BTK inhibitor (ibrutinib or acalabrutinib) plus venetoclax

A prospective randomized trial included 523 patients with previously untreated CLL. Patients received either ibrutinib plus venetoclax for up to 6 years or FCR for six cycles.[27] This comparison was embedded in a larger three-arm randomization that also included ibrutinib alone for up to 6 years; the statistics were thought too preliminary to analyze the ibrutinib-alone group versus the other arms.

A prospective randomized trial included 523 patients with previously untreated CLL. Patients received either ibrutinib plus venetoclax for up to 6 years or FCR for six cycles.[27] This comparison was embedded in a larger three-arm randomization that also included ibrutinib alone for up to 6 years; the statistics were thought too preliminary to analyze the ibrutinib-alone group versus the other arms.

With a median follow-up of 43.7 months, the 3-year OS rate was 98.0% (95% CI, 95.2%–99.2%) in the ibrutinib-plus-venetoclax group and 93.0% (95% CI, 88.9%–95.6%) in the FCR group (HR, 0.31; 95% CI, 0.15–0.67).[27][Level of evidence A1]

A prospective randomized trial included 523 patients with previously untreated CLL. Patients received either ibrutinib plus venetoclax for up to 6 years or FCR for six cycles.[27] This comparison was embedded in a larger three-arm randomization that also included ibrutinib alone for up to 6 years; the statistics were thought too preliminary to analyze the ibrutinib-alone group versus the other arms.

The 3-year OS benefit favored ibrutinib plus venetoclax (HR, 0.23; 95% CI, 0.06–0.81) for patients without IGH pathogenic variants, but not for those with IGH pathogenic variants (HR, 0.61; 95% CI, 0.20–1.82).

A prospective randomized trial included 523 patients with previously untreated CLL. Patients received either ibrutinib plus venetoclax for up to 6 years or FCR for six cycles.[27] This comparison was embedded in a larger three-arm randomization that also included ibrutinib alone for up to 6 years; the statistics were thought too preliminary to analyze the ibrutinib-alone group versus the other arms.

The 3-year PFS rate was 97.2% (95% CI, 94.1%–98.6%) in the ibrutinib-plus-venetoclax group and 76.8% (95% CI, 70.8%–81.7%) in the FCR group (HR, 0.13; 95% CI, 0.07–0.24; P < .001).

A prospective randomized trial included 523 patients with previously untreated CLL. Patients received either ibrutinib plus venetoclax for up to 6 years or FCR for six cycles.[27] This comparison was embedded in a larger three-arm randomization that also included ibrutinib alone for up to 6 years; the statistics were thought too preliminary to analyze the ibrutinib-alone group versus the other arms.

MRD negativity was a requirement for stopping therapy with venetoclax and ibrutinib after 2 years. This trial did not randomly assign patients to either continued therapy or cessation of therapy based on MRD status. The utility and value of MRD could not be determined from this trial due to its design.

A prospective randomized trial (GLOW [NCT03462719]) included 211 patients with previously untreated CLL. Patients were aged 65 and older or aged 18 to 64 with comorbidities and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients were randomly assigned to receive either fixed-duration ibrutinib and venetoclax (15 months total) or chlorambucil and obinutuzumab (6 months total).[28]

A prospective randomized trial (GLOW [NCT03462719]) included 211 patients with previously untreated CLL. Patients were aged 65 and older or aged 18 to 64 with comorbidities and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients were randomly assigned to receive either fixed-duration ibrutinib and venetoclax (15 months total) or chlorambucil and obinutuzumab (6 months total).[28]

With a median follow-up of 46 months, the 42-month PFS rate was 74.6% in the ibrutinib-plus-venetoclax group and 24.8% in the chlorambucil-plus-obinutuzumab group (HR, 0.214; 95% CI, 0.138–0.334; P < .0001).[28][Level of evidence B1]

A prospective randomized trial (GLOW [NCT03462719]) included 211 patients with previously untreated CLL. Patients were aged 65 and older or aged 18 to 64 with comorbidities and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients were randomly assigned to receive either fixed-duration ibrutinib and venetoclax (15 months total) or chlorambucil and obinutuzumab (6 months total).[28]

Ibrutinib was given for 3 months prior to the combination of venetoclax with ibrutinib to avoid tumor lysis syndrome.

A prospective randomized trial (GLOW [NCT03462719]) included 211 patients with previously untreated CLL. Patients were aged 65 and older or aged 18 to 64 with comorbidities and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients were randomly assigned to receive either fixed-duration ibrutinib and venetoclax (15 months total) or chlorambucil and obinutuzumab (6 months total).[28]

At 3 months after the end of therapy, 40.6% of patients who received ibrutinib and venetoclax achieved undetectable MRD (<10-5 by next-generation sequencing) in the bone marrow, and 43.4% of patients achieved undetectable MRD in the peripheral blood.[28] However, the PFS rate exceeded 90% at 12 months after the end of therapy regardless of if the MRD was detectable or not.

A prospective trial included 867 patients with previously untreated CLL. Patients were randomly assigned to one of three treatment regimens: (1) AV (acalabrutinib and venetoclax), (2) AVO (acalabrutinib, venetoclax, and obinutuzumab), or (3) either BR or FCR (at the discretion of the investigator).[29]

A prospective trial included 867 patients with previously untreated CLL. Patients were randomly assigned to one of three treatment regimens: (1) AV (acalabrutinib and venetoclax), (2) AVO (acalabrutinib, venetoclax, and obinutuzumab), or (3) either BR or FCR (at the discretion of the investigator).[29]

With a median follow-up of 41 months, the 3-year OS rate was 94.1% for patients who received AV and 85.9% for patients who received BR or FCR (HR, 0.33; 95% CI, 0.18–0.56; P < .0001). However, the 3-year OS rate was 87.7% for patients who received AVO compared with 85.9% for patients who received BR or FCR (HR, 0.76; 95% CI, 0.49–1.18; P = nonsignificant).[29][Level of evidence A1]

A prospective trial included 867 patients with previously untreated CLL. Patients were randomly assigned to one of three treatment regimens: (1) AV (acalabrutinib and venetoclax), (2) AVO (acalabrutinib, venetoclax, and obinutuzumab), or (3) either BR or FCR (at the discretion of the investigator).[29]

The 3-year PFS rate was 76.5% for patients who received AV, 83.1% for patients who received AVO, and 66.5% for patients who received BR or FCR. The PFS for patients who received AV versus those who received BR or FCR had an HR of 0.65 (95% CI, 0.49–0.87; P = .004). The PFS for patients who received AVO versus those who received BR or FCR had an HR of 0.42 (95% CI, 0.30–0.59; P < .001).

A prospective trial included 867 patients with previously untreated CLL. Patients were randomly assigned to one of three treatment regimens: (1) AV (acalabrutinib and venetoclax), (2) AVO (acalabrutinib, venetoclax, and obinutuzumab), or (3) either BR or FCR (at the discretion of the investigator).[29]

Although treatment with AVO resulted in a better PFS than AV, there were increased infectious deaths with AVO, especially from COVID-19 (SARS-CoV-2). These deaths accounted for a nonsignificant difference in OS rates between patients who received AVO (87.7%) and patients who received BR or FCR (85.9%).

A phase II trial included 80 previously untreated patients who were aged 65 or older or had high-risk disease. Patients were treated with ibrutinib for 3 months followed by combined ibrutinib plus venetoclax for a total of 24 months.[30]

A phase II trial included 80 previously untreated patients who were aged 65 or older or had high-risk disease. Patients were treated with ibrutinib for 3 months followed by combined ibrutinib plus venetoclax for a total of 24 months.[30]

With a median follow-up of 38.5 months, the 2-year response rate was 82%, the 3-year PFS rate was 93% (95% CI, 88%–99%), and the 3-year OS rate was 96%.[30][Level of evidence C1]

A phase II trial included 80 previously untreated patients who were aged 65 or older or had high-risk disease. Patients were treated with ibrutinib for 3 months followed by combined ibrutinib plus venetoclax for a total of 24 months.[30]

The toxicity of the combination is similar to either agent alone and avoids the tumor lysis syndrome seen when starting with venetoclax.

A phase II trial included 80 previously untreated patients who were aged 65 or older or had high-risk disease. Patients were treated with ibrutinib for 3 months followed by combined ibrutinib plus venetoclax for a total of 24 months.[30]

High rates of undetectable MRD (<10-4 by 8-color flow cytometry) in the peripheral blood (75%) and bone marrow (72%) is unprecedented. The clinical significance of this finding awaits prospective randomized trials to establish clinical outcomes versus either drug alone. This combination has also been tested in the relapsed/refractory setting.[31]

A phase II trial included 159 previously untreated patients aged 70 years or older. Patients received 3 cycles of ibrutinib alone followed by 12 cycles of ibrutinib plus venetoclax.[32]

A phase II trial included 159 previously untreated patients aged 70 years or older. Patients received 3 cycles of ibrutinib alone followed by 12 cycles of ibrutinib plus venetoclax.[32]

With a median follow-up of 27.9 months, the complete response rate was 55% (95% CI, 48%–63%), the undetectable MRD rate was 77% (95% CI, 70%–83%) for blood and 60% (95% CI, 52%–67%) for bone marrow, the 2-year PFS rate was 95% (95% CI, 90%–97%), and the 2-year OS rate was 98% (95% CI, 94%–99%).[32][Level of evidence C1]

A phase II trial included 159 previously untreated patients aged 70 years or older. Patients received 3 cycles of ibrutinib alone followed by 12 cycles of ibrutinib plus venetoclax.[32]

The toxicity of the ibrutinib-venetoclax combination was similar to either agent alone, and the ibrutinib-alone lead-in avoided tumor lysis syndrome.

A phase II trial included 41 previously untreated patients who received ibrutinib plus venetoclax and obinutuzumab. Patients with undetectable MRD at cycle 16 could opt to discontinue treatment if they had a complete response.[33]

A phase II trial included 41 previously untreated patients who received ibrutinib plus venetoclax and obinutuzumab. Patients with undetectable MRD at cycle 16 could opt to discontinue treatment if they had a complete response.[33]

With a median follow-up of 38.4 months, the 3-year PFS rate was 79.9% and the 3-year OS rate was 92.6%.[33][Level of evidence C1]