Background
Decision to treat
Consideration of health-related quality of life
Early intervention
Current treatment strategies
BTK inhibitors
Agent | Trial name | Trial design and patients | Outcomes | Citation |
---|---|---|---|---|
Approved agents | ||||
Ibrutinib (second-line or later monotherapy) | RESONATE (NCT01578707) | Phase 3 study of the efficacy and safety of ibrutinib versus ofatumumab in patients with relapsed or refractory CLL | Ibrutinib versus ofatumumab: Median PFS (9.4-month median follow up): not reached versus 8.1 months 12-month OS: 90% versus 81% ORR: 42.6% versus 4.1% Grade ≥ 3 AEs: 57% versus 47% | [28] |
Ibrutinib (first-line monotherapy) | RESONATE-2 (NCT01722487) | Phase 3 study of the efficacy and safety of ibrutinib versus chlorambucil in treatment-naïve patients (≥ 65 years of age) with CLL | Ibrutinib versus chlorambucil: Median PFS (18.4-month median follow up): not reached versus 18.9 months 24-month OS: 98% versus 85% ORR: 86% versus 35% | [29] |
Ibrutinib (first-line combination) | iLLUMINATE (NCT02264574) | Phase 3 study of the efficacy and safety of ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in treatment-naïve patients with CLL/SLL | Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: Median PFS (31.3-month median follow up): not reached versus 19.0 months 30-month PFS: 79% versus 31% SAEs: 58% versus 35% | [30] |
Ibrutinib (first-line combination) | ECOG1912 (NCT02048813) | Phase 3 study of the efficacy and safety of ibrutinib plus rituximab or fludarabine plus cyclophosphamide plus rituximab (chemo-immunotherapy) in treatment-naïve patients (≤ 70 years of age) with CLL | Ibrutinib plus rituximab versus fludarabine plus cyclophosphamide plus rituximab: 3-year PFS: 89.4% versus 72.9% 3-year OS: 98.8% versus 91.5% Subgroup analysis of patients without IGHV mutation: 3-year PFS: 90.7% versus 62.5% Grade ≥ 3 AEs: 80.1% versus 79.7% | [31] |
Ibrutinib (first-line monotherapy or combination) | ALLIANCE (NCT01722487) | Phase 3 study of the efficacy of ibrutinib, ibrutinib plus rituximab, or bendamustine plus rituximab in treatment-naïve patients (≥ 65 years of age) with CLL | Ibrutinib, ibrutinib plus rituximab, bendamustine plus rituximab: Median PFS: not reached, not reached, 43 months 2-year PFS: 87%, 88%, 74% No differences in OS Grade ≥ 3 hematological AEs: 41%, 39%, 61% | [32] |
Acalabrutinib (second-line or later monotherapy) | NCT02029443 | Phase 1b/2 study of the safety and efficacy of acalabrutinib in patients with relapsed CLL | Median PFS (41-month median follow up): not reached Median duration of response: not reached 45-month estimated PFS: 62% ORR: 94% Responses were similar regardless of the presence of del(11q), del(17p), complex karyotype, of IGHV mutation status Most AEs were mild or moderate | |
Acalabrutinib (first-line monotherapy or combination therapy) | ELEVATE TN (NCT02475681) | Phase 3 study of the efficacy and safety of acalabrutinib or acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in treatment-naïve patients with CLL | Acalabrutinib, acalabrutinib plus obinutuzumab, chlorambucil plus obinutuzumab: Median PFS (28.3-month median follow up): not reached, not reached, 22.6 months Estimated 24-month PFS: 87%, 93%, 47% Consistent across subgroups, including del(17p) Median OS: not reached in any arm Estimated 24-month OS: 95%, 95%, 92% ORR: 86%, 94%, 79% | [43] |
Acalabrutinib (second-line or later monotherapy) | ASCEND (NCT02970318) | Phase 3 study of the efficacy and safety of acalabrutinib versus rituximab plus idelalisib or bendamustine in patients with relapsing or refractory CLL | Interim analysis (acalabrutinib versus rituximab plus idelalisib/bendamustine): Median PFS (16.1-month median follow-up): not reached versus 16.5 months 12-month PFS rate: 88% versus 68% Improvement was seen across subgroups, including del(17p) and TP53 mutation 12-month OS: 94% versus 91% ORR: 81% versus 75% | [44] |
Investigational agents | ||||
Zanubrutinib (second-line or later monotherapy) | NCT02343120 | Phase 1 study of the safety and efficacy of zanubrutinib in patients with CLL | ORR: 96% Estimated 12-month PFS rate: 100% Most AEs were grade 1/2 | [38] |
Zanubrutinib (first-line monotherapy [Arm C]) | SEQUOIA (NCT03336333) | Phase 3 study of zanubrutinib versus bendamustine plus rituximab in treatment-naïve patients with CLL/SLL | Interim analysis (Arm C: del(17p)): Median PFS (18.2 month median follow-up): not reached Estimated 18-month PFS: 89% Median duration of response: not reached Estimated 18-month duration of response: 84% Median OS: not reached Estimated 18-month OS: 95% ORR: 95% Low rate of discontinuation due to AEs | [76] |
Zanubrutinib (second-line or later monotherapy) | ALPINE (NCT03734016) | Phase 3 study of zanubrutinib versus ibrutinib in patients with relapsing or refractory CLL/SLL | Trial is ongoing | [74] |
Orelabrutinib (second-line or later monotherapy) | Phase 2 study of orelabrutinib in Chinese patients with relapsing or refractory CLL/SLL | Median PFS (median follow-up 14.3 months): not reached Estimated 12-month PFS: 81.1% Median duration of response: not reached Estimated 12-month duration of response: 77.1% Estimated 12-month OS: 86.3% ORR (≥ 12 cycles): 91.3% del(17p): 100% del(11q): 94.7% TP53 mutation: 100% Unmutated IGHV: 93.9% Most AEs were mild to moderate | [79] | |
LOXO-305 (any-line monotherapy) | BRUIN (NCT03740529) | Phase 1/2 study of LOXO-305 in treatment-naïve patients or those with previously treated CLL or NHL | Interim analysis (patients with CLL): ORR: 57% among 65 efficacy-evaluable patients ORR with ≥ 6 months follow-up: 77% Median follow-up: 3 months for all patients; 6.7 months for responders | [81] |
ARQ 531 (second-line or later monotherapy) | NCT03162536 | Phase 1/2 study of ARQ 531 in patients with relapsing or refractory hematologic malignancies (including CLL) | Trial is ongoing |
Inhibitors of BCL-2 and PI3Kδ
BCL-2 inhibitor
Agent | Trial name | Trial design and patients | Outcomes | Citation |
---|---|---|---|---|
Venetoclax (second-line or later monotherapy) | NCT01889186 | Phase 2 single-arm study of the safety and efficacy of venetoclax in patients with del(17p) relapsed or refractory CLL | ORR: 12.1-month median follow-up, 79.4%; final, 77% 24-month PFS: 54% SAEs: 12.1-month median follow-up, 55%; final, 58% | |
Venetoclax (first-line combination therapy) | CLL14 (NCT02242942) | Phase 3 study of the efficacy and safety of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in treatment-naïve patients with CLL who have coexisting conditions | Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab: 24-month PFS: 88.2% versus 64.1% Results were similar for TP53 deletion/mutation or unmutated IGHV Grade ≥ 3 AEs: 78.8% versus 76.6% | [51] |
Venetoclax (second-line or greater combination therapy) | MURANO (NCT02005471) | Phase 3 study of the efficacy and safety of venetoclax plus rituximab versus bendamustine plus rituximab in patients with relapsed or refractory CLL/SLL | Venetoclax plus rituximab versus bendamustine plus rituximab: 24-month PFS: 84.9% versus 36.3% Results were similar for TP53 deletion or unmutated IGHV Grade ≥ 3 AEs: 82.0% versus 70.2% | [50] |
Agent | Trial name | Trial design and patients | Outcomes | Citation |
---|---|---|---|---|
Approved agents | ||||
Idelalisib (second-line or later combination therapy) | NCT01539512 | Phase 3 study of the efficacy and safety of idelalisib plus rituximab versus placebo plus rituximab in patients with relapsed CLL and significant coexisting medical conditions | Idelalisib plus rituximab versus placebo plus rituximab: Median PFS: not reached versus 5.5 months 12-month OS: 92% versus 80% ORR: 81% versus 13% SAEs: 40% versus 35% | [56] |
Idelalisib (first-line monotherapy followed by combination therapy) | NCT02135133 | Phase 2 study to evaluate idelalisib as first-line therapy; patients were treated with idelalisib monotherapy for 2 months then switched to combination therapy of idelalisib plus ofatumumab for an additional 6 months | Safety data after a median follow-up of 14.7 months: Hepatotoxicity was reported as a frequent, and often severe, AE 79% of patients experienced grade ≥ 1 ALT or AST elevation 54% of patients experienced grade ≥ 3 transaminitis (median time to development: 28 days) Younger age and mutated IGHV status were found to be significant risk factors for developing hepatotoxicity The development of idelalisib-related toxicities was reported to be associated with increased levels of inflammatory cytokines and decreased levels of regulatory T cells | [57] |
Idelalisib (second-line or later combination therapy) | NCT01659021 | Phase 3 study of the efficacy and safety of idelalisib plus ofatumumab versus ofatumumab monotherapy in patients with relapsed CLL | Idelalisib plus ofatumumab versus ofatumumab monotherapy: Median PFS: 16.3 versus 8.0 months Serious infections were more common in the idelalisib plus ofatumumab group versus the ofatumumab monotherapy group Pneumonia: 13% versus 10% Sepsis: 6% versus 1% Pneumocystis jirovecii pneumonia: 5% versus 1% Treatment-related deaths: 22 versus 6 | [59] |
Idelalisib (second-line or later combination followed by monotherapy) | NCT01539291 | Phase 3 study of the long-term efficacy and safety of idelalisib plus rituximab followed by idelalisib monotherapy (extension of NCT01659021) in patients with relapsed CLL | Median PFS (18-month median follow-up): 20.3 months Median OS: 40.6 months ORR: 85.5% Prolonged exposure to idelalisib resulted in an increased incidence of AEs including diarrhea, colitis, and pneumonitis; the incidence of elevated hepatic aminotransferases was not increased | [60] |
Idelalisib (second-line or later combination therapy) | NCT01569295 | Phase 3 study of the efficacy and safety of idelalisib plus bendamustine plus rituximab versus placebo plus bendamustine plus rituximab in patients with relapsed or refractory CLL | Idelalisib plus bendamustine plus rituximab versus placebo plus bendamustine plus rituximab: Median PFS (14-month median follow-up): 20.8 versus 11.1 months All-grade AEs of infections and infestations: 69% versus 59% Grade ≥ 3 AEs of infections and infestations: 39% versus 25% | [61] |
Duvelisib (second-line or greater monotherapy) | DUO (NCT02004522) | Phase 3 study of the efficacy and safety of duvelisib versus ofatumumab monotherapy in patients with relapsed or refractory CLL | Duvelisib versus ofatumumab: Median PFS: 13.3 versus 9.9 months ORR: 74% versus 45% PFS and ORR was similar for patients with del(17p)/TP53 mutations Grade ≥ 3 AEs: 87% versus 48% Infectious AEs: 69% versus 43% | [64] |
Duvelisib (second-line or later monotherapy) | NCT02049515 | Phase 3 study of the efficacy and safety of duvelisib in patients with relapsed or refractory CLL who were enrolled in the DUO trial and progressed after ofatumumab (DUO extension) | After crossover versus before crossover (to duvelisib): Median PFS: 15.7 and 9.4 months ORR: 77% versus 29% Median duration of response: 14.9 versus 10.4 months Responses were similar for patients with del(17p) and/or TP53 mutation 73% of patients with disease refractory to ofatumumab achieved a response on duvelisib Safety profile was manageable | [65] |
Investigational agents | ||||
Umbralisib (second-line or later monotherapy) | NCT02742090 | Phase 2 study of umbralisib in patients with CLL who are intolerant of kinase inhibitor therapy | Median PFS: 23.5 months 12% discontinuations due to AEs | [84] |
Umbralisib (second-line or later combination therapy) | NCT02006485 | Phase 1 study of triplet treatment (umbralisib, ublituximab, and ibrutinib) in patients with advanced B-cell malignancies | ORR: 84% Tolerable safety profile | [86] |
Umbralisib (second-line or later combination therapy) | NCT02268851 | Phase 1/1b study of umbralisib plus ibrutinib in patients with CLL or mantle cell lymphoma | Interim analysis: Most frequent AEs were diarrhea (52%), infection (50%) and transaminitis (24%) SAEs occurred in 29% of patients | [85] |
ME-401 (second-line or later monotherapy or combination therapy) | NCT02914938 | Phase 1 study of ME-401 alone, in combination with rituximab, or in combination with zanubrutinib in patients with relapsing or refractory CLL/SLL or B cell NHL | Interim analysis (patients with CLL/SLL [n = 10] treated with monotherapy or combination with rituximab): Median PFS: not reached (median follow-up: 9.7 months) Median duration of response: not reached ORR: 89% (monotherapy: 100%; combination with rituximab: 83%) No apparent safety differences between monotherapy or ME-401 plus rituximab treatment | [91] |