Venetoclax produces deep responses in ultra-high-risk CLL
As of the data lock on April 30, 2015, patients remained a median of 12.1 months on study (range, 0.03–21.5). Seventy are still active on venetoclax, and 37 discontinued the treatment.
Eleven patients discontinued due to Richter’s transformation, 11 due to CLL progression, and 9 due to adverse events. Three patients proceeded to stem cell transplant, 2 withdrew consent, and 1 was noncompliant.
Eighteen patients died, 14 due to disease progression.
Response
Eighty-five patients responded, for an ORR of 79.4% by IRC. Eight patients (7.5%) achieved a CR or CRi, 3 (2.8%) had an nPR, and 74 (69.2%) had a PR. Twenty-two patients (20.6%) had no response.
Twenty-five of 48 patients had no evidence of CLL in their bone marrow by immunohistochemistry, and 18 of 45 patients assessed were MRD-negative in the peripheral blood.
Reduction in lymphocytosis “was quite a universal phenomenon across this trial,” Dr Stilgenbauer said. Only 4 patients of 87 with baseline lymphocytosis failed to reduce their lymphocyte count to below 4 x 109/L, the usual threshold for a CR. And the median time to normalization was 22 days (range, 2–122).
Eighty-nine of 96 patients had 50% or more reduction in their nodal size in a median of 2.7 months (range, 0.7–8.4).
The median time to first response was 0.8 months (range, 0.1–8.1), and the median time to CR/CRi was 8.2 months (range, 3.0–16.3).
“And this number still appears to evolve over the duration of the trial,” Dr Stilgenbauer said.
The median duration of response has not yet been reached. But investigators estimated that of the 85 responders, 84.7% would maintain their response at 12 months, 100% of patients in the CR/CRi and nPR groups would maintain their response, and 94.4% of patients who were MRD-negative would maintain their response.
The median PFS and OS have not been reached. The PFS estimate for 12 months was 72.0%, and the OS estimate was 86.7%.
Adverse events
Treatment-emergent adverse events of any grade occurred in 96% of patients. The most frequent were neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), fatigue (22%), pyrexia (20%), thrombocytopenia (19%), hyperphosphatemia (16%), vomiting (15%), and upper respiratory tract infection (15%).
The most frequent grade 3/4 adverse events were neutropenia (40%), anemia (18%), and thrombocytopenia (15%).
Dr Stilgenbauer pointed out that 22.4% of patients had neutropenia at baseline. Neutropenia was managed with dose interruption or reduction, G-CSF, and/or antibiotics.
Infections occurred in 72% of patients, with 20% of patients experiencing grade 3 or higher.
“The types of infections were the usual expected ones,” Dr Stilgenbauer said.
Laboratory TLS occurred in 5 patients exclusively during the ramp-up period. Two required a dose interruption of 1 day each. There were no clinical TLS events.
Serious adverse events occurred in 55% of patients, the most common being pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).
The investigators concluded that venetoclax offers a favorable risk-benefit profile. The risk of TLS can be effectively mitigated with no clinical TLS, and the incidence of neutropenia and infection are similar to frontline chemoimmunotherapy.
“Venetoclax may provide an attractive treatment option for 17p-deleted CLL as monotherapy or as a component of novel combination strategies,” Dr Stilgenbauer said.
AbbVie and Genentech, collaborators in the development of venetoclax, provided financial support for the study design, study conduct, analysis, data interpretation, writing, and review. 
