Table 1.
Emerging treatments with completed or ongoing clinical trials
| Agent Trial (location) |
Phase | N | Patients | Results/efficacy | Most common AEs (all grades, unless otherwise stated) |
|---|---|---|---|---|---|
| Antimetabolites | |||||
| Cladribine | |||||
| Tobinai [44] (Japan) | 2 | 15 | R/R ATL (acute, lymphoma, or unfavorable chronic) | ORR: 7% (1 PR) |
Grade ≥ 3 Neutropenia (44%) Leukopenia (31%) Anemia (25%) All grades Neutropenia (63%) Leukopenia (56%) Anemia (31%) Thrombocytopenia (31%) |
| Clofarabine | |||||
| NCT00416351 (USA) | 1/2 | 29 | R/R T-cell or NK cell lymphoma, including ATL | Study is ongoing; not recruiting | |
| Pralatrexate | |||||
|
+ Romidepsin NCT01947140 (USA) |
1/2 | 93 | R/R lymphoid malignancies and multiple myeloma (phase 1); R/R T-cell lymphoma (phase 2) | Study is recruiting | |
| AZT/IFN combinations | |||||
| AZT and/or IFN plus arsenic trioxide | |||||
| Hermine [45] (France) | 2 | 7 | R/R ATL (4 acute, 3 lymphoma) |
ORR: 57% (4/7; 1 CR) Median OS: 1.5 months |
Hematologic toxicity (86% [6/7]) Neuropsychiatric (86%) GI (57%) |
| Monoclonal antibodies | |||||
| Mogamulizumab | |||||
| Yamamoto [46] (Japan) | 1 | 16 | Relapsed CCR4+ ATL/PTCL |
ORR: 31% (5/16) CR: 13% (2/16) Median PFS: 46 days |
Hematologic toxicity (88%) Infusion-related reaction (88%) |
| Ishida [47] (Japan) | 2 | 26 | Relapsed aggressive CCR4+ ATL |
ORR: 50% (13/26) CR: 31% (8/26) Median PFS: 5.2 months Median OS: 13.7 months |
Hematologic toxicity (96%) Infusion-related reaction (89%) Skin rash (63%) |
| Phillips [48] (US/EU/LA) | 2 |
71 (Moga: 47; IC: 24) |
R/R ATL |
ORR: Moga: 28% (13/47); IC: 8% (2/24) Median PFS: Moga: 0.9 months; IC: 0.9 months Median OS: Moga: 4.9 months; IC: 6.9 months |
TEAEs occurring more often in the Moga group than the IC group: Infections (51% vs 21%) Respiratory disorders (49% vs 29%) Infusion-related reactions (47% vs 0%) Skin disorders (43% vs 8%) TEAEs ≥ grade 3 Moga: 62% (29/47) IC: 54% (13/24) |
| Daclizumab | |||||
| Berkowitz [49] (USA) | 2 | 20 | ATL (all subtypes; 70% had received previous therapy) |
ORR: 20% (all indolent) Median PFS: 12 weeks Median OS: 132.6 weeks |
Hypoglycemia (50%) Hyperuricemia (45%) AST (40%) Hypoalbuminemia (40%) Diarrhea (25%) |
| Brentuximab | |||||
| NCT01703949 (USA) | Pilot | 8 | R/R CD30+ lymphoma (including ATL) | Study is ongoing; not recruiting | |
| NCT02588651 (USA) | 2 | 31 | R/R CD30-low mature T-cell lymphoma (including ATL) | Study is recruiting | |
| Alemtuzumab | |||||
| Sharma [50] (USA) | 2 | 29 | Acute, chronic, or lymphomatous ATL with at least 10% of malignant cells expressing CD52 and CD25 (69% had prior treatment) |
ORR: 52% CR: 21% Median PFS: 2.0 months Median OS: 5.9 months |
All patients developed CMV antigenemia Grade 3 and 4 AEs ≥ 10% Leukopenia (41% grade 3; 17% grade 4) Neutropenia (31% grade 3; 3% grade 4) Lymphocytopenia (59% grade 3) Anemia (24% grade 3) Infections (14% grade 3) Thrombocytopenia (10% grade 3) Hypotension (10% grade 3) Fever in absence of neutropenia (10% grade 3) |
| Proteasome inhibitor | |||||
| Bortezomib | |||||
| Ishitsuka [51] (Japan) | 2 | 15 | R/R ATL |
ORR: 7% PFS: 38.0 days (study terminated because of unpromising results) |
Fever (47%) Anorexia (40%) Thrombocytopenia (73%) Leukopenia (33%) Lymphopenia (33%) |
|
+ EPOCH and raltegravir Ratner [35] (USA) |
1/2 | 18 | Previously treated (n = 4) or untreated (n = 14) acute or lymphoma ATL |
ORR: 61% (11/18) CR: 17% (3/18) Median PFS: 5.8 months Median OS: 6.2 months |
Grade 4 toxicities Neutropenias (n = 5) Thrombocytopenias (n = 4) Leukopenias (n = 2) Sepsis (n = 1) Neutropenic fever (n = 1) Grade 3 toxicities Hematologic (n = 11) Gastrointestinal (n = 5) Metabolic (n = 5) Pulmonary (n = 2) Infectious (n = 2) |
| Carfilzomib | |||||
| NCT01336920 (USA) | 1 | 15 | R/R T-cell lymphoma (including ATL) | Study is ongoing, not recruiting | |
| Aurora A kinase inhibitor | |||||
| Alisertib | |||||
| Barr [52] (USA) | 2 | 37 (ATL: n = 4) | R/R PTCL (including ATL) | ORR (ATL): 25% (1/4) |
Grade ≥ 3 (all patients) Neutropenia (32%) Anemia (30%) Thrombocytopenia (24%) Any grade (all patients) Anemia (59%) Thrombocytopenia (46%) Fatigue (46%) |
|
+ Vorinostat NCT01567709 (USA) |
1 | 60 | R/R Hodgkin lymphoma, B-cell NHL, or PTCL (including ATL) | Study is ongoing; not recruiting | |
| Immunomodulatory agents | |||||
| Lenalidomide | |||||
| Ishida [53] (Japan) | 2 | 26 | R/R aggressive (acute, lymphoma, or unfavorable chronic) ATL |
ORR: 42% (11/26) CR/CRu: 19% (5/26) Median PFS: 3.8 months Median OS: 20.3 months |
Grade 3/4 Neutropenia (65%) Leukopenia (38%) Lymphopenia (38%) Thrombocytopenia (23%) Anemia (19%) |
| Phillips [54] (North America) | 2 | 4 (study closed early because of limited patient accrual) | R/R acute or lymphoma ATL |
ORR: 0 OS: range: 7–62 months |
Grade 1 fatigue (75%) Grade 1 thrombocytopenia (50%) No grade 3 or 4 AEs |
| Ogura [55] (Japan) | 1 | 13 (ATL: n = 9) | Advanced (previously treated; relapsed/progressed) ATL (acute, lymphoma, or unfavorable chronic)/PTCL |
ORR: 36% (4/13; all PR) Median PFS: 3.4 months |
Lymphopenia (11 [85%]) Neutropenia (11 [85%]) Thrombocytopenia (10 [77%]) Anemia (10 [77%]) Increased alanine aminotransferase (11 [85%]) Increased aspartate aminotransferase (11 [85%]) Maculopapular rash (9 [69%]) Increased blood alkaline phosphatase (8 [62%]) Increased C-reactive protein (8 [62%]) Hypoalbuminemia (8 [62%]) Hypophosphatemia (8 [62%]) |
| Therapeutic vaccines | |||||
| TAX DC vaccine | |||||
| Suehiro [56] (Japan) | Pilot | 3 | Previously treated ATL |
ORR: 2/3 (PR) Duration of remission (range): 19+–24+ months |
Fever (3/3) Dermatitis (3/3) Diarrhea (1/3) |
| THV-02 | |||||
| Trials planned [57] | N/A | N/A | N/A | N/A | N/A |
| Immune toxins | |||||
| IMTOX-25 | |||||
| NCT01378871 (USA) | 2 | 1 | R/R CD25+ ATL | Study completed; no results available | |
| LMB-2 | |||||
|
+ Fludarabine and cyclophosphamide Kreitman [58] (USA) |
2 | 17 | Previously treated (n = 16) or untreated (n = 1) CD25+ ATL |
CR: 6/15 PR: 2/15 Median PFS: 11.6 months (responders); 1.1 months (nonresponders) |
Grade ≥ 3 Neutropenia (n = 12) Leukopenia/lymphopenia (n = 12) Anemia (n = 8) Transaminases (n = 5) Thrombocytopenia (n = 6) Fever/chills (n = 4) |
| JAK inhibitor | |||||
| Ruxolitinib | |||||
| NCT01712659 (USA) | 2 | 20 | Smoldering or chronic ATL or previously treated lymphomatous or acute ATL with clinically indolent behavior (lack of significant symptoms and treatment-free interval > 6 months) | Study is recruiting | |
| NCT01431209 (USA) | 2 | 90 | R/R diffuse large B-cell or peripheral T-cell NHL | Study is recruiting | |
| Histone deacetylase inhibitor | |||||
| Panobinostat | |||||
| NCT01261247 (USA) | 2 | 41 | R/R NHL (including recurrent ATL) | Study is ongoing; not recruiting | |
| HBI-8000 | |||||
| NCT02955589 (Japan) | 2 | 30 | R/R ATL | Study is recruiting | |
| Checkpoint inhibitor (PD-1 antibody) | |||||
| Pembrolizumab | |||||
| NCT02535247 (USA) | 2 | 24 (planned) | R/R peripheral T-cell NHL (including ATL) | Study is recruiting | |
| PI3K inhibitor | |||||
| RP6530 | |||||
| NCT02567656 (USA) | 1 | 58 (planned) | R/R peripheral or cutaneous T-cell lymphoma | Study is recruiting | |
AE adverse event, AST aspartate aminotransferase, ATL adult T-cell leukemia–lymphoma, CCR4 C–C chemokine receptor 4, CR complete response, CRu complete response unconfirmed, GI gastrointestinal, IC investigator’s choice, JAK Janus kinase, NHL non-Hodgkin lymphoma, NK natural killer, ORR overall response rate, OS overall survival, PFS progression-free survival, PR partial response, PTCL peripheral T-cell lymphoma, R/R relapsed/refractory, TEAE treatment emergent adverse event