Table 3.
Reported adverse events related to the investigated LRAs according to published studies.
| Author, publication year | LRA which AEs are related to | Discontinuation rate/participants receiving LRAs (%) | Total number of events |
SAEs | Reported grading of AEs | |
|---|---|---|---|---|---|---|
| > grade 2 | ≤ grade 2 | |||||
| Chromatin modulators | ||||||
| Histone deacetylase inhibitors (HDACis) | ||||||
| Archin et al., 200818 | Valproic acid | 0/12 (0%) | 0 | 4 | NI | NI |
| Archin et al., 201019 | Valproic acid | 0/8 (0%) | 0 | NI | NI | NI |
| Routy et al., 201220 | Valproic acid | 5/56 (9%) | NI | NI | NI | 5 AEs-withdrawal on valproic acid (9%): mood change, GI symptoms, pulmonary emboli in 1 (2%). Only side-effect participants who withdrew described |
| Archin et al., 201221 | Vorinostat | 0/8 (0%) | 0 | NI | NI | NI |
| Archin et al., 201422 | Vorinostat | 0/5 (0%) | 0 | 1 | 0 | Mild GI symptoms; headache: no grade I severity; 5 (100%) transient platelet decline (thrombocytopenia grade 1 in 1) |
| Elliott et al., 201423 | Vorinostat | 0/20 (0%) | 0 | 69 | NI |
51 clinical AEs (74%): 27 GI symptoms (53%) of which 8 diarrhoea (30%), 11 neurological (22%) of which 4 headache (36%) and 4 impaired concentration (36%); 18 lab AEs (26%): most frequent: 8 thrombocytopenia (44%) |
| Archin et al., 201724 | Vorinostat | 0/16 (0%) | 0 | 0 | 0 | Mild GI symptoms not grade 1; no grade I severity; 3 (13 doses, 100%) platelet decline of -15-35% |
| Fidler et al., 202025 | Vorinostat | 0/30 (0%) | 0 | 28 | 1 |
1 SAE: vasovagal syncope probably related to blood draw venepuncture; Most frequent AEs: 7 diarrhoea (16%), 4 nausea (9%), 9 fatigue (21%) |
| Gay et al., 202026 | Vorinostat | 0/5 (0%) | 0 | NI | 0 | Mild, transient GI symptoms, not greater than grade 1 |
| Kroon et al., 202027 | Vorinostat | 1/10 (10%) | 2 | 115 | 2 |
34 lab AEs: most frequent: 8 decreased eGFR (24%) and 15 thrombocytopenia (44%) 81 clinical AEs:, most frequent: 9 diarrhoea (11%), 13 nausea (16%), 9 dizziness (11%) and 7 upper respiratory tract infection (9%) SAEs: treatment discontinuation in 1 (10%), hospitalisation in 2 (20%) |
| Gay et al., 202228 | Vorinostat | 0/8 (0%) | 0 | 3 | NI | 1 nausea (33.3%), 1 diarrhoea (33.3%), 1 pruritus (33.3%) |
| Scully et al., 202229 | Vorinostat | 0/31 (0%) | 0 | 2 | 0 | 1 mild dysgeusia (50%) and 1 moderate thirst (50%) |
| Rasmussen et al., 201430 | Panobinostat | 0/15 (0%) | 0 | 16 | 0 | Most frequent AEs: 8 fatigue (50%), 2 diarrhoea (13%) |
| Sogaard et al., 201531 | Romidepsin | 0/5 (0%) | 0 | 35 | 0 | Most frequent AEs: 11 nausea (31%), 4 borborygmia (11%), 2 abdominal pain (6%) and 5 fatigue (14%) |
| Leth et al., 201632 | Romidepsin | 0/20 (0%) | 0 | 57 | 0 | Most frequent AEs: 18 fatigue (32%), 24 nausea (42%), 3 vomiting (5%), 3 constipation (5%), 2 headache (4%) |
| Mothe et al., 202033 | Romidepsin | 0/15 (0%) | 2 | 202 | 1 |
2 grade 4 AEs: 1 shigella sonnei sepsis 4 h after RMD (SAE) (0.5%), 1 creatinine kinase elevation (0.5%) Most frequent lab AEs: 8 hypophosphatemia (4%) and 5 thrombocytopenia (2%) Most frequent clinical AEs: headache/fatigue in 14 (93%), GI symptoms: nausea in 11 (73%), anorexia in 9 (60%), abdominal pain in 7 (47%), constipation/metallic taste in 6 (40%), abdominal distension in 5 (33%), vomiting in 4 (27%) |
| McMahon et al., 202134 | Romidepsin | 0/49 (0%) | 1 | 24 | NI | Most frequent AEs: 2 headache (16%) (grade 1), 3 fatigue (25%) (grade 2), 4 nausea (31%) (grade 2), 6 neutropenia (2 grade 1 (15%), 3 grade 2 (23%), 1 grade 3 (7%)) |
| Gruell et al., 202235 | Romidepsin | 0/20 (0%) | 1 | 177 | 1 |
Most frequent AEs: 38 nausea (21%), 23 headache (13%), 16 fatigue (9%), 10 chills (6%), 10 vomiting (6%), 3 prolonged QTc (2%), 7 increased QTc >10 ms post-infusion vs pre- infusion (35%) SAE: (= grade 3) increased direct bilirubin |
| Gunst et al., 202236 | Romidepsin | 0/28 (0%) | 0 | 85 | 0 | Most frequent AEs: nausea (63%) and fatigue (52%) |
| Li et al., 202037 | Chidamide | 0/7 (0%) | 0 | 6 | 0 | 3 fatigue (50%), 1 rash (17%), 2 somnolence (29%) |
| IKAROS Family Zinc Finger 1 protein (IKZF1) degradation | ||||||
| Liu et al., 202238 | Lenalidomide | 0/13 (0%) | 0 | 2 | 0 | 2 (15.3%) participants developed a mild rash |
| BRG-1-associated factors complex inhibitors (BAFi's) | ||||||
| Prins et al., 202339 | Pyrimethamine, valproic acid | 5/21 (%) | 3 | 88 | 0 |
Most frequent AEs: nausea, vomiting and headache, 3 in the combination arm discontinued, 1 in pyrimethamine arm discontinued and 1 in valproic acid arm discontinued. |
| Transcription activation | ||||||
| Phosphatase and tensin homolog (PTEN) dysregulation | ||||||
| Spivak et al., 201340 | Disulfiram | NI | 0 | NI | NI | NI |
| Elliot et al., 201541 | Disulfiram | 0/30 (0%) | 0 | 76 | 0 |
62 clinical AEs (82%): 23 GI symptoms (37%) (most frequent: 6 abdominal pain (26%) and 6 diarrhoea (26%)), 16 neurological (26%) (most frequent: 6 headache (38%), 23 constitutional (37%) of which most frequent 4 sleepiness (13%), 4 fatigue (13%), 3 light-headedness (9%)); 14 lab AEs (18%): most frequent: 7 hypophosphatemia (50%) |
| McMahon et al., 202242 | Disulfiram + vorinostat | 2/2 (100%) | 2 | 0 | 2 | Grade 3 neurotoxicity in 2 leading to suspension of enrolment (SAEs): Possibly disulfiram: 1 (50%) left sigmoid sinus thrombosis, transient; Probably disulfiram/possibly VOR: 1 (50%) lethargy; dysgeusia; emotionally labile; paranoid ideation; ataxia |
| Toll-like receptor (TLR) agonists | ||||||
| Vibholm et al., 201743 | MGN1703 | 0/15 (0%) | 1 | 56 | 0 | 1 grade 3 neutropenia AE; Most frequent AEs: 23 injection site reaction (40%), 7 fatigue (12%), 11 neutropenia (19%) (3 neutropenia grade 2) |
| Vibholm et al., 201944 | MGN1703 | NI | 2 | 25 | 0 | Grade 3 neutropenia in 2 participants (16%); Most frequent AEs: Grade 1 injection site reaction in 7 participants (58%), neutropenia in 9 participants (75%), grade 2 dizziness in 1 participant (8%) |
| Saxena et al., 201945 | Poly-ICLC | 0/12 (0%) | 1 | 34 | 0 | Most frequent AEs: 15 (43%) injection site reactions (10 pain (66%) and 5 erythema (33%)), 4 fever (11%) and 10 (29%) fatigue |
| Riddler et al., 202046 | Vesatolimod | 0/36 (0%) | 0 | 56 | 0 | Grade 3 neutropenia in 1 participant (3%); Most frequent AEs: fatigue in 7 (30%), nausea in 5 (22%), myalgia/headache/nasal congestion in 4 (18%) |
| Non-canonical NFKb agonists | ||||||
| Lafeuillade et al., 201447 | Maraviroc | 0/11 (0%) | 0 | 0 | 0 | 0 |
| Protein kinase C (PKC) agonists | ||||||
| Gutiérrez et al., 201650 | Bryostatin | 0/8 (0%) | 0 | 5 | NI | 2 transient headache (20 μg arm) (40%), 2 transient myalgia (20 μg arm) (40%), 1 rash post infusion (20%) (all grade 1) |
| Interleukins and interleukin (IL) agonists | ||||||
| Stellbrink et al., 200251 | IL-2 | 1/56 (2%) | 6 | NI | 6 | AEs leading to dose reduction in 8 (31%) participants, discontinuation in 1 (4%) |
| Katlama et al., 201652 | IL-7 + maraviroc | 0/15 (0%) | NI | NI | 1 | 19 ≥ grade 2 AEs in 9 participants (60% of IL-7 arm); SAE: phlebitis lower limb (right) probably related to IL-7, transient |
| Miller et al., 202253 | N-803 | 1/16 (6%) | 38 | 263 | NI |
Most frequent clinical AEs: 154 injection site reactions (51%) (34 grade 3 (22%), in 1 (6%) participant leading to withdrawal), 21 (7%) pain, 12 (4%) QTc prolongation; Most frequent lab AEs: 34 grade 1 (72%); 9 grade 2 (19%): 6 decreased eGFR (66%), 1 low Hb (11%); 4 grade 3 (9%): 2 decreased eGFR (50%) and 2 increased bilirubin (50%) |
| Immune checkpoint (IC) inhibitors | ||||||
| Wightman et al., 201554 | Ipilimumab | 0/1 (0%) | NI | NI | NI | NI |
| Lau et al., 202155 | Avelumab, ipilimumab + nivolumab | 0/3 (0%) | 0 | 0 | 0 | 0 |
| Vaccines | ||||||
| Achenbach et al., 201558 | HIV DNA vaccine + rAD5 boost | 0/14 (0%) | NI | NI | 0 | No severe post-vaccine reactions, only mild/moderate localised reactions: tenderness-redness-swelling at injection site; general symptoms of fatigue, malaise, and myalgia were noted after 10 (24%) DNA prime injections and 3 (21%) rAd5 boost injections |
| Other | ||||||
| Cummins et al., 202162 | Ixazomib | 1/17 (6%) | 0 | 5 | NI | 3 diarrhoea (60%), 2 maculo-papular rash (40%) with treatment interruption at 20 weeks due to maculo-papular rash in 1 participant (4 mg arm) |
†Hepatitis A, Hepatitis B, Influenza, Pneumococcal, Tetanus-diphtheria, Varicella, Measles-Mumps-Rubella. LRA: Latency- reversing agent, SAE: severe adverse event, AE: adverse event, NI: no information, RMD: romidepsin, GI: gastro-intestinal, eGFR: estimated glomerular filtration rate, VOR: vorinostat, IL: interleukin, Hb: haemoglobin