1. Fuerst, Mark L.

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ATLANTA-A combination of the anti-CD20 monoclonal antibody obinutuzumab and venetoclax shows a high level of deep, durable responses with unprecedented minimal residual disease (MRD)-negativity rates compared with chemo-immunotherapy regimens and other novel chemotherapy-free therapies in previously untreated patients with chronic lymphocytic leukemia (CLL).

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"Despite the recent development of novel targeted therapies to treat CLL or small lymphocytic lymphoma (SLL), the disease remains incurable and many patients will eventually relapse despite optimal treatment. Additional therapies targeting novel pathways are needed for patients with relapsed/refractory disease," said Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute, Nashville, Tenn., at the 2017 American Society of Hematology (ASH) Annual Meeting.


Venetoclax is a highly selective, potent BCL-2 inhibitor with significant anti-tumor activity as a monotherapy and in combination regimens in CLL. Preclinical data suggest that venetoclax plus obinutuzumab, a type II, glycoengineered anti-CD20 antibody, may have synergistic activity in CLL. Preliminary clinical data found this combination showed an acceptable safety profile and promising efficacy in relapsed/refractory or previously untreated CLL.


Flinn presented updated safety, efficacy, and MRD-negativity data in previously untreated CLL patients from this study (Abstract 430). Venetoclax 400 mg was the recommended target dose for the safety-expansion cohorts determined from an earlier dose-finding cohort. A group of 32 patients, median age 63 years, were given first-line therapy with obinutuzumab cycle 1: 100 mg on day 1, 900 mg on day 2, 1,000 mg on days 8 and 15; cycles 2-6: 1,000 mg day 1, based on a 28-day cycle plus venetoclax 400 mg daily.


Risk for tumor lysis syndrome (TLS) was assessed based on lymph node tumor burden and lymphocyte count. A gradual venetoclax ramp-up to the final dose was used to mitigate TLS risk. Previously untreated CLL patients received six cycles of the combination therapy, followed by an additional six cycles of venetoclax monotherapy. Venetoclax could be extended after 1 year of treatment depending on CLL disease status (MRD positivity or partial response).


All 32 patients responded to the treatment, and 72 percent achieved complete remission (CR) or CR with incomplete blood count recovery. In partial response patients, one patient was considered a partial response due to a lymph node of more than 15 mm (20 mm), but all other components were consistent with CR, Flinn noted.


MRD negativity (best response) in peripheral blood was noted in all patients. MRD negativity in bone marrow was noted in 20 patients (74% in patients with samples available). Undetectable peripheral blood MRD rates were maintained after end of treatment. The 18-month estimated progression-free survival (PFS) was 90.5 percent.


The therapy was well-tolerated with no clinical TLS. No deaths were reported. There was no synergistic toxicity. The adverse event profile was consistent with known safety profiles, he said.


"High rates of CR, MRD-negativity, and preliminary PFS results predict durable clinical outcomes for patients treated with this 1-year fixed duration, chemotherapy-free regimen in previously untreated CLL," said Flinn. "Venetoclax plus obinutuzumab is well-tolerated and may be administered with a favorable benefit/risk profile; no clinical TLS or high-grade infusion-related reactions were reported."


MRD-negativity, a measure of disease burden, has been shown to independently predict clinical outcomes of patients receiving combination chemo-immunotherapy. "The high rate of MRD-negativity achieved in patients receiving venetoclax plus obinutuzumab, including del(17p) patients, suggests that this combination may represent a potentially important treatment option for previously untreated CLL patients," Flinn stated.


"Obinutuzumab appears to be a better anti-CD20 antibody than rituximab, with higher efficacy. Combinations with venetoclax are safe, well-tolerated, and moving earlier in the course of treatment into the front-line setting." A combination of venetoclax plus obinutuzumab is now being tested in a phase III trial.


Duvelisib Monotherapy

In another presentation at ASH, Flinn reported that the oral PI3K inhibitor duvelisib as monotherapy holds potential as a new, convenient treatment option for previously treated CLL/SLL patients (Abstract 493).


Duvelisib is an oral dual inhibitor of PI3K-[delta] and PI3K-[gamma] being developed for the treatment of advanced B-cell malignancies, including CLL/SLL. In a phase I study, the overall response rate (ORR) for duvelisib monotherapy in 55 patients with relapsed/refractory CLL/SLL was 56 percent, with one CR. Based on the safety and efficacy findings in this study, duvelisib 25 mg twice daily was selected as the recommended phase II dose in CLL/SLL.


An international, phase III randomized study evaluated duvelisib monotherapy 25 mg twice daily continuously versus ofatumumab monotherapy 300 mg IV infusion on day 1 and 2,000 mg IV weekly (x7) then monthly (x4) in 319 patients, median age 69 years, with relapsed/refractory CLL/SLL.


About half the patients had bulky disease and about one-third of them had 17p deletion and/or TP53 mutation. They had a median of two prior therapies for a median of about 20 months.


Duvelisib monotherapy met the primary endpoint, achieving significant improvement in PFS (13.3 months) over ofatumumab (9.9 months). Similar benefit was seen in patients with del(17p) (PFS 12.7 months with duvelisib versus 9 months with ofatumumab). "Duvelisib maintained the PFS advantage in all subgroups analyzed," said Flinn.


In addition, duvelisib achieved significant improvement in ORR (74%) as compared to ofatumumab (45%).


Duvelisib significantly reduced lymph node burden more than 50 percent in most patients (85%) as compared to ofatumumab (16%). With a median exposure of 50 weeks, the adverse event profile of duvelisib was manageable and consistent to what has been previously observed. Adverse events of interest (neutropenia, diarrhea, pneumonia, colitis, transaminase elevations, pneumonitis, rash) infrequently led to discontinuation, Flinn noted.


Mark L. Fuerst is a contributing writer.