Venetoclax produces durable effects in relapsed/refractory CLL

ORLANDO – In patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the results with venetoclax continue to be encouraging, and recent findings from a multicenter phase Ib study hint that venetoclax may also provide durable responses – even with treatment discontinuation.

Venetoclax is an orally bioavailable selective BCL2 inhibitor that is typically given in an open-ended fashion. Toxicity – including tumor lysis syndrome – is always a concern, however, and the issue of whether open-ended administration is necessary is an important question, Andrew D. Zelenetz, MD, PhD, said at the annual conference of the National Comprehensive Cancer Network.

In one phase II multicenter study of venetoclax monotherapy in 107 patients with relapsed/refractory CLL with del(17p) at 31 centers in the United States, Canada, and Europe, the overall response rate was 79.4% based on an independent review committee assessment, (Lancet Oncol. 2016[17]:768-78).

Treatment included once-daily venetoclax beginning with a dose of 20 mg that was ramped up to 50, 100, 200, and 400 mg over 4-5 weeks, followed by daily 400 mg continuous dosing until disease progression or discontinuation for another reason.

Dr. Andrew Zelenetz

Notably, 18 of 85 patients from the study who achieved an objective response were minimal residual disease (MRD)–negative in peripheral blood samples – an outcome that has not been seen with tyrosine kinase inhibitors, noted Dr. Zelenetz of Memorial Sloan Kettering Cancer Center, New York.

The durability of venetoclax’s activity in the study was 84.7% at 12 months in all responders; 100% in those who achieved complete response, complete response with incomplete recovery of blood counts, or nodular partial remission; and 94.4% in the MRD-negative patients.

The authors concluded that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukemia, and that given the distinct mechanism of action of this new therapeutic option for these very poor-prognosis patients, it deserves further investigation as part of a combination or as part of sequential treatment with other novel targeted agents.

The finding that patients on venetoclax can achieve MRD negativity also raised the question of whether treatment can be stopped, Dr. Zelenetz said.

“Because who wants to be on a drug forever? Nobody,” he added.

This question was explored in a study published in February by Seymour et al., which provided early evidence that stopping treatment may indeed be feasible in some patients (Lancet Oncol. 2017;18[2]:230-40).

Venetoclax in this study was given in a dose-escalating fashion to target doses of 200-600 mg daily, in 49 patients with relapsed or refractory “moderately heavily pretreated” CLL. Rituximab was added at a dose of 375 mg/m² in month 1 and 500 mg/m² in months 2-6.

Patients had the option of stopping treatment if they achieved a complete response.

The overall response rate was 86%, including a complete response in 51% of patients. Two-year estimates for progression-free survival and ongoing response were 82% and 89% respectively.

MRD negativity was attained in 80% of complete responders and 57% of patients overall. Thirteen responders discontinued all treatment, and at the time of publication, 11 MRD-negative responders who discontinued therapy remained progression free off therapy. Two MRD-positive patients who achieved complete response and discontinued therapy progressed after 2 years, but were able to recapture response once they restarted the drug.

“So it’s really quite interesting. We might have durable responses after discontinuation of this drug in an MRD-negative state,” Dr. Zelenetz said.

Of note, the latest update to the NCCN guidelines for the treatment of CLL/SLL (small lymphocytic lymphoma) included the addition of “+/– rituximab” as part of the “suggested treatment regimen” of venetoclax in the relapsed/refractory disease setting. This recommendation is category 2A, meaning it is based on lower level evidence with uniform NCCN consensus that the intervention is appropriate.

Venetoclax: adverse events of special interest

In these studies, venetoclax was considered well tolerated, but attention to adverse events and their prevention and management – particularly with respect to tumor lysis syndrome – is essential, Dr. Zelenetz said.

In the phase II study by Stilgenbauer et al., adverse events of special interest included grade 3/4 neutropenia, which occurred in 40% of patients. This was manageable with dose interruptions (five patients) or reductions (four patients), or with granulocyte–colony stimulating factor and antibiotics (six patients, including one who received only antibiotics). None of the patients permanently discontinued treatment.

Infections occurred in 72% of patients, and grade 3 or greater infections occurred in 20% of patients. The most common overall were upper respiratory infections (15%), nasopharyngitis (14%), and urinary tract infections (9%).

Serious infections occurring in two or more patients were pneumonia, lower respiratory tract infection, and upper respiratory tract infection. One patient died from septic shock, 10 had infections leading to venetoclax interruption, and 2 had infections leading to dose reduction.

No mandated infection prophylaxis was used in this study.

Serious adverse events occurred in 59 patients (55%). The most common, occurring in at least 5% of patients, were pyrexia, autoimmune hemolytic anemia, pneumonia, and febrile neutropenia. Thirteen had adverse events leading to dose reductions, most commonly due to neutropenia, thrombocytopenia, and febrile neutropenia.

Laboratory-confirmed tumor lysis syndrome was reported in five patients during the ramp-up period, including four who developed the syndrome within the first 2 days of treatment. All cases resolved without clinical sequelae. Treatment was continued without interruption in three patients with tumor lysis syndrome, who received only electrolyte management, and two patients had a 1-day treatment interruption. Both resumed dosing the next day.

In the phase Ib study by Seymour et al., common grade 1-2 toxicities included upper respiratory tract infections, diarrhea, and nausea occurring in 57%, 55%, and 53% of patients, respectively. Grade 3-4 adverse events occurred in 76% of 49 patients, and most often included neutropenia (12% of patients), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (12%). The most common serious adverse events were pyrexia (12%), febrile neutropenia (10%), lower respiratory tract infection (6%), and pneumonia (6%). Clinical tumor lysis syndrome occurred in two patients who initiated venetoclax at 50 mg, one of whom died as a result.

After enhancement of tumor lysis syndrome prophylaxis measures and reduction of the starting dose of venetoclax to 20 mg, no additional cases occurred, the authors reported.

Mitigating tumor lysis syndrome risk

General measures for mitigating the risk of tumor lysis syndrome include identification of patients at increased risk, initiation of prophylaxis with hydration and a uric acid reducing agent, and initiation of venetoclax at a 20 mg dose for 1 week, with gradual step-wise ramp-up over 5 weeks to the target dose, Dr. Zelenetz noted.

As reported by Stilgenbauer, et al., patients with a nodal mass less than 5 cm and absolute lymphocyte count (ALC) of 25,000 or less are considered at low risk for tumor lysis syndrome, those with a nodal mass of 5 cm to less than 10 cm or ALC greater than 25,000 are at medium risk, and those with a nodal mass of 10 cm or greater or nodal mass of 5 cm or greater and ALC of greater than 25,000 are considered to be at high risk.

High-risk patients in the study received inpatient venetoclax dosing and monitoring at 4, 8, 12, and 24 hours with 20 mg and 50 mg dosing, as well as outpatient intravenous hydration at 100 mg if there was no indication to hospitalize, and post-dose 8-24 hour laboratory monitoring at 100 mg and above.

Medium-risk patients received IV hydration at 20 and 50 mg dosing, inpatient care if creatinine clearance was less than 80 mL/min or if there was a high tumor burden, and postdose 8- and 24-hour laboratory monitoring after the initial dose and at dose escalations. Low-risk patients received outpatient dosing at all dose levels in the absence of an indication to hospitalize, and postdose 8- and 24-hour laboratory monitoring after the initial dose and at dose increases.

“Unfortunately, the dose-limiting toxicity of venetoclax is fatal tumor lysis,” Dr. Zelenetz said, adding that by increasing the dose slowly over time according to current treatment recommendations – from 20 mg, to 50, 100, 200, and 400 mg at weekly intervals, this complication can be avoided.

Dr. Zelenetz reported receiving consulting fees, honoraria, and/or grant/research support from Genentech, the maker of venetoclax (Venclexta), and a wide variety of other drug companies.

sworcester@frontlinemedcom.com