Table 2.
Experimental agents and combinations of licensed agents in relapsed/refractory setting
| Agent | Target | Trial/phase | Subtype | N | ORR (%), CR (%) | Median DOR (months) | PFS (months) | OS (months) | AEs |
|---|---|---|---|---|---|---|---|---|---|
| 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 |