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Clinical Trial
. 2016 Jan 28;374(4):311-22.
doi: 10.1056/NEJMoa1513257. Epub 2015 Dec 6.

Targeting BCL2 With Venetoclax in Relapsed Chronic Lymphocytic Leukemia

Free PMC article
Clinical Trial

Targeting BCL2 With Venetoclax in Relapsed Chronic Lymphocytic Leukemia

Andrew W Roberts et al. N Engl J Med. .
Free PMC article


Background: New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.

Methods: We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.

Results: The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.

Conclusions: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; number, NCT01328626.).


Figure 1.
Figure 1.. Venetoclax Schedules, Pharmacokinetic Response, and Activity against Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).
Panel A shows the administration schedule for the 53 patients in the dose-escalation cohort who were enrolled after the first 3 patients (in a 3+3 design). On day –7 (7 days before week 1), an initial single 50-mg dose was administered to 50 patients and a 20-mg dose to 3 patients. Daily administration of a 50-mg dose started in week 1 and was stepped up to 100 mg in week 2 for patients in groups that were scheduled to receive 150 mg to 400 mg per day or to 150 mg for those in groups scheduled to receive 600 mg to 1200 mg per day before reaching the designated group dose in week 3; in the 600-mg group, an additional 400-mg step was incorporated. Panel B shows the administration schedule for the 60 patients in the expansion cohort. Daily administration started with 20 mg per day, followed by weekly ramp-up in three steps to 400 mg. Panel C shows plasma levels of venetoclax at steady state, grouped according to the dose at the time of collection. Panels D through F show the activity of venetoclax against CLL or SLL in blood (Panel D), lymph nodes (Panel E), and bone marrow (Panel F), which are shown as normalized changes from baseline. For each patient, the best response is presented, with color coding according to the designated dose group. Data for the absolute lymphocyte count in peripheral blood are included only for the 66 patients who had lymphocytosis immediately before the administration of venetoclax. Among 65 of these patients, the median time to a lymphocyte count of less than 4000 per cubic millimeter was 22 days (range, 1 to 451). Data for lymph-node disease are derived from the sums of the products of the perpendicular dimensions of target lesions as seen on computed tomography (CT) and as defined and reported by investigators for 110 patients who had at least one follow-up CT scan during the study. The median time to a 50% reduction in nodal size (as reported for 99 patients) was 42 days (range, 20 to 417), and the median time to a normalization in nodal diameter to less than 1.5 cm (as reported in 34 patients) was 8 months (range, 1 to 27). Data for changes in bone marrow infiltration in the 85 patients who underwent at least one bone marrow biopsy after the initiation of venetoclax are derived from hematopathological analysis of CLL infiltration. The median time until complete clearance of bone marrow infiltrate in 26 patients was 6 months (range, 2 to 22).
Figure 2.
Figure 2.. Durability of Benefit with Ongoing Venetoclax Therapy.
The proportions of patients with progression-free survival are shown for the dose-escalation and expansion cohorts (Panel A), for patients with CLL with or without chromosome 17p deletions, abbreviated del(17p) (Panel B), and for patients according to dose group (Panel C). Panel D shows the duration of response, according to whether patients had a complete response (including a complete remission with incomplete marrow recovery) or a partial response as their best response during the trial. Tick marks represent censored data. The number of patients at risk for an event at each time point is shown for the first 30 months of follow-up. When the numbers of patients at risk are low because of data censoring, estimates of median values may be unstable. Point estimates at 15 months are provided in Table S10 in the Supplementary Appendix.

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