For Refractory CLL, Venetoclax's Complete Response Rate Is Tops

Nancy A. Melville

June 15, 2015

VIENNA — The combination therapy of the novel anti-BCL-2 drug venetoclax (formerly ABT-199/GDC-0199, AbbVie, Genentech) and rituximab shows encouraging results in the treatment of refractory chronic and lymphocytic leukemia (CLL), according to early results from an ongoing clinical trial.

The complete response rate seen with venetoclax is especially notable, said lead investigator Andrew W. Roberts, MBBS, PhD, from the Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research, in Australia.

Dr Roberts reported that 41% (20) of 49 patients have achieved either a complete response or complete response with incomplete marrow recovery (CRi).

"The depth of responses seen with this therapy are impressive,” he told Medscape Medical News.

"We've also seen high response rates with ibrutinib and rituximab combined and idelalisib plus rituximab, but the complete response rates are considerably lower, and the data (with venetoclax) on being negative for minimal residual disease are exceptional," he told Medscape Medical News.

The findings offer new insights into increasing evidence of the important benefits venetoclax could offer, according to Paul Barr, MD, from the University of Rochester Medical Center in New York, who was not involved in the study.

"Venetoclax remains one of the most exciting agents being developed for CLL," he told Medscape Medical News. "It is very active, and the depth of response suggests we may be able to stop therapy in some patients rather than continue until progression."

"Still, we need to wait and see the progression-free survival to better understand its efficacy," he added.

In the current open-label study, CLL patients with a median age of 68 (50-88) were started on treatment of oral tablet formulation of 20 mg or 50 mg of venetoclax daily, increased weekly to final doses of 200 mg to 600 mg. Monthly doses of rituximab were added at 375 mg/m2 and then 500 mg/m 2, for six doses after the weekly lead-in phase.

Patients had previously been treated with a median of two prior therapies.

The results were reported for 49 patients, including 48 with CLL and one with small lymphocytic lymphoma (SLL). Overall, with a median time in the study of 13 (0.03-28) months, 84% (41 of 49) of patients achieved an objective response to the treatment.

Dr Barr said the objective response rate is "unparalleled."

A rapid reduction in absolute lymphocyte counts (ALC) was seen early in the venetoclax dosing regimen, with 32 of 32 patients (100%) with baseline lymphocytosis achieving ALC counts lower than 4 x 109/L, with a median time to the reduction of 3 weeks (range 1-9).

Deep reductions in bone marrow infiltrates were seen, with 34 patients (69%) achieving complete marrow clearance by morphology and immunohistochemistry, with a median time to complete marrow clearance of 7 months (range 6-16).

In addition, 20 (41%) patients achieved reduction in all target lesions to 1.5 cm or less, with a median time to normalization of 8 months (range 6-18).

In assessing patients with bone marrow minimal residual disease, the researchers found that in 20 complete response or CRi, 13 were minimal residual disease (MRD)-negative and five were MRD-positive.

"The minimal residual disease-negative rate is both surprising and very exciting," said Dr Roberts. Of the partial response patients, 10 were MRD-negative and 10 were MRD-positive.

The minimal residual disease-negative rate is both surprising and very exciting.

Dr Barr said, again, that this degree of MRD negativity is "unparalleled." Six patients were able to interrupt venetoclax after achieving a complete response or CRi, and while all six remained free of recurrence after a median time of 12 months (0-21) off the therapy, one MRD-positive patient had asymptomatic progression at 23.7 months after stopping therapy.

The most common treatment-emergent side effect was neutropenia, occurring in 53% of patients, and it was also the most common adverse event (AE) reaching grade 3/4 in more than 10% of patients (reaching that level in 51%).

Other side effects included diarrhea and nausea (each 47%), upper respiratory tract infection in 41% of patients, pyrexia (37%) and fatigue, headache and cough, each in 33% of patients.

Other adverse events reaching grade 3/4 in more than 10% of patients included thrombocytopenia (16%) and anemia (14%).

Serious adverse events occurred in 21 (43%) patients, including pyrexia in 8% and febrile neutropenia in 6%.

There was one treatment-emergent AE that led to death (tumor lysis syndrome) and two patients died after a progression of disease.

"Regarding safety, I'm concerned how venetoclax will be used in multicenter settings," Dr Barr noted. "Tumor lysis syndrome remains a concern and requires close monitoring." To date, 38 patients remain on the study, while 11 patients have discontinued; six due to progression of disease, three withdrew consent, and two discontinued due to adverse events.

Previous research from the first-in-human phase 1 study of venetoclax used as a single agent showed a rapid reduction in disease burden in as many as 80% of relapsed or refractory CLL or SLL patients, and complete response rates have also previously been reported to be substantial (23%).

Dr Roberts noted that combination therapy nevertheless suggested a potential for even better response, particularly with rituximab.

"Rituximab was a logical combination, with pre-clinical models of CD20-positive lymphoid cancers showing a synergy between the two drugs," he said.

Venetoclax combined with rituximab is currently undergoing a randomized phase 3 trial (MURANO), comparing the combination with bendamustine plus rituximab.

The study received funding from AbbVie and Genentech. Dr Roberts received research funding from AbbVie and Genentech and is an employee of the Walter and Eliza Hall Institute of Medical Research, which receives milestone payments related to venetoclax. Dr Barr has been a consultant for AbbVie and Genentech.

20th Congress of the European Hematology Association (EHA): Abstract S431. Presented June 13, 2015.


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