Immunotherapy in the treatment of lymphoma

Table 1 Monoclonal antibody studies

Drug [Ref.]	Target	No. of patients	Study design	Study phase	Results
Obinutuzumab	CD20
[42]		781	CLL (CIRS ≥ 6) O + Clb vs R + Clb	3	PFS: 28.9 mo vs 15.7 mo (HR 0.49, P < 0.0001; OS: NR vs 73.1 mo (HR 0.76, P = 0.0245) Grade ≥ 3 AEs: Infusion reactions 20% vs 4%, Neutropenia 33% vs 28%
[44]		1202	FL (untreated) O + Chemo vs R + Chemo	3	3-yr PFS rate: 80.0% vs 73.3% HR 0.66 P = 0.001 ORR: 88.5% vs 86.9% 3-yr OS rate: 94.0% vs 92.1% (HR 0.75, P = 0.21) Grade ≥ 3 AEs: 74.6% vs 67.8%
[45]		413	FL (rituximab refractory) O + Benda vs Benda	3	PFS: NR vs 14.9 mo (HR 0.55, P = 0.0001) OS: ND Grade ≥ 3 AEs: Neutropenia 33% vs 26%; Infusion reactions 11% vs 6%
Tafasitamab[47]	CD19	92	DLBCL R/RT + Lenalidomide	2	ORR: 43% CR: 18% PFS: 12.1 mo Grade ≥ 3 AEs: Neutropenia 48%, Thrombocytopenia 17%, Febrile neutropenia 12%
Magrolimab[52]	CD47	22	R/R DLBCL or FL M + R	1b	DLBCL ORR/CR: 40%/33% FL ORR/CR: 71%/43% AEs: Anemia, Infusion reactions
Mogamulizumab[53]	CCR4	372	CTCL R/R Mo vs Vorinostat	3	PFS: 7.7 mo vs 3.1 mo (HR 0.53, P < 0.0001) Grade ≥ 3 AEs: Mo: pyrexia 4%, cellulitis 3%; V: cellulitis 3%, PE 3%, sepsis 3%

AE: Adverse event; Benda: Bendamustin; CCR4: C chemokine receptor 4; Chemo: Chemotherapy; CIRS: Cumulative illness rating scale; Clb: Chlorambucil; CLL: Chronic lymphocytic leukemia; CR: Complete response; CTCL: Cutaneous T-cell lymphomas; DLBCL: Diffuse large B-cell lymphoma; FL: Follicular lymphoma; M: Macrolimab; Мо: Mogalizumab; NR: Not reached; O: Obinutuzumab; ORR: Objective response rate; OS: Overall survival; PE: Pulmonary embolism. PFS: Progression-free survival; R: Rituximab; R/R: Relapsed/refractory; V: Vorinostat.

Table 2 Antibody-drug conjugate studies

Drug [Ref.]	Target	No. of patients	Study design	Study phase	Results
Brentuximab-vedotin	CD30
[10,58]		102	R/R cHL	2	ORR/CR: 72%/33% PFS 9.3 mo; OS 40.5 mo; AEs: PSN 42%, nausea 35%, fatigue 34%
[59,60]		329	R/R high-risk cHL maint BV vs Pbo	3	5-yr PFS rate 59% vs 41% (HR 0.52) OS: NR AEs: PSN (90% resolved)
[61]		1334	Untreated cHL CS III/IV BV + AVD vs ABVD	3	2-yr mPFS rate: 82.1% vs 77.2% (HR 0.77, P = 0.04) AEs: Neutropenia 58% vs 45%, PSN 67% vs 43%, PN 1% vs 3%
[62]		131	R/R CTCL or cALCL; vs MTX or BV	3	ORR4: 56.3% vs 12.5% (P < 0.0001); EFS: 9.4 mo vs 2.3 mo (HR 0.28, P < 0.0001) Grade ≥ 3 AEs: 41% vs 47%; PSN: 67% vs 6%
[63]		58	R/R ALCL	2	ORR/CR: 86%/66%; 5-yr OS rate: 60%, 5-yr OS rate (in CR vs non-CR): 79% vs 25%
[64]		601	Untreated CD30+ sALCL; BV + CHP vs CHOP	3	PFS: 48.2 mo vs 20.8 mo (HR 0.71, P = 0.011); OS: NR vs NR (HR 0.66, P = 0.024) AEs: febrile neutropenia 18% vs 15%, PSN 52% vs 55%
Polatuzumab vedotin[65]	CD79b	80	R/R DLBCL; PV + R + Benda vs R + Benda	2	CR: 40% vs 17.5% PFS: 9.5 mo vs 3.7 mo (HR 0.63, P < 0.001) Grade ≥ 3 AEs: Anemia 28.2% vs 17.9%, Neutropenia 46.2% vs 33.3% Thrombocytopenia 41.0% vs 23.1%
Moxetumomab-pasudotox[68]	CD22	80	R/R HCL	2	ORR: 75% CR: 30% (85% MRD-); AEs: Edema 39%, nausea 35%, fatigue 34%, headache 33%

ABVD: Doxorubicin, bleomycin, vinblastine, dacarbazine; AE: Adverse event; AE: Adverse event; ALCL: Anaplastic large-cell lymphoma; AVD: Doxorubicin, bleomycin, vinblastine, dacarbazine; Benda: Bendamustin; BV: Brentuximab vedotin; cHL: Classic Hodgkin lymphoma; CHOP: Cyclophosphamide, adriamycin, oncovin, prednisone; CHP: Cyclophosphamide, adriamycin, prednisone; CR: Complete response; CS: Clinical stage; CTCL: Cutaneous large-cell lymphoma; DLBCL: Diffuse large b-cell lymphoma; EFS: Event-free survival; HCL: Hairy cell leukemia; maint: MAINTENANCE; MRD: Minimal residual disease. MTX: Methotrexate; NR: Not reached; ORR: Objective response rate; OS: Overall survival; Pbo: Placebo; PFS: Progression-free survival; PNS: Peripheral neuropathy syndrome; PV: Polatuzumab vedotin; R: Rituximab; R/R: Relapsed/refractory.

Table 3 Bispecific antibody studies

Drug	Target	No. of patients	Study design	Study phase	Results
Blinatumomab[71]	CD3/CD19	38	R/R FL, MCL, DLBCL	1	ORR/CR: 64%/38%; PFS 6.7 mo; OS 4.6 yr; OS ( for CR/PR): 7.7 yr; AEs: Infections (pneumonia, diarrhea, sepsis)
Mosunetuzumab[72]	CD3/CD20	218	R/R B-NHL	1	NHL ORR/CR: 64.1%/42.2%; DLBCL ORR/CR: 34.7%/16.6% AEs: CRS 28.4%, NAEs: 44%
CD20-TCB[73]	CD3/CD20	38	R/R DLBCL	1	ORR/CR: 47%/34% AEs: CRS 55.1%, Neutropenia 34.7%

AE: Adverse event; CR: Complete response; CRS: Cytokine releasing syndrome; DLBCL: Diffuse large B-Cell lymphoma; FL: Follicular lymphoma; MCL: Mantle cell lymphoma; NHL: Non-Hodgkin lymphoma; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; R/R: Relapsed/refractory.

Table 4 Checkpoint inhibitor studies

Drug [Ref.]	Target	No. of patients	Study design	Study phase	Results
Nivolumab	PD-1
[84]		243	R/R cHL (after ASCT)	2	ORR/CR: 69%/40%; PFS: 14.7 mo, Grade ≥ 3 AEs: lipase increases 5%, neutropenia 3%, ALT increases 3%
[88]		61	R/R cHL with BV	1/2	ORR/CR: 82%/61%; AEs: Infusion reactions 44% (BV), corticosteroid therapy 8%
[89]		64	R/R cHL Nivo + BV, Ipi + BV, Nivo + Ipi + BV	1/2	ORR: 89%, 76%, 82% Grade ≥ 3 AEs: 16%, 42%, 50%
Pembrolizumab	PD-1
[85]		210	R/R cHL	2	ORR/CR: 69%/22.4% 6-mos DoR rate: 75.6% TRAEs: hypothyroidism 12.4%, pyrexia 10.5%
[86]		304	R/R cHL vs BV	3	PFS: 13.2 mo vs 8.3 mo (HR 0.65, P = 0.00271), ORR/CR: 65.6%/24.5% vs 54.2%/24.2% TRAEs: 19.6% vs 25%
[91]		74	R/R PMBCL	2	ORR/CR: 45%/13% DoR: NR (12.5 mo FU); Grade ≥ 3 TRAEs: 23%
[92]		24	R/R CTCL	2	ORR: 38%; IRAEs: 17%

AE: Adverse event; ALT: Alanine amino transferase; ASCT: Autologous stem cell transplantation; BV: Brentuximab vedotin; cHL: Classic Hodgkin lymphoma; CR: Complete response; CTCL: Cutaneous T-cell lymphoma; DoR: Duration of response; Ipi: Ipilimumab; IRAEs: Immune related adverse event; Nivo: Nivolumab; NR: Not reached. ORR: Objective response rate; PFS: Progression-free survival; PMBCL: Primary mediastinal B-cell lymphoma; R/R: Relapsed/refractory; TRAEs: Treatment-related adverse event.

Table 5 Chimeric antigen receptor T cell studies

Drug [Ref.]	Target/co-stimulator	No. of patients	Study design	Study phase	Results
Axicabtagene-ciloleucel[96]	CD19/CD28	111	R/R DLBCL	2	ORR/CR: 82%/54%; DoR (FU 15.4 mo): 42%, 40% CR; 18-mos OS rate: 52% Grade ≥ 3 AEs: neutropenia 78%, CRS 13%, ICANS 28%
Tisagenlecleucel[97]	CD19/4-1BB	93	R/R DLBCL	2	ORR/CR: 52%/40%; DoR (FU 12 mo): 65%, 79% CR; Grade ≥ 3 AEs: CRS 22%, ICANS 12%, cytopenias 28%, infections 20%
Lisocabtagene-maraleucel[98]	CD19/4-1BB	344	R/R DLBCL	2	ORR/CR: 73%/53%; Grade ≥ 3 AEs: CRS 2%, ICANS 10%
Brexucabtagene-autoleucel (KTE-X19)[99]	CD19/CD28	74	R/R MCL	2	ORR/CR: 93%/67%; 1-yr PFS/ OS rate: 61%/83%; Grade ≥ 3 AEs: cytopenias 94%, infections 32%, CRS 15%, ICANS 31%
Tisagenlecleucel[100]	CD19/4-1BB	14	R/R CLL	1	ORR/CR: 57%/28%; No relapses in CR patients (n = 4). All CR patients developed CRS
Lisocabtagene-maraleucel[101]	CD19/4-1BB	23	R/R CLL (56.5% progressed after ibrutinib and venetoclax)	1/2	ORR/CR: 82%/45.5%; Grade ≥ 3 AEs: anemia 96%, thrombocytopenia 70%, CRS 9%, ICANS 22%
Axicabtagene-ciloleucel[102]	CD19/CD28	94	R/R FL, MZL	2	ORR/CR: FL 95%/80% MZL 86%/71%; Grade ≥ 3 AEs: neutropenia 33%, anemia 28%, CRS 11%, ICANS 19%

AE: Adverse event; CLL: Chronic lymphocytic leukemia; CR: Complete response; CRS: Cytokine releasing syndrome; DLBCL: Diffuse large B-cell lymphoma; DoR: Duration of response; FL: Follicular lymphoma. FU: Follow-up; ICANS: Immune effector cell-associated neurotoxicity syndrome; MCL: Mantle cell lymphoma; MZL: Marginal zone lymphoma; ORR: Objective response; OS: Overall survival; PFS: Progression-free survival; R/R: Relapsed/refractory.