Table 1.

Front-line studies comparing novel agents to chemoimmunotherapy regimens

Drug	Control Arm	Study Population	Efficacy Outcomes	Selected toxicities with novel agent
Ibrutinib RESONATE-2 study54	Chlorambucil	Age ≥ 65 years Excluded pts with del17p	5-year PFS: ibrutinib 70% vs chlorambucil 12% (HR 0.146) 5-year OS: ibrutinib 83% vs chlorambucil 68% (HR 0.450)	Ibrutinib (grade ≥3 unless specified): Neutropenia (13%) Pneumonia (12%) Hypertension (8%) Anemia (7%) Hyponatremia (6%) Any grade hypertension (26%) Any grade atrial fibrillation (16%) Any major hemorrhage (11%)
Ibrutinib and rituximab E1912 Study4	Fludarabine cyclophosphamide and rituximab (FCR)	Age ≤ 70 years Excluded pts with del17p	3-year PFS: ibrutinib + rituximab 89.4% vs FCR 72.9% (HR 0.35) 3-year OS: ibrutinib + rituximab 98.9% vs FCR 91.5% (HR 0.17)	Ibrutinib + rituximab (grade ≥3 unless specified) Neutropenia (25.6%) Hypertension (18.8%) Infection (9.1%) Anemia (4.8%) Arthralgia (4.8%) Diarrhea (4.3%) Atrial fibrillation (3.2%) Rash (3.1%) Hemorrhage (1.1%) Any grade atrial fibrillation (7.4%)
Ibrutinib Ibrutinib + rituximab ALLIANCE study6	Bendamustine and rituximab	Age ≥ 65	2-year PFS: 87% ibrutinib (HR 0.39 compared to CIT) vs 88% ibrutinib + rituximab (HR 0.39 compared to CIT) vs 74% bendamustine + rituximab; no significant difference between ibrutinib and ibrutinib + rituximab OS: No significant difference between groups at a median follow-up of 38 months	Ibrutinib (grade ≥3) Any hematologic 41% Neutropenia 15% Infection 20% Atrial fibrillation 9% Hypertension 29% Bleeding 2% Ibrutinib + Rituximab (grade ≥3) Any hematologic 39% Neutropenia 21% Infection 20% Atrial fibrillation 6% Hypertension 34% Bleeding 4%
Ibrutinib and Obinutuzumab ILLUMINATE study7	Chlorambucil and Obinutuzumab	Age ≥ 65 years or < 65 years with co-existing conditions	Median PFS: ibrutinib + obinutuzumab not reached vs chlorambucil + obinutuzumab 19 months (HR 0.23, median follow-up 31.3 months) Median overall survival: not reached in either group	Ibrutinib + Obinutuzumab (grade ≥3 unless specified) Neutropenia 37%) Pneumonia 7% Hypertension 4% Atrial fibrillation 5% Hypertension any grade 17% Atrial fibrillation any grade 12%
Acalabrutinib Acalabrutinib and Obinutuzumab ELEVATE-TN Study4,8	Chlorambucil and Obinutuzumab	Age ≥ 65 years old or Age 18-65 years and creatinine clearance 30-69 mL/min or Cumulative Illness Rating Scale for Geriatrics score greater than 6	Median PFS: acalabrutinib + obinutuzumab not reached (HR 0.1 compared with CIT) vs acalabrutinib not reached (HR 0.2 compared with CIT) vs 22.6 months with chlorambucil with obinutuzumab (median follow-up 28.3 months)	Acalabrutinib (grade ≥3 unless specified) Headache any grade 36.9% Neutropenia 9.5% Diarrhea 0.6% Hypertension 3% Upper respiratory tract infection any grade 18.4% Bleeding 2% Atrial fibrillation any grade 4% Acalabrutinib + Obinutuzumab (grade ≥3 unless specified) Headache any grade 39.9% Neutropenia 29.8% Diarrhea 4.5% Upper respiratory tract infection any grade 21.3% Hypertension 2% Bleeding 2% Atrial fibrillation any grade 3%
Venetoclax and Obinutuzumab (VO) CLL-14 Study11	Chlorambucil and Obinutuzumab	Age 18 years or older, and creatinine clearance 30-69 mL/min or Cumulative Illness Rating Scale for Geriatrics score greater than 6	Median PFS VO not reached vs 35.6 months chlorambucil + obinutuzumab (median follow-up 39.6 months)	VO (grade ≥3 unless specified) Neutropenia (53%) Infusion related reaction (9%) Infusion related reaction any grade (36%) Pneumonia (5%) Febrile neutropenia (5%) Diarrhea (4%)
Ibrutinib and venetoclax (I+V) GLOW Study19	Chlorambucil and Obinutuzumab	Age ≥ 65 years old or Age 18-65 years and creatinine clearance <70 mL/min or Cumulative Illness Rating Scale score greater than 6	Median PFS I+V not reached vs chlorambucil + obinutuzumab 21.0 months (HR 0.216, median follow-up 27.7 months)	I+V (grade ≥3) Neutropenia 34.9% Diarrhea 10.4% Hypertension 7.5%
Umbralisib + Ublituximab (U2) UNITY38	Chlorambucil + Obinutuzumab (CO)	Included treatment naïve and relapsed/refractory CLL patients	Median PFS: 31.9 months (U2) vs 17.9 months (CO, HR 0.482, treatment naïve subgroup)	U2 (grade ≥3) Neutropenia (30.6%) Thrombocytopenia (3.4%) Diarrhea (12.1%) Elevated AST/ALT (8.3%) Colitis (3.4%) Pneumonitis (2.9%)