Venetoclax shows muscle against CLL relapsed after idelalisib

For patients with relapsed or refractory chronic lymphocytic leukemia despite therapy with idelalisib (Zydelig), venetoclax (Venclexta) was associated with relatively high overall response and progression-free survival rates, results of a phase 2 study show.

Among 36 patients with relapsed/refractory CLL who had received idelalisib as their most recent B-cell receptor pathway inhibitor (BCRi), the overall response rate (ORR) was 67%, and median progression-free and overall survival (PFS and OS) had not been reached after 14 months of follow-up, reported Steven Coutre, MD, of Stanford (Calif.) University, and his colleagues.

“[V]enetoclax monotherapy is active and well-tolerated in patients with CLL progression after therapy with idelalisib, including a significant number of patients who also received prior therapy with ibrutinib [Imbruvica]. These results from the first prospective trial in this high-risk population provide evidence that venetoclax should be considered as a treatment option for such patients,” the investigators wrote. The report was published in Blood.

In clinical trials with idelalisib, approximately one-third of patients with CLL experienced disease progression on therapy, and other patients had to discontinue the drug, an inhibitor of the delta isoform of phosphoinositide 3-kinase (PI3K), because of toxicities, the investigators noted.

“The optimal treatment of patients with CLL progressing after idelalisib has not been well characterized,” they wrote. “Outcomes in patients who discontinued idelalisib treatment early are poor, with one retrospective analysis reporting a median overall survival (OS) after idelalisib discontinuation of approximately 2 months (range, 0-10 months).”

Venetoclax, an inhibitor of the apoptotic BCL-2 protein, has been shown to have activity against CLL, including in patients with high-risk features such as the chromosome 17p deletion (del17p), prompting the investigators to evaluate it as a follow-on in patients with relapsed/refractory CLL treated with a B-cell receptor pathway inhibitor.

They reported on the idelalisib cohort in a phase 2 trial in which patients with CLL that progressed on either idelalisib or ibrutinib were subsequently treated with venetoclax. The patients in this analysis included those treated with idelalisib in the main study cohort or an expansion cohort.

Patients were started on venetoclax 20 mg daily, followed by weekly dose escalations to a target of 400 mg daily by week 5, or to a maximum of 600 mg for patients who did not have a response by the week 12 assessment.

The overall response rate – the primary efficacy endpoint – was 67%. There were two complete remissions (CR) and one CR with incomplete bone marrow recovery. The remaining 21 patients with responses had partial responses.

At a median of 14 months of follow-up, neither median PFS, duration of response, or OS had been reached.

The investigator-estimated 12-month PFS rate was 79%.

The most common grade 3 or 4 adverse events were neutropenia in 50% of patients, thrombocytopenia in 25%, and anemia in 17%. There were no cases of clinical tumor lysis syndrome, which has been known to occur when venetoclax is initiated at full dose without a ramp-up.

The most common adverse events of any grade included neutropenia, diarrhea, upper respiratory tract infection, thrombocytopenia, nausea, fatigue, cough, rash, and anemia.

“The low number of CRs reported at the time of analysis may be a result of the follow-up time, particularly for patients in the expansion cohort, as other clinical studies with venetoclax report CR occurring after 1 year on therapy. Patients with prior ibrutinib exposure who had progressed on idelalisib as their most recent therapy before study entry had similar efficacy results,” the investigators wrote.

Genentech and AbbVie funded the study. Dr. Coutre is an advisory board member for both companies and others, and receives institutional funding from AbbVie and others. Multiple coauthors disclosed financial relationships with AbbVie, Genentech, or both, as well as other companies.

SOURCE: Coutre S et al. Blood. 2018;131(15):1704-11.

For patients with relapsed or refractory chronic lymphocytic leukemia despite therapy with idelalisib (Zydelig), venetoclax (Venclexta) was associated with relatively high overall response and progression-free survival rates, results of a phase 2 study show.

Among 36 patients with relapsed/refractory CLL who had received idelalisib as their most recent B-cell receptor pathway inhibitor (BCRi), the overall response rate (ORR) was 67%, and median progression-free and overall survival (PFS and OS) had not been reached after 14 months of follow-up, reported Steven Coutre, MD, of Stanford (Calif.) University, and his colleagues.

“[V]enetoclax monotherapy is active and well-tolerated in patients with CLL progression after therapy with idelalisib, including a significant number of patients who also received prior therapy with ibrutinib [Imbruvica]. These results from the first prospective trial in this high-risk population provide evidence that venetoclax should be considered as a treatment option for such patients,” the investigators wrote. The report was published in Blood.

In clinical trials with idelalisib, approximately one-third of patients with CLL experienced disease progression on therapy, and other patients had to discontinue the drug, an inhibitor of the delta isoform of phosphoinositide 3-kinase (PI3K), because of toxicities, the investigators noted.

“The optimal treatment of patients with CLL progressing after idelalisib has not been well characterized,” they wrote. “Outcomes in patients who discontinued idelalisib treatment early are poor, with one retrospective analysis reporting a median overall survival (OS) after idelalisib discontinuation of approximately 2 months (range, 0-10 months).”

Venetoclax, an inhibitor of the apoptotic BCL-2 protein, has been shown to have activity against CLL, including in patients with high-risk features such as the chromosome 17p deletion (del17p), prompting the investigators to evaluate it as a follow-on in patients with relapsed/refractory CLL treated with a B-cell receptor pathway inhibitor.

They reported on the idelalisib cohort in a phase 2 trial in which patients with CLL that progressed on either idelalisib or ibrutinib were subsequently treated with venetoclax. The patients in this analysis included those treated with idelalisib in the main study cohort or an expansion cohort.

Patients were started on venetoclax 20 mg daily, followed by weekly dose escalations to a target of 400 mg daily by week 5, or to a maximum of 600 mg for patients who did not have a response by the week 12 assessment.

The overall response rate – the primary efficacy endpoint – was 67%. There were two complete remissions (CR) and one CR with incomplete bone marrow recovery. The remaining 21 patients with responses had partial responses.

At a median of 14 months of follow-up, neither median PFS, duration of response, or OS had been reached.

The investigator-estimated 12-month PFS rate was 79%.

The most common grade 3 or 4 adverse events were neutropenia in 50% of patients, thrombocytopenia in 25%, and anemia in 17%. There were no cases of clinical tumor lysis syndrome, which has been known to occur when venetoclax is initiated at full dose without a ramp-up.

The most common adverse events of any grade included neutropenia, diarrhea, upper respiratory tract infection, thrombocytopenia, nausea, fatigue, cough, rash, and anemia.

“The low number of CRs reported at the time of analysis may be a result of the follow-up time, particularly for patients in the expansion cohort, as other clinical studies with venetoclax report CR occurring after 1 year on therapy. Patients with prior ibrutinib exposure who had progressed on idelalisib as their most recent therapy before study entry had similar efficacy results,” the investigators wrote.

Genentech and AbbVie funded the study. Dr. Coutre is an advisory board member for both companies and others, and receives institutional funding from AbbVie and others. Multiple coauthors disclosed financial relationships with AbbVie, Genentech, or both, as well as other companies.

SOURCE: Coutre S et al. Blood. 2018;131(15):1704-11.

For patients with relapsed or refractory chronic lymphocytic leukemia despite therapy with idelalisib (Zydelig), venetoclax (Venclexta) was associated with relatively high overall response and progression-free survival rates, results of a phase 2 study show.

Among 36 patients with relapsed/refractory CLL who had received idelalisib as their most recent B-cell receptor pathway inhibitor (BCRi), the overall response rate (ORR) was 67%, and median progression-free and overall survival (PFS and OS) had not been reached after 14 months of follow-up, reported Steven Coutre, MD, of Stanford (Calif.) University, and his colleagues.

“[V]enetoclax monotherapy is active and well-tolerated in patients with CLL progression after therapy with idelalisib, including a significant number of patients who also received prior therapy with ibrutinib [Imbruvica]. These results from the first prospective trial in this high-risk population provide evidence that venetoclax should be considered as a treatment option for such patients,” the investigators wrote. The report was published in Blood.

In clinical trials with idelalisib, approximately one-third of patients with CLL experienced disease progression on therapy, and other patients had to discontinue the drug, an inhibitor of the delta isoform of phosphoinositide 3-kinase (PI3K), because of toxicities, the investigators noted.

“The optimal treatment of patients with CLL progressing after idelalisib has not been well characterized,” they wrote. “Outcomes in patients who discontinued idelalisib treatment early are poor, with one retrospective analysis reporting a median overall survival (OS) after idelalisib discontinuation of approximately 2 months (range, 0-10 months).”

Venetoclax, an inhibitor of the apoptotic BCL-2 protein, has been shown to have activity against CLL, including in patients with high-risk features such as the chromosome 17p deletion (del17p), prompting the investigators to evaluate it as a follow-on in patients with relapsed/refractory CLL treated with a B-cell receptor pathway inhibitor.

They reported on the idelalisib cohort in a phase 2 trial in which patients with CLL that progressed on either idelalisib or ibrutinib were subsequently treated with venetoclax. The patients in this analysis included those treated with idelalisib in the main study cohort or an expansion cohort.

Patients were started on venetoclax 20 mg daily, followed by weekly dose escalations to a target of 400 mg daily by week 5, or to a maximum of 600 mg for patients who did not have a response by the week 12 assessment.

The overall response rate – the primary efficacy endpoint – was 67%. There were two complete remissions (CR) and one CR with incomplete bone marrow recovery. The remaining 21 patients with responses had partial responses.

At a median of 14 months of follow-up, neither median PFS, duration of response, or OS had been reached.

The investigator-estimated 12-month PFS rate was 79%.

The most common grade 3 or 4 adverse events were neutropenia in 50% of patients, thrombocytopenia in 25%, and anemia in 17%. There were no cases of clinical tumor lysis syndrome, which has been known to occur when venetoclax is initiated at full dose without a ramp-up.

The most common adverse events of any grade included neutropenia, diarrhea, upper respiratory tract infection, thrombocytopenia, nausea, fatigue, cough, rash, and anemia.

“The low number of CRs reported at the time of analysis may be a result of the follow-up time, particularly for patients in the expansion cohort, as other clinical studies with venetoclax report CR occurring after 1 year on therapy. Patients with prior ibrutinib exposure who had progressed on idelalisib as their most recent therapy before study entry had similar efficacy results,” the investigators wrote.

Genentech and AbbVie funded the study. Dr. Coutre is an advisory board member for both companies and others, and receives institutional funding from AbbVie and others. Multiple coauthors disclosed financial relationships with AbbVie, Genentech, or both, as well as other companies.

SOURCE: Coutre S et al. Blood. 2018;131(15):1704-11.