Table 2 Clinical trials for HDACis in PTCLs

Romidepsin

HDAC1,2

2017

R/R PTCL

II

ORR (43%), CRR (25%), mPFS (5.6 months), and mDOR (11.1 months)

Lymphopenia (74%), Neutropenia (54%), Leukopenia (46%), and Thrombocytopenia (38%)

NCT01456039

[59]

Romidepsin + CHOP

HDAC1,2

2022

Untreated PTCL

III

ORR (63%), CRR (41%), mPFS (12.0 months), and mOS (51.8 months)

Thrombocytopenia (50%), Neutropenia (49%), Anemia (47%), and Leukopenia (32%)

NCT01796002

[61]

Romidepsin + pembrolizumab

HDAC1,2 and PD-1

2020

R/R PTCL, MF(N = 3)

II

ORR (50.0%) and CRR (35.7%)

NA

NCT03278782

[62]

Romidepsin + 5-azacitidine

HDAC1,2 and DNMT

2021

R/R PTCL

II

ORR (61%), CRR (48%), mPFS (8.0 months), and mDOR (20.3 months)

Thrombocytopenia (48%), Neutropenia (40%), Lymphopenia (32%), and Anemia (16%)

NCT01998035

[64]

Romidepsin + alisertib

HDAC1,2 and AAK

2020

R/R Lymphoma

I

ORR (28%), CRR (12%), and mOS (12.0 months)

Thrombocytopenia (40%), Anemia (28%), and Neutropenia (24%)

NCT01897012

[66]

Romidepsin + bendamustine

HDAC1,2

2019

R/R PTCL

NA

ORR (42.9%), CRR (28.6%), and mPFS (7 months)

Thrombocytopenia (42.9%), Neutropenia (28.6%), Anemia (14.3%), and Nausea and vomiting (42.9%)

NA

[67]

Romidepsin + duvelisib

HDAC1,2 and PI3K-δ, γ

2018

R/R PTCL (N = 36) and CTCL

I

PTCL: ORR (47.2%, 17/36), and CRR (25.0%);

CTCL: ORR (37.0%) and no CR

Neutropenia (15.9%) and Stevens-Johnson syndrome (n = 1, grade 5)

NCT02783625

[69]

Romidepsin + tenalisib

HDAC1,2, PI3K-δ, γ, and SIK3

2021

R/R PTCL (N = 12) and CTCL

I/II

PTCL: ORR (75%), CRR (50%), and mDOR (5.03 months);

CTCL: ORR (53.3%), CRR (6.3%), and mDOR (3.8 months)

Thrombocytopenia (21%), ALT elevation (18%), and Neutropenia (15%)

NCT03770000

[70]

Romidepsin + pralatrexate

HDAC1,2 and DHFR

2018

R/R Lymphoma

(PTCL, N = 14)

I

ORR (57%), CR (17%), and mPFS (4.4 months)

Thrombocytopenia (28%), Anemia (24%), and Oral mucositis (14%)

NCT01947140

[71]

Romidepsin + lenalidomide

HDAC1,2 and CRBN

2021

R/R Lymphoma

(PTCL, N = 15)

I

ORR (49%), CRR (18%), mPFS (5.7 months), mOS (24.0 months), and mDOR (15.7 months)

Thrombocytopenia (53%), Lymphopenia (51%), Neutropenia (49%), and Leukopenia (45%)

NCT01755975

[73]

Romidepsin + lenalidomide + carfilzomib

HDAC1,2, CRBN, and proteasome

2021

R/R Lymphoma (PTCL, N = 13)

I

ORR (48%), CRR (20%), mPFS (3.4 months), mOS (26.5 months), and mDOR (10.6 months)

Thrombocytopenia (16%) and Neutropenia (14%)

NCT02341014

[73]

Romidepsin + gemcitabine

HDAC1,2

2016

R/R PTCL

II

ORR (30%), CRR (15%), 2-year OS (50%), mOS (22 months), 2-year PFS (11.2%), and mPFS (2.5 months)

Thrombocytopenia

(60%), Neutropenia (50%), Anemia (20%), and Transaminase increase (15%)

NCT01822886

[75]

Romidepsin + GDP

HDAC1,2

2019

R/R PTCL (N = 10) and DLBCL

I

ORR (50%), no CR, 1-year PFS (15%), mPFS (2.3 months), 1-year OS (42%), and mOS (7.16 months)

Thrombocytopenia

(55%), Neutropenia (55%), and Anemia (30%)

NCT01846390

[77]

Romidepsin + liposomal doxorubicin

HDAC1,2

2020

R/R PTCL (N = 11) and CTCL

I

PTCL: ORR (27%), CRR (27%), mPFS (2.1 months), mOS (17.5 months), mTTR (3.5 months), and mDOR (4.2 months);

CTCL: ORR (70%), CRR (10%), mPFS (6.9 months), mOS (not reached), mTTR (2 months), and mDOR (5.1 months)

Thrombocytopenia (17%), Anemia (13%), and Neutropenia (9%)

NCT01902225

[78]

Belinostat

Class I, II, IV HDACs

2015

R/R PTCL

II

ORR (25.8%), CRR (10.8%), mDOR (13.6 months), mPFS (1.6 months), and mOS (7.9 months)

Anemia (10.8%), Thrombocytopenia (7%), Dyspnea (6.2%), and Neutropenia (6.2%)

NCT00865969

[83]

Belinostat + CHOP

Class I, II, IV HDACs

2021

Untreated PTCL

I

ORR (86%), and CRR (66.7%)

Neutropenia (30%) and Anemia (17%)

NCT01839097

[87]

Chidamide

HDAC1,2,3,10

2015

R/R PTCL

II

ORR (28%), CRR (14%), mPFS (2.1 months), and mOS (21.4 months)

Thrombocytopenia (22%), Leukopenia (13%), and Neutropenia (11%)

ChiCTR-TNC-10000811

[91]

Chidamide

HDAC1,2,3,10

2022

R/R ATLL

IIb

ORR (30.4%), CRR (4.3%), mPFS (1.7 months), mDOR (9.2 months), mOS (7.9 months)

Thrombocytopenia (39.1%), Neutropenia (39.1%), Leukopenia (30.4%), and Anemia (17.4%)

NCT02955589

[92]

Chidamide + CHOP

HDAC1,2,3,10

2021

Untreated PTCL

Ib

ORR (89.3%), CR/CRu rate (57.1%), and mPFS (14.0 months)

Leukopenia (90.0%), Neutropenia (83.3%), Vomiting (13.3%), Thrombocytopenia (10.0%) and Febrile neutropenia (10.0%)

NCT02809573

[93]

Chidamide + CHOEP

HDAC1,2,3,10

2021

Untreated PTCL

II

ORR (60.2%), CRR (40.7%), mPFS (10.7 months), and mDOR (9.2 months)

Leucopenia (69.0%), Neutropenia (69.0%), Anemia (37.2%), Thrombocytopenia (31.0%), and Hypokalemia (15.0%)

NCT02987244

[94]

Ib

ORR (46.7%) and CRR (26.7%)

Leucopenia (60.0%), Neutropenia (66.7%), Anemia (26.7%), Thrombocytopenia (33.3%), Fever (13.3%), and Hyponatremia (13.3%)

Chidamide + PET

HDAC1,2,3,10

2022

Untreated AITL

II

ORR (90.2%), CR/CRu rate (54.9%), mPFS (42.6 months), 2-year PFS (66.5%), and 2-year OS (82.2%)

Neutropenia (32.3%), Lymphopenia (5.8%), and Thrombopenia (5.9%)

NCT03273452

[40]

Panobinostat + bortezomib

Class I, II, IV HDACs and proteasome

2015

R/R PTCL

II

ORR (43.5%), CRR (21.7%), DOR (5.6 months), mPFS (2.59 months), mOS (9.90 months)

Thrombocytopenia (68%), Neutropenia (40%), and Diarrhea (20%)

NCT00901147

[95]

Vorinostat + CHOP

Class I, II, IV HDACs

2013

Untreated PTCL

II

ORR (85.7%), CRR (85.7%), mDOR (29 months), 2-year PFS (79%), and 2-year OS (81%)

Neutropenia (64%), Thrombocytopenia (14%), and Pain (14%)

NCT00787527

[97]

Vorinostat + lenalidomide + dexamethasone

Class I, II, IV HDACs and CRBN

2014

R/R PTCL

I/II

ORR (25%), CRR (12.5%), mPFS (2.2 months), and mOS (6.7 months)

Thrombocytopenia (23%), Leukocytopenia (15%), Anemia (8%), and Neutropenia (8%)

NCT00972842

[98]

Vorinostat + alisertib

Class I, II, IV HDACs and AAK

2020

R/R lymphoma (PTCL, N = 2)

I

ORR (11.8%) and CRR (5.9%),

Neutropenia (22%), Leukocytopenia (17%), and Anemia (17%),

NCT01567709

[99]