© Todd Buchanan 2016
SAN DIEGO—The oral BCL-2 inhibitor venetoclax can produce high objective response rates (ORRs) in chronic lymphocytic leukemia (CLL) patients who have failed treatment with at least one B-cell receptor inhibitor, according to investigators.
In a phase 2 study, venetoclax produced an ORR of 67% among all patients enrolled.
The drug produced a 70% ORR among patients who had failed treatment with ibrutinib and a 62% ORR among patients who had failed idelalisib.
“This represents the first prospective study in this patient population and does demonstrate high rates of durable responses, certainly making [venetoclax] a very viable option for a challenging group of patients to treat,” said study investigator Jeffrey Jones, MD, of The Ohio State University in Columbus.
Dr Jones presented results from this trial at the 2016 ASH Annual Meeting (abstract 637*). This study is sponsored by AbbVie in collaboration with Genentech/Roche.
The trial enrolled patients with CLL who relapsed after or were refractory to ibrutinib (arm A) or idelalisib (arm B). At the time of the data cut-off, 64 patients had been enrolled and treated with venetoclax, including 43 patients in arm A and 21 in arm B.
Patients received venetoclax via a recommended dose-titration schedule—20 mg once daily in week 1, 50 mg daily in week 2, 100 mg daily in week 3, 200 mg daily in week 4, and 400 mg daily from week 5 onward. Patients continued to receive the drug until disease progression or unacceptable toxicity.
To mitigate the risk of tumor lysis syndrome (TLS), patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before the first dose of venetoclax.
Patients with a high tumor burden were hospitalized for the first 20 mg dose and the first 50 mg dose, and they received intravenous hydration and rasburicase. Laboratory values were monitored at the first dose and all dose increases.
Patient characteristics: Arm A
Among patients who had failed ibrutinib, the median age was 66 (range, 48-80). Forty-nine percent of the patients had del(17p), and 35% had bulky nodal disease (5 cm or greater).
The median number of prior treatments was 4 (range, 1-12). All patients had received ibrutinib, but 9% had also received idelalisib. Ninety-one percent of patients were refractory to ibrutinib, and 5% were refractory to idelalisib.
The median time on ibrutinib was 17 months (range, 1-56), and the median time on idelalisib was 10 months (range, 2-31).
Patient characteristics: Arm B
Among patients who had failed idelalisib, the median age was 68 (range, 56-85). Ten percent of patients had del(17p), and 52% had bulky nodal disease (5 cm or greater).
The median number of prior treatments was 3 (range, 1-11). All patients had received idelalisib, but 24% had also received ibrutinib. Sixty-seven percent of patients were refractory to idelalisib, and 10% were refractory to ibrutinib.
The median time on idelalisib was 8 months (range, 1-27), and the median time on ibrutinib was 6 months (range, 2-11).
Results: Arm A
The median time on study in arm A was 13 months (range, 0.1-18). Eighteen patients in this arm discontinued the study—12 due to disease progression, 3 due to adverse events (AEs), 2 due to stem cell transplant, and 1 patient withdrew consent.
The ORR was 70% according to an independent review committee (IRC) and 67% according to investigators.
The rate of complete response (CR) was 0%, and the rate of CR with incomplete bone marrow recovery (CRi) was 2% according to the IRC. According to investigators, the CR rate was 5%, and the CRi rate was 2%.
Sixty-seven percent of patients had a partial response (PR) according to the IRC, and 56% had a PR according to investigators.
Results: Arm B
The median time on study in arm B was 9 months (range, 1.3-16). Four patients in this arm discontinued the study—3 related to disease progression and 1 for an “other” reason.
The ORR was 62% according to the IRC and 57% according to investigators.
The rate of CR/CRi was 0% according to the IRC. According to investigators, the CR rate was 10%, and the CRi rate was 5%.
Sixty-two percent of patients had a PR according to the IRC, and 43% had a PR according to investigators.
Results: Overall
The ORR was 67% according to the IRC and 64% according to investigators.
Forty-five percent of patient samples analyzed (14/31) demonstrated minimal residual disease (MRD) negativity in the peripheral blood between weeks 24 and 48. Five patients with sustained MRD negativity had bone marrow evaluations, and 1 was MRD negative.
At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival for all patients was 80%.
“Venetoclax has been well-tolerated,” Dr Jones noted. “The toxicity profile in this study is consistent with previous reports. Most of the toxicity has been cytopenias, which can be managed with dose adjustments or supportive care interventions, such as G-CSF.”
All 64 patients experienced an AE. Common AEs were neutropenia (58%), thrombocytopenia (44%), diarrhea (42%), nausea (41%), anemia (36%), fatigue (31%), decreased white blood cell count (22%), and hyperphosphatemia (22%).
Eighty-three percent of patients had grade 3/4 AEs, including neutropenia (45%), thrombocytopenia (28%), anemia (22%), decreased white blood cell count (13%), febrile neutropenia (11%), and pneumonia (11%).
Fifty-three percent of patients had serious AEs, including febrile neutropenia (9%), pneumonia (8%), multi-organ failure (3%), septic shock (3%), and increased potassium (3%).
There were no cases of clinical TLS. However, 1 patient with high tumor burden met Howard criteria for laboratory TLS.
*Information presented at the meeting differs from the abstract.