulated cultures subtracted by those in the negative control cultures Outcome: No difference in percentage increase in influenza-specific CD4⁺ subsets in patients treated with anti-CD20 therapy compared with DMARD-treated patients (median, 0.1% to 0.3% and 0.1% to 0.2%, respectively); healthy controls had higher baseline influenza-specific CD4⁺ T cells, but their CD4⁺ subsets decreased by half postvaccination (0.6% to 0.3%)
de Lavallade et al, 2011⁴⁰	Cohort	United Kingdom	RTX	B-cell malignancies	12	57†	40†	19 mo (range, 2-83 mo)	Pandemic influenza	Measurement: Effector function of antigen-specific CD8⁺ and CD4⁺ T cells assessed by intracellular-cytokine staining for IFN-γ and TNF-α; response considered positive if combined percentage of H1N1-specific TNF-α plus IFN-γ–producing CD4⁺ or CD8⁺ T cells was twofold or higher compared with background level (nonstimulated PBMCs) and if there was a minimum of 0.05% H1N1-specific TNF-α plus IFN-γ–producing CD4⁺ or CD8⁺ T cells (after subtracting background) Outcome: Cellular data only available for all B-cell malignancy patients together (not RTX specific); 7% pre- and 36% postvaccine had H1N1-specific T-cell response; no effect of prior chemotherapy; healthy controls had 44% pre and 48% post; no effect of prior chemotherapy on induction of H1N1-specific T cells after 2 doses of vaccine (data NR)
Eisenberg et al, 2013⁴²	Cohort	United States	RTX	Rheumatologic disease	17	49	94	7-9 mo	Seasonal influenza	Measurement: T-cell ELISPOTs were performed using a standard γ-IFN T-cell ELISPOT assay Outcome: T-cell responses similar in anti-CD20–treated patients at baseline compared with healthy controls, but no significant increases after vaccination, no increase in proliferation (data NR); no changes in the T-cell repertoire as detected by spectratyping over time (data NR)
Muller et al, 2013⁴³	Cohort	Switzerland	RTX	Autoimmune rheumatic diseases	16	45	88	Median, 6 mo (range, 1-36 mo)	Pandemic influenza	Measurement: Presence of IFN-γ–producing 2009 H1N1 influenza virus–specific CD4⁺ and CD8⁺ T cells Outcomes: After first vaccination, virus-specific CD4⁺ and CD8⁺ T-cell responses were significantly lower in patients with low B cells than those with normal B cells; booster vaccination stimulated the antiviral T-cell response only in patients with low B cells
Nazi et al, 2013³⁸	Phase 3 substudy	Canada	RTX	ITP	17	40	71	6 mo	Tetanus toxoid	Measurement: IFN-γ ELISPOT assay to measure frequency of tetanus toxoid–specific T cells Outcomes: Mean number of IFN-γ–producing T cells was reduced in patients who had received rituximab compared with placebo at 1 wk (38 cells vs 93 cells per 5 × 10⁵ total cells) and 1 mo (14 cells vs 43 cells per 5 × 10⁵ total cells)
Parrino et al, 2017⁴¹	Phase 1	Worldwide	RTX	B-cell lymphoma	80	61	54	On active treatment	Inactivated VZV	Measurement: IFN-γ ELISPOT assay was used to detect the presence of IFN-γ–secreting VZV-specific cells from PBMCs before and after immunization Outcome: GMFR met primary outcome at 4.34 (95% CI, 3.01-6.24)

Study, year	Design	Location	Anti-CD20 drug	Population	N	Median age, y^*	Sex, % F	Interval between anti-CD20 and vaccination	Vaccine type	Measurement of T-cell response and outcomes
Arad et al, 2011³⁹	Cohort	Israel	RTX	RA	29	62	79	16 patients: <5 mo; 13 patients: >5 mo	Seasonal influenza	Measurement: Flow cytometry for activated CD4 T cells; influenza-specific cells were defined as the percentage of CD69⁺/IFN-γ–producing cells within the total CD4⁺ T-cell population in the antigen-stimulated cultures subtracted by those in the negative control cultures Outcome: No difference in percentage increase in influenza-specific CD4⁺ subsets in patients treated with anti-CD20 therapy compared with DMARD-treated patients (median, 0.1% to 0.3% and 0.1% to 0.2%, respectively); healthy controls had higher baseline influenza-specific CD4⁺ T cells, but their CD4⁺ subsets decreased by half postvaccination (0.6% to 0.3%)
de Lavallade et al, 2011⁴⁰	Cohort	United Kingdom	RTX	B-cell malignancies	12	57†	40†	19 mo (range, 2-83 mo)	Pandemic influenza	Measurement: Effector function of antigen-specific CD8⁺ and CD4⁺ T cells assessed by intracellular-cytokine staining for IFN-γ and TNF-α; response considered positive if combined percentage of H1N1-specific TNF-α plus IFN-γ–producing CD4⁺ or CD8⁺ T cells was twofold or higher compared with background level (nonstimulated PBMCs) and if there was a minimum of 0.05% H1N1-specific TNF-α plus IFN-γ–producing CD4⁺ or CD8⁺ T cells (after subtracting background) Outcome: Cellular data only available for all B-cell malignancy patients together (not RTX specific); 7% pre- and 36% postvaccine had H1N1-specific T-cell response; no effect of prior chemotherapy; healthy controls had 44% pre and 48% post; no effect of prior chemotherapy on induction of H1N1-specific T cells after 2 doses of vaccine (data NR)
Eisenberg et al, 2013⁴²	Cohort	United States	RTX	Rheumatologic disease	17	49	94	7-9 mo	Seasonal influenza	Measurement: T-cell ELISPOTs were performed using a standard γ-IFN T-cell ELISPOT assay Outcome: T-cell responses similar in anti-CD20–treated patients at baseline compared with healthy controls, but no significant increases after vaccination, no increase in proliferation (data NR); no changes in the T-cell repertoire as detected by spectratyping over time (data NR)
Muller et al, 2013⁴³	Cohort	Switzerland	RTX	Autoimmune rheumatic diseases	16	45	88	Median, 6 mo (range, 1-36 mo)	Pandemic influenza	Measurement: Presence of IFN-γ–producing 2009 H1N1 influenza virus–specific CD4⁺ and CD8⁺ T cells Outcomes: After first vaccination, virus-specific CD4⁺ and CD8⁺ T-cell responses were significantly lower in patients with low B cells than those with normal B cells; booster vaccination stimulated the antiviral T-cell response only in patients with low B cells
Nazi et al, 2013³⁸	Phase 3 substudy	Canada	RTX	ITP	17	40	71	6 mo	Tetanus toxoid	Measurement: IFN-γ ELISPOT assay to measure frequency of tetanus toxoid–specific T cells Outcomes: Mean number of IFN-γ–producing T cells was reduced in patients who had received rituximab compared with placebo at 1 wk (38 cells vs 93 cells per 5 × 10⁵ total cells) and 1 mo (14 cells vs 43 cells per 5 × 10⁵ total cells)
Parrino et al, 2017⁴¹	Phase 1	Worldwide	RTX	B-cell lymphoma	80	61	54	On active treatment	Inactivated VZV	Measurement: IFN-γ ELISPOT assay was used to detect the presence of IFN-γ–secreting VZV-specific cells from PBMCs before and after immunization Outcome: GMFR met primary outcome at 4.34 (95% CI, 3.01-6.24)

DMARD, disease-modifying antirheumatic drug; ELISPOT, enzyme-linked immune absorbent spot; GMFR, geometric mean fold rise; PBMC, peripheral blood mononuclear cell; TNF, tumor necrosis factor; VZV, varicella zoster virus. See Table 1 for expansion of other abbreviations.

Median age; where not reported, mean age reported.

†

Rituximab-specific age and percentage female not reported, thus age and percentage female of entire study population reported.

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