Table 2.
Adverse events of immune-checkpoint-based therapy blockade for the treatment of B-cell lymphomas.
| Targets | Drug/Regimen | Trial ID | Phase | N | Disease | All-Grade AEs | Grade ≥3 AEs | SAEs and Discontinuation | Ref |
|---|---|---|---|---|---|---|---|---|---|
| PD-L1 CD20 |
Atezolizumab + Obinutuzumab + Bendamustine/ Atezolizumab + Obinutuzumab + CHOP |
NCT02596971 | 1/2 | 40 | FL, DLBCL | 100% Neutropenia (52%) Constipation (43%) Fatigue (40.5%) |
67% | 36% DAEs 1 TRD |
[121] |
| PD-L1 CD20 |
Atezolizumab + Obinutuzumab + Lenalidomide |
NCT02631577 | 1/2 | 20 | FL | 100% | 73.6% | 29% SAEs 23.7% DAEs |
[122] |
| PD-L1 CD20 EZH2 |
Atezolizumab + Obinutuzumab/ Atezolizumab + Tazemetostat |
NCT02220842 | 1 | 43 | FL, DLBCL | 95% Anaemia (26%) Fatigue (23%) |
47% | 35% SAEs 14% DAEs |
[123] |
| PD-L1 CD20 BCL2 |
Atezolizumab + Obinutuzumab + Venetoclax |
NCT03276468 | 2 | 58 | DLBCL | 84% Lymphopenia (35%) Neutropenia (33%) TP (17.5%) |
10.5% DAEs | [124] | |
| PD-L1 | Mosunetuzumab/ Atezolizumab + Mosunetuzumab |
NCT02500407 | 1 | 218 | FL, DLBCL, tFL, iNHL |
CRS (28.4%) Neurologic AE (44%) |
CRS (1.4%) Neurologic AE (3.2%) |
5.5% DAEs | [125] |
| PD-L1 CD20 |
Atezolizumab + CD20-TCB (RG6026) |
NCT03533283 | 1 | 36 | FL, DLBCL, MCL, PMBL, LPL | CRS (42%) Pyrexia (37%) Anaemia (29%) |
Neutropenia (18%) Anaemia (13%) No G ≥ 3 CRS |
[126] | |
| PD-L1 | Atezolizumab + KTE-C19 (Axi-cel) |
NCT02926833 | 1/2 | 28 | DLBCL | 100% | 86% Neurologic AE (29%) CRS (4%) |
[127] | |
| PD-L1 BTK |
Durvalumab + Ibrutinib |
NCT02401048 | 1/2 | 61 | FL, DLBCL | Diarrhoea (52%) Fatigue (46%) Nausea (34%) |
56% Neutropenia 13% Dyspnea (10%) |
51% SAEs 32% DAEs |
[120] |
| PD-L1 | Durvalumab + JCAR014 |
NCT02706405 | 1 | 13 | DLBCL, HG-BCL, PMBL | CRS (38%) Neurotoxicity (8%) |
[129] | ||
| PD-1 | Pembrolizumab | NCT01953692 | 1b | 31 | DLBCL, FL, PMBL, cHL, MM | 61% Hypothyroidism (11%) Diarrhoea (11%) Nausea (11%) |
11% Neutropenia Liver disease |
No DAEs No TRD |
[130] |
| PD-1 | Pembrolizumab | NCT02576990 | 2 | 53 | PBML | 57% Neutropenia (19%) Hypothyroidism (8%) |
23% Neutropenia (13%) |
2% DAEs No TRD |
[108] |
| PD-1 | Nivolumab | NCT02038933 | 2 | 121 | DLBCL, B-NHL | 98% Nausea (17%) Fatigue (17%) Diarrhoea (12%) |
62% Neutropenia (4%) TP (3%) |
12% SAEs 3% DAEs No TRD |
[7] |
| PD-1 | Pembrolizumab + ASCT |
NCT02362997 | 2 | 31 | DLBCL, PMBL, iNHL | 79% Neutropenia (26%) |
19% DAEs No TRD |
[102] | |
| PD-1 CD20 |
Nivolumab + Rituximab |
NCT03245021 | 1 | 19 | FL, B-NHL | Fatigue (74%) Infection (59%) Nausea (36%) |
Lipase increased (11%) Hyperglycemia (11%) Infection (11%) |
No DAEs | [132] |
| PD-1 | Pembrolizumab + R-CHOP |
NCT02541565 | 1 | 33 | DLBCL, FL | 43% Neutropenia (23%) Infection (10%) Syncope (10%) |
13% SAEs | [133] | |
| PD-1 TLR4 CD20 |
Pembrolizumab + G100 + Rituximab |
NCT02501473 (Discontinued) |
1/2 | 18 | FL, MZL | 100% | Abdominal pain (16%) Diarrhoea (16%) Anaemia (10%) |
10% SAEs 6% DAEs |
N/A |
| PD-1 BTK |
Nivolumab + Ibrutinib |
NCT02329847 | 1/2 | 144 | DLBCL, FL, CLL-RT, SLL | Diarrhoea (33%) Neutropenia (31%) Fatigue (26%) |
82% Neutropenia (28%) Anaemia (23%) |
77% SAEs 28% DAEs No TRD |
[135] |
| PD-1 BTK |
Pembrolizumab + Acalabrutinib |
NCT02362035 | 1/2 | 61 | DLBCL, cHL, CLL, MM, WM | Neutropenia (15%) Anaemia (11%) |
41% DAEs | [136] | |
| PD-1 CDK |
Pembrolizumab + Dinaciclib |
NCT02684617 | 1 | 128 | DLBCL, FL, CLL, MM | 63% TP (21%) Lymphopenia (16%) Anaemia (13%) |
32% Lymphopenia (13%) Neutropenia (11%) TP (8%) |
3% DAEs No TRD |
[137] |
| PD-1 HDAC |
Pembrolizumab + Entinostat |
NCT03179930 | 2 | 22 | FL, cHL | 62% Neutropenia (48%) TP (19%) Anaemia (10%) |
18% SAEs 15% DAE |
[139] | |
| PD-1 CD30 |
Nivolumab + Brentuximab Vedotin |
NCT02581631 | 1/2 | 30 | DLBCL, PMBL, PTCL, CTCL, MF, SS | 83% Neutropenia (30%) Peripheral neuropathy (27%) |
53% Neutropenia (30%) TP (10%) Peripheral neuropathy (10%) |
13% SAEs 7% DAEs No TRD |
[106] |
| PD-1 CD19 CD22 |
Pembrolizumab + AUTO3 |
NCT03287817 | 1/2 | 24 | DLBCL, tFL, PMBL | Neutropenia (89%) TP (58%) Anaemia (47%) |
[140] | ||
| PD-1 CD19 |
Pembrolizumab + Tisagenlecleucel |
NCT03630159 | 1 | 8 | DLBCL | 100% CRS (25%) Tachycardia (25%) |
50% Anaemia (25%) Pancreatitis (25%) |
No DAEs | [141] |
| PD-1 CTLA-4 | Nivolumab + Ipilimumab |
NCT01592370 | 1/2 | 65 | cHL, B-NHL, T-NHL, MM | Fatigue (26%) Pyrexia (23%) Diarrhoea (18%) |
29% | 48% SAEs 8% DAEs No TRD |
[142] |
| CTLA-4 | Ipilimumab | NCT00089076 | 1/2 | 18 | DLBCL, FL, MCL | 100% Diarrhoea (56%) Fatigue (56%) TP (28%) |
44.4% Diarrhoea (28%) Fatigue (6%) Neutropenia (6%) |
[143] | |
| CTLA-4 CD20 |
Ipilimumab + Rituximab |
NCT01729806 | 1 | 33 | DLBCL, FL, MCL | Fatigue (33%) Anaemia (30%) Diarrhoea (15%) |
Lymphopenia (18%) Diarrhea (12%) Anaemia (12%) |
[144] | |
| CTLA-4 | Ipilimumab | NCT01822509 | 1 | 28 | B-NHL | TP (27%) Chronic GVHD of liver (10%) Anaemia (7%) |
18% DAEs | [145] | |
| CTLA-4 | Ipilimumab + Lenalidomide |
NCT01919619 | 2 | 11 | DLBCL, FL, MCL, others | Neutropenia (44%) GVHD (9%) |
[146] | ||
| CD47 CD20 |
Hu5F9-G4 + Rituximab |
NCT02953509 | 1b/2 | 115 | DLBCL, iNHL | Infusion reaction (38%) Headache (34%) Fatigue (30%) |
Anaemia (15%) | 7% DAEs | [147] |
| CD47 CD20 |
TTI-621 + Rituximab |
NCT02663518 | 1 | 32 | DLBCL | Infusion reaction Transient TP |
[148] | ||
| CD47 CD38 |
TTI-622 + Daratumumab |
NCT03530683 | 1 | 19 | DLBCL, MCL, FL | Abdominal pain (10.5%) Fatigue (10.5%) Nausea (10.5%) |
Neutropenia (10.5%) No G ≥ 3 anaemia or TP |
[149] | |
| CD47 CD20 |
ALX148 + Rituximab |
NCT03013218 | 1 | 33 | DLCBL, MCL, FL, MZL | 79% Rash (18%) Fatigue (9%) |
Neutropenia (6%) | [150,151] | |
| CD40 | Dacetuzumab | NCT00103779 | 1 | 50 | DLBCL, MCL, FL, MZL | 98% Fatigue (28%) Headache (20%) Pyrexia (18%) |
30% | 26% SAEs No TRD |
[152] |
| CD40 | Dacetuzumab | NCT00435916 | 2 | 46 | FL, DLBCL, MZL | 98% Fatigue (41%) Headache (35%) Chills (33%) |
46% | 39% SAEs | [153] |
| CD40 | Lucatumumab | NCT00670592 | 1/2 | 111 (74) | FL, MZL, MCL, DLBCL | 100% Chills (39%) Pyrexia (34%) Fatigue (25%) |
65% Lipase elevation (25%) |
28% SAEs | [154] |
| CD40 CD20 |
Dacetuzumab + Rituximab + chemotherapy |
NCT00655837 | 1 | 30 | DLBCL | 100% CRS (61%) Nausea (36%) TP (36%) |
21% TP (6%) AST/ALT elevation (3%) |
45% SAEs 1 TRD |
[155] |
| CD40 CD20 |
Dacetuzumab Rituximab + chemotherapy |
NCT00529503 | 2 | 154 (101) | DLBCL, FL | 80% | 44% SAEs 8% DAEs |
[156] | |
| CD27 | Varlilumab | NCT01460134 | 1 | 90 (18) | MCL, MZL, DLBCL, CLL, cHL, TCL | 59% Fatigue (24%) Anaemia (12%) |
3% ALP elevation | [157] | |
| CD80 CD20 |
Galiximab + Rituximab |
NCT00363636 | 3 | 337 | FL | Pyrexia (18%) Anaemia (12%) |
No TRD | [158] | |
| CD80 | Galiximab | NCT00575068 | 1/2 | 38 | FL | 60% Fatigue (32%) Nausea (14%) Headache (11%) |
3% Axillary pain (3%) Venous thrombosis (3%) |
No SAEs No DAEs |
[159] |
| CD80 CD20 |
Galiximab + Rituximab |
NCT00048555 | 1/2 | 73 | FL | 96% Lymphopenia (48%) Leukopenia (36%) Fatigue (36%) |
26% Lymphopenia (14%) Leukopenia (3%) Anaemia (3%) |
13% SAEs 1 possible TRD |
[159] |
| CD80 CD20 |
Galiximab + Rituximab |
NCT00117975 | 2 | 61 | FL | 13% Lymphopenia Leukopenia Neutropenia |
13% of events Lymphopenia |
[160] | |
| 4-1BB | Urelumab | NCT01471210 | 1 | 60 | DLBCL, FL, B-NHL | 52% Fatigue (15%) Neutropenia (12%) |
15% | 3.3% DAEs | [161] |
| 4-1BB CD20 |
Urelumab + Rituximab |
NCT01775631 | 1 | 46 | DLBCL, FL |
72% Fatigue (20%) AST/ALT elevation (15/13%) |
28% | 2% TRD (CRS) | [161] |
| 4-1BB PD-1 |
Urelumab + Nivolumab | NCT02253992 | 1/2 | 22 | DLBCL | 63% Fatigue (26%) ALT/AST elevation (13/9%) |
ALT/AST elevation (3/3%) | 7% DAEs | [172] |
| 4-1BB CD20 |
Utomilumab + Rituximab |
NCT01307267 | 1 | 67 | FL, MCL, DLBCL | 95.5% Fatigue (16%) |
3% Neutropenia Diarrhoea ALT elevation |
4.5% DAEs No TRD |
[162] |
| CD70 | SGN-CD70A |
NCT02216890 Terminated |
1 | 38 | DLBCL, FL, MCL | 100% TP 75% Anaemia 50% |
90% TP 65% |
55% SAEs | [163] |
Abbreviations: FL, follicular lymphoma; tFL, transformed follicular lymphoma; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; B-NHL, B-cell non-Hodgkin lymphoma; iNHL, indolent B-cell non-Hodgkin lymphoma; aNHL, aggressive B-cell non-Hodgkin lymphoma; LBCL, large B-cell lymphoma; HG-BCL, high-grade B-cell lymphoma; cHL, classical Hodgkin lymphoma; CLL-RT, chronic lymphocytic leukaemia Richter transformation; PMBL, primary mediastinal B-cell lymphoma; PTCL, peripheral T-cell lymphoma; CTCL, cutaneous T-cell lymphoma; MF, myelofibrosis; SS, Sezary syndrome; MM, multiple myeloma; AE, adverse event; SAE, serious adverse event; TP, thrombocytopenia; AST, alanine aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; CRS, cytokine release syndrome; GVHD, graft-versus-host disease; TRD, treatment-related death; DAE, discontinuation due to adverse event; NA, not available.