Table 2 Experimental agents and combinations of licensed agents in relapsed/refractory setting

Alisertib

Aurora A kinase inhibitor

SWOG1108 phase II [62]

R/R PTCL or transformed MF (tMF),PTCL-NOS 35%, AITL 24%, ATLL 11%

37

30, 7

Not reported

3

8

Gr ≥ 3 AEs: neutropenia (32%), anemia (30%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%), rash (5%)

Lumiere phase III [87],alisertib vs. investigator’s choice

R/R PTCL, PTCL-NOS 45%, AITL 22%,

ACLC 6% (ALK− 5% ALK+ 1%), EATL 2%, ENKTL 1%

120

33, 16

5

2.7

9.9

Gr ≥ 3 AEs (alisertib vs. comparator):neutropenia (43% vs 25%), thrombocytopenia (29% vs 27%), anemia (33% vs 11%)

Alemtuzumab

Anti-CD52 mAb

European phase II [20]

R/R PTCL

14

36, 21.4

Not reported

Not reported

Not reported

CMV reactivation in 6 pts

Pulmonary aspergillosis in 2 pts

EBV-related hemophagocytosis in 2 pts

5 treatment-related deaths

5-Azacitadine

Hypo-methylating agent

Retrospective series [38]

R/R AITL (1 pt previously untreated), (41% with concomitant myeloid neoplasm)

12

75, 50

Not reported

15

21

TET2 mutations detected in all 12 patients

Crizotinib

ALK ROS1 inhibitor

Retrospective series [53]

R/R ALK+ lymphoma, ALCL, ALK+ 82%

11

100, 100

Not reported

63.7% at 2 years

72.7% at 2 years

No Gr ≥ 3 AEs

Phase I/II Children’s Oncology Group [52]

R/R ALK+ ALCL

*Pediatric patients (aged 18 months–22 years old)

26

165 mg/m²:

83, 90 280 mg/m²: 83, 36

Not reported

Not reported

Not reported

Gr ≥ 3 AEs: 165 mg/m² 22%, 280 mg/m² 70%

Duvelisib

PI3K δ/γ inhibitor

Phase I [56]

R/R PTCL

16

50, 19

Not reported

4.4

Not reported

Gr ≥ 3 AEs: transaminase increases (40% ALT, 17% AST), maculopapular rash (17%), neutropenia (17%)

Everolimus

mTOR inhibitor

Phase II [58]

R/R PTCL + MF,PTCL-NOS 25%, ALCL 12.5%, AITL 6% ENKTL 6%

16

44

8.5

4.1

10.2

Gr ≥ 3 AEs : hematologic toxicity 37.5%

Lenalidomide

Immuno-modulator

EXPECT, phase I/II [50]

R/R PTCL, AITL 48%, PTCL-NOS 37%, ALCL 6%

54

22, 11

AITL:

31, 15

3.6

AITL: 3.5

2.5

AITL: 4.6

Not reported

Gr ≥ 3 AEs experienced by 54%

12 treatment-related deaths: acute respiratory distress syndrome, dyspnea, lung infiltration, neutropenic sepsis, pneumonia and cerebral ischemia (n = 1 each)

ATLL-002 phase II [51]

R/R ATLL, acute 58%, lymphomatous 27%, chronic 15%

26

42, 19

Not reported

3.8

20.3

Gr ≥ 3 AEs: neutropenia (65%), leukopenia (38%), lymphopenia (38%), thrombocytopenia (23%)

Nivolumab

Anti-PDL-1 mAb

Phase Ib [48]

R/R PTCL, AITL 50%, PTCL-NOS 25%, ALCL, ALK− 8%

12

33, 17

3.6

1.9

7.9

Immune-mediated AEs in 34%; 53.5% required treatment for immune-mediated AE

Phase II [47]

ATLL: 1 acute, 1 lymphomatous, 1 chronic

3

n/a

n/a

n/a

n/a

All 3 patients developed rapid progression of disease after the 1st dose

Pembrolizumab

Anti-PDL-1 mAb

Retrospective series [88]

R/R EBV+ NKTCL, failing L-asparaginase

7

100, 71.4

Not reported

Not reported

Not reported

1 patient (post-alloHSCT) developed grade 2 rash; no other AEs

Phase II [49]

R/R PTCL

18

33, 27

2.9

3.2

10.6

Trial halted early after preplanned interim futility analysis

Grade ≥ 3 rash (17%), grade ≥ 3 pneumonitis (11%)

Romidepsin + henalidomide

Phase I/II [32], phase II ongoing NCT022325-16

R/R TCL, 10 CTCL, 11 PTCL

21

50

Not reported

13.5 weeks*

Not reached

Grade ≥ 3 AEs: neutropenia (48%), thrombocytopenia (38%), anemia (33%), electrolyte abnormalities (K, Phos, glucose, Mg (43%)

Romidepsin + lenalidomide + carfilzomib

Phase Ib/IIa [33]

R/R TCL, PTCL-NOS 47%, AITL 21%

19

50, 31

AITL: 80% CR

9.8 weeks*

9.7 weeks*

Not reached

Grade ≥ 3 AEs in ≥ 10% of patients: neutropenia, thrombocytopenia

Romidepsin + pralatrexate

Phase I/II [34]

R/R lymphomas

,TCL 62%, ATLL 21%, ALCL, ALK− 10%

23

71, 40

4.29

4.4

12.4

Grade 4 AEs: thrombocytopenia (14%), neutropenia (10%), sepsis (7%), fever (3%), and pneumonia (3%)

Romidepsin + azacitadine

Phase I [39]

R/R lymphomas, TCL 35%, AITL 10%, ATLL 6%

31

32, 23

TCL: 73, 55 AITL: 100% CR

2.5; TCL: not reached

Not reached

Not reported

Grade ≥ 3 AEs: thrombocytopenia (27%), neutropenia (42%), lymphopenia (42%), hypotension (12%), hyponatremia (8%)

Duvelisib + romidepsin + bortezomib

Phase I/II [57]

Arm A: duvelisib + romidepsinArm B: duvelisib + bortezomib

R/R PTCL + CTCL

Arm A: 22Arm B: 14

Arm A: 55, 27Arm B: 36, 21

Arm A: 8.8

Arm B: 3.5

Arm A: 9.1 (all patients)

Arm B: 9.3 (all patients)

Not reported

Arm A: 65% with Gr ≥ 3 AEs: increased ALT/AST (15%), neutropenia (18%), hyponatremia (12%)

Arm B: 45% with Gr ≥ 3 AEs: neutropenia (18%), 1 pt with Stevens-Johnson syndrome