Venetoclax approved to treat CLL patients regardless of genotype

The approval of Bcl-2 inhibitor venetoclax was expanded by the US Food and Drug Administration in June 2018 to include the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), regardless of their genotype, who have received at least 1 prior therapy.¹ It was previously approved in 2016 for the treatment of patients who had a chromosome 17p deletion, which leads to loss of the tumor-suppressor gene TP53.

Approval was based on the positive results of the phase 3, randomized, multicenter, open-label MURANO trial in which 389 patients were randomized 1:1 to receive a combination of venetoclax and the CD20-targeting monoclonal antibody rituximab (venetoclax–rituximab) or bendamustine in combination with rituximab (bendamustine–rituximab).

Eligible patients were 18 years of age or older, had been diagnosed with relapsed/refractory CLL that required treatment, had received 1-3 prior therapies (including at least 1 chemotherapy regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale, with 5 indicating the greatest level of disability), and had adequate bone marrow, renal, and hepatic function.

Patients who had received prior bendamustine treatment were eligible for the trial provided they had experienced a duration of response of 24 months or longer. However, patients with transformed CLL, central nervous system involvement, prior treatment with allogeneic or autologous stem cell transplant, major organ dysfunction, other active malignancy, or who were pregnant or breastfeeding, were excluded from the study.

Patients in the venetoclax arm received a 5-week ramp-up schedule, followed by a dose of 400 mg once daily for 24 months. Rituximab treatment started at the end of the venetoclax ramp-up period and was administered at a dose of 375 mg/m² intravenously on cycle 1 day 1 and 500 mg/m² on day 1 of cycles 2-6. In the control arm, patients received 6 cycles with the same rituximab dosing and schedule as the study group and bendamustine at a dose of 70 mg/m² on days 1 and 2 of each 28-day cycle.

The primary endpoint was progression-free survival (PFS), as assessed by an independent review committee over a median follow-up of 23 months. Median PFS was significantly improved in the venetoclax arm (not yet reached versus 18.1 months in the bendamustine arm [HR, 0.19; P < .001]). In addition, objective response rate (ORR) and event-free survival (EFS) also favored the venetoclax arm; ORR was 92% compared with 72%, respectively, and 2-year EFS was 84.9% compared with 34.8%. There was also a trend toward improved 24-month overall survival (OS) rate (91.9% vs 86.6%), however this did not achieve statistical significance, nor did median OS.

The most common adverse events (AEs) in patients treated with venetoclax were neutropenia, diarrhea, upper-respiratory tract infection, fatigue, cough, and nausea. Grade 3/4 neutropenia occurred in 64% of patients, and serious AEs in 46% of patients. Serious infections occurred in 21% of patients, most commonly pneumonia. Ten deaths in the venetoclax arm were attributed to treatment, compared with 11 deaths in the bendamustine arm.²

The prescribing information details warnings and precautions relating to the risk of tumor lysis syndrome, which is increased in patients with higher tumor burden, reduced renal function, or in receipt of strong or moderate CYP3A inhibitors or P-gp inhibitors during the ramp-up stage. Patients should receive appropriate preventive strategies, including hydration and antihyperuricemics, blood chemistry should be monitored and abnormalities managed promptly, and dosing should be interrupted or adjusted as necessary.

Other warnings relate to neutropenia (complete blood counts should be monitored throughout treatment and venetoclax treatment interrupted or dose reduced for severe neutropenia, alongside possible use of supportive measures), immunization (live vaccines should not be administered before or during treatment or after treatment until B-cell recovery, and patients should be advised of the potentially reduced efficacy of vaccines), and embryofetal toxicity (patients should be advised of the risks and the need for effective contraception during and after treatment). Venetoclax is marketed as Venclexta by Genentech.³

The approval of Bcl-2 inhibitor venetoclax was expanded by the US Food and Drug Administration in June 2018 to include the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), regardless of their genotype, who have received at least 1 prior therapy.¹ It was previously approved in 2016 for the treatment of patients who had a chromosome 17p deletion, which leads to loss of the tumor-suppressor gene TP53.

Approval was based on the positive results of the phase 3, randomized, multicenter, open-label MURANO trial in which 389 patients were randomized 1:1 to receive a combination of venetoclax and the CD20-targeting monoclonal antibody rituximab (venetoclax–rituximab) or bendamustine in combination with rituximab (bendamustine–rituximab).

Eligible patients were 18 years of age or older, had been diagnosed with relapsed/refractory CLL that required treatment, had received 1-3 prior therapies (including at least 1 chemotherapy regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale, with 5 indicating the greatest level of disability), and had adequate bone marrow, renal, and hepatic function.

Patients who had received prior bendamustine treatment were eligible for the trial provided they had experienced a duration of response of 24 months or longer. However, patients with transformed CLL, central nervous system involvement, prior treatment with allogeneic or autologous stem cell transplant, major organ dysfunction, other active malignancy, or who were pregnant or breastfeeding, were excluded from the study.

Patients in the venetoclax arm received a 5-week ramp-up schedule, followed by a dose of 400 mg once daily for 24 months. Rituximab treatment started at the end of the venetoclax ramp-up period and was administered at a dose of 375 mg/m² intravenously on cycle 1 day 1 and 500 mg/m² on day 1 of cycles 2-6. In the control arm, patients received 6 cycles with the same rituximab dosing and schedule as the study group and bendamustine at a dose of 70 mg/m² on days 1 and 2 of each 28-day cycle.

The primary endpoint was progression-free survival (PFS), as assessed by an independent review committee over a median follow-up of 23 months. Median PFS was significantly improved in the venetoclax arm (not yet reached versus 18.1 months in the bendamustine arm [HR, 0.19; P < .001]). In addition, objective response rate (ORR) and event-free survival (EFS) also favored the venetoclax arm; ORR was 92% compared with 72%, respectively, and 2-year EFS was 84.9% compared with 34.8%. There was also a trend toward improved 24-month overall survival (OS) rate (91.9% vs 86.6%), however this did not achieve statistical significance, nor did median OS.

The most common adverse events (AEs) in patients treated with venetoclax were neutropenia, diarrhea, upper-respiratory tract infection, fatigue, cough, and nausea. Grade 3/4 neutropenia occurred in 64% of patients, and serious AEs in 46% of patients. Serious infections occurred in 21% of patients, most commonly pneumonia. Ten deaths in the venetoclax arm were attributed to treatment, compared with 11 deaths in the bendamustine arm.²

The prescribing information details warnings and precautions relating to the risk of tumor lysis syndrome, which is increased in patients with higher tumor burden, reduced renal function, or in receipt of strong or moderate CYP3A inhibitors or P-gp inhibitors during the ramp-up stage. Patients should receive appropriate preventive strategies, including hydration and antihyperuricemics, blood chemistry should be monitored and abnormalities managed promptly, and dosing should be interrupted or adjusted as necessary.

Other warnings relate to neutropenia (complete blood counts should be monitored throughout treatment and venetoclax treatment interrupted or dose reduced for severe neutropenia, alongside possible use of supportive measures), immunization (live vaccines should not be administered before or during treatment or after treatment until B-cell recovery, and patients should be advised of the potentially reduced efficacy of vaccines), and embryofetal toxicity (patients should be advised of the risks and the need for effective contraception during and after treatment). Venetoclax is marketed as Venclexta by Genentech.³

The approval of Bcl-2 inhibitor venetoclax was expanded by the US Food and Drug Administration in June 2018 to include the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), regardless of their genotype, who have received at least 1 prior therapy.¹ It was previously approved in 2016 for the treatment of patients who had a chromosome 17p deletion, which leads to loss of the tumor-suppressor gene TP53.

Approval was based on the positive results of the phase 3, randomized, multicenter, open-label MURANO trial in which 389 patients were randomized 1:1 to receive a combination of venetoclax and the CD20-targeting monoclonal antibody rituximab (venetoclax–rituximab) or bendamustine in combination with rituximab (bendamustine–rituximab).

Eligible patients were 18 years of age or older, had been diagnosed with relapsed/refractory CLL that required treatment, had received 1-3 prior therapies (including at least 1 chemotherapy regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale, with 5 indicating the greatest level of disability), and had adequate bone marrow, renal, and hepatic function.

Patients who had received prior bendamustine treatment were eligible for the trial provided they had experienced a duration of response of 24 months or longer. However, patients with transformed CLL, central nervous system involvement, prior treatment with allogeneic or autologous stem cell transplant, major organ dysfunction, other active malignancy, or who were pregnant or breastfeeding, were excluded from the study.

Patients in the venetoclax arm received a 5-week ramp-up schedule, followed by a dose of 400 mg once daily for 24 months. Rituximab treatment started at the end of the venetoclax ramp-up period and was administered at a dose of 375 mg/m² intravenously on cycle 1 day 1 and 500 mg/m² on day 1 of cycles 2-6. In the control arm, patients received 6 cycles with the same rituximab dosing and schedule as the study group and bendamustine at a dose of 70 mg/m² on days 1 and 2 of each 28-day cycle.

The primary endpoint was progression-free survival (PFS), as assessed by an independent review committee over a median follow-up of 23 months. Median PFS was significantly improved in the venetoclax arm (not yet reached versus 18.1 months in the bendamustine arm [HR, 0.19; P < .001]). In addition, objective response rate (ORR) and event-free survival (EFS) also favored the venetoclax arm; ORR was 92% compared with 72%, respectively, and 2-year EFS was 84.9% compared with 34.8%. There was also a trend toward improved 24-month overall survival (OS) rate (91.9% vs 86.6%), however this did not achieve statistical significance, nor did median OS.

The most common adverse events (AEs) in patients treated with venetoclax were neutropenia, diarrhea, upper-respiratory tract infection, fatigue, cough, and nausea. Grade 3/4 neutropenia occurred in 64% of patients, and serious AEs in 46% of patients. Serious infections occurred in 21% of patients, most commonly pneumonia. Ten deaths in the venetoclax arm were attributed to treatment, compared with 11 deaths in the bendamustine arm.²

The prescribing information details warnings and precautions relating to the risk of tumor lysis syndrome, which is increased in patients with higher tumor burden, reduced renal function, or in receipt of strong or moderate CYP3A inhibitors or P-gp inhibitors during the ramp-up stage. Patients should receive appropriate preventive strategies, including hydration and antihyperuricemics, blood chemistry should be monitored and abnormalities managed promptly, and dosing should be interrupted or adjusted as necessary.

Other warnings relate to neutropenia (complete blood counts should be monitored throughout treatment and venetoclax treatment interrupted or dose reduced for severe neutropenia, alongside possible use of supportive measures), immunization (live vaccines should not be administered before or during treatment or after treatment until B-cell recovery, and patients should be advised of the potentially reduced efficacy of vaccines), and embryofetal toxicity (patients should be advised of the risks and the need for effective contraception during and after treatment). Venetoclax is marketed as Venclexta by Genentech.³