Table 4.
Clinical trials evaluating the efficacy and toxicity of immune checkpoint inhibitors, used as single agents or in combination regimens, for the treatment of patients with CLL.
| Drug regimen | Setting | Efficacy | Toxicities | References |
|---|---|---|---|---|
| Pembrolizumab every 3 weeks for up to 2 years | Phase II: 25 patients (9 Richter syndrome) R/R CLL |
ORR 16% 1% CR Median PFS 3 months Median OS 10.7 months |
G≥3 neutropenia 20% G≥3 thrombocytopenia 20% G≥3 anemia 20% G≥3 dyspnea 8% G≥3 hypoxia 8% G≥3 fatigue 8% G≥3 febrile neutropenia 8% G≥3 fever 4% G≥3 maculopapular rash 4% G3 lung infection 12% G3 hepatic toxicity 8% G5 sepsis 4% |
Ding et al. (285) NCT02332980 |
| Nivolumab 3 mg/kg IV every 2 weeks and ibrutinib 420 mg/day | Phase II 8 patients (4 Richter sydrome) R/R CLL vs 3 patients PR CLL to 9-month ibrutinib therapy |
ORR 75% 50% PR vs ORR 100% 100% PR |
No G≥3 AEs | Jain et al. (286) NCT02420912 |
| Pidilizumab | Phase I 3 patients R/R CLL |
ORR 0 67% SD |
No G≥3 AEs | Berger et al. (287) |
| Samalizumab once every 28 days until progression or toxicity | Phase I 23 patients R/R CLL |
ORR 4% 4PR |
G≥3 hematological AEs 12% G≥3 reduced visual acuity 4% G≥3 muscular weakness 4% G≥3 RSV infection 4% G≥3 rash 4% |
Mahadevan et al. (288)1
NCT00648739 |
| Ibrutinib (420 mg or 560 mg) and nivolumab | Phase I-IIa 56 patients (20 Richter syndrome) |
ORR 97% | G≥3 neutropenia 28% G≥3 anemia 23% G≥3 rash 8% G≥3 increased ALT 2% Serious AEs: anemia 4% and pneumonia 4% |
Younes et al. (289)1
NCT02329847 |
| For CLL: induction with umbralisib and ublituximab, consolidation with pembrolizumab, umbralisib and ublituximab, maintenance with umbralisib until progression or unacceptable AE. For Richter syndrome: umbralisib, ublituximab and pembrolizumab |
Phase I/II 14 patients (5 Richter syndrome) R/R CLL |
CLL: ORR 89% Richter syndrome: ORR 50%, 50% CR PFS 71% (median follow-up 15 months) |
G≥3 neutropenia 43% G≥3 ALT/AST increase 21% G≥3 hypophosphatemia 21% G≥3 pneumonitis 7% |
Mato et al. (290) |
| Nivolumab vs pembrolizumab and ibrutinib in 3 patients and venetoclax in 1 patient |
7 vs 3 patients R/R CLL (Richter syndrome) |
ORR 10% | ND | Rogers et al. (291) |
| Ipilimumab and lenalidomide | Phase II 2 patients R/R CLL to allogeneic HSCT |
ORR 0 | G≥3 neutropenia 40% G2 anemia 40% G2 thrombocytopenia 20% Flare of GVHD 10% G2 nausea 10% G2 headache 10% G2 diarrhea 10%% G2 elevated transaminase 10% G2 hypertension 10% G2 hypothyroidism 10% |
Khouri et al. (292)1
NCT01919619 |
| Nivolumab single agent until progression or unacceptable toxicity, with planned deescalation based on toxicity | Phase I 1 patient R/R CLL to allogeneic HSCT |
ORR 32% 1-year PFS 23%, 1-year OS 56% |
G≥3 thrombocytopenia 14% G≥3 neutropenia 14% G≥3 anemia 11% G≥3 febrile neutropenia 11% G≥3 fatigue 7.1% G≥3 rash 3.6% G≥3 transaminitis 7.1% G≥3 fever 3.6% G≥3 lipase elevation 14% G≥3 pneumonitis 3.6% G≥3 abdominal pain 3.6% G≥3 nausea 3.6% G≥3 arthralgia 3.6% G≥3 bilirubin elevation 11% G 5 acute GVHD (liver and gut) 7.1% G 5 APS complicated by thrombotic CVA 3.6% G 5 sepsis with ARDS 3.6% |
Davids et al. (293)1
NCT01822509 |
| Umbralisib and pembrolizumab | Phase I R/R CLL |
ND | ND | NCT03283137 |
| Pembrolizumab | Phase II R/R CLL with Richter Syrndrome |
ND | ND | NCT02576990 |
| Ublituximab and umbralisib in combination with targeted immunotherapy | Phase I R/R CLL or Richter syndrome |
ND | ND | NCT02535286 |
| Ibrutinib, fludarabine and pembrolizumab | Phase II high-risk or R/R CLL/SLL |
ND | ND | NCT03204188 |
| Atezolizumab, obinutuzumab and venetoclax | Phase II CLL, SLL, R/R Richter syndrome |
ND | ND | NCT02846623 |
| Durvalumab monotherapy and in combination (with lenalidomide and rituximab; with ibrutinib; with bendamustine and rituximab) | Phase I-II lymphoma or CLL |
ND | ND | NCT02733042 |
| Anti-LAG-3 (BMS-986016) single agent and in combination with nivolumab | Phase I/IIa R/R CLL |
ND | ND | NCT02061761 |
AE, adverse events; APS, anti-phospholipid antibody syndrome; ARDS, acute respiratory distress syndrome; CLL, chronic lymphocytic leukemia; CR, complete response; CVA, cerebral vascular accident; G≥3, grade ≥3; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; ND, no data; ORR, overall response rate; OS, overall survival; PFS, progression free survival; PR, partial response; R/R, relapsed or refractory; SD, stable disease; SLL, small lymphocytic lymphoma.
1Data for CLL patients only non-available.