Front-line acalabrutinib regimen appears safe, induces complete response in chronic lymphocytic leukemia
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ORLANDO — The combination of acalabrutinib, venetoclax and obinutuzumab demonstrated high rates of complete response and undetectable minimal residual disease in bone marrow among patients with previously untreated chronic lymphocytic leukemia, according to results of a single-arm phase 2 study presented at ASH Annual Meeting and Exposition.
“Over the past few years, three signaling pathways have emerged as important therapeutic targets for front-line treatment of CLL. These targets have each been validated in phase 3 settings,” Benjamin L. Lampson, MD, PhD, hematologist at Dana-Farber Cancer Institute and instructor of medicine at Harvard University, said during the presentation. “Because all three of these drugs are so effective and have nonoverlapping toxicities, it makes sense to ask if we can combine them to achieve even deeper and more durable remissions in CLL.”
About half of patients with CLL who receive front-line therapy with venetoclax (Venclexta; AbbVie, Genentech), which selectively binds and inhibits the BCL-2 protein, and obinutuzumab (Gazyva, Genentech), a humanized anti-CD20 monoclonal antibody, achieve undetectable minimal residual disease (MRD) in bone marrow with 1 year of treatment.
The addition of the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica; Pharmacyclics, Janssen), to this regimen resulted in high rates of neutropenia and infusion reactions, as well as other toxicities.
Acalabrutinib (Calquence, AstraZeneca), a more selective Bruton TKI, has demonstrated activity and tolerability as single-agent therapy and when combined with obinutuzumab. It also appears to sensitize CLL cells to venetoclax.
For this reason, Lampson and colleagues assigned 37 patients (median age, 63 years; range, 41-78; 73% men) to one 28-day cycle lead-in with 100 mg acalabrutinib daily, followed by two cycles of acalabrutinib in combination with obinutuzumab at standard dosage, venetoclax ramp-up beginning at cycle 4, and three more cycles of all three drugs.
After 6 months of obinutuzumab, therapy with acalabrutinib and venetoclax continued through 15 cycles.
Most patients (n = 23) had unmutated IGHV, whereas 10 had deletion 17p and/or TP53 mutations, 10 had deletion 11q and seven had complex karyotype.
The rate of complete response with undetectable MRD in bone marrow after 15 treatment cycles served as the study’s primary endpoint.
Median time on therapy was 8 months (range, 2-11).
Among 32 patients who completed restaging at cycle 8, researchers observed an overall response rate of 100%, including 24 partial responses and eight complete responses.
At cycle 8 restaging, 67.8% of patients had undetectable MRD in peripheral blood, 48.3% of patients had undetectable MRD in bone marrow and 16.7% had complete response with undetectable MRD in bone marrow.
The most common grade 3 to grade 4 adverse events included neutropenia (32%). Eight patients experienced infusion-related reactions.
Two patients received dose reductions of acalabrutinib due to headaches. One patient with pre-existing erosive gastritis, duodenitis and symptomatic splenomegaly experienced worsening gastrointestinal symptoms and discontinued treatment.
“A 35-patient expansion cohort limited to TP53-aberrant disease is now accruing to explore [this combination therapy] in this high-risk subgroup,” Lampson said. “A phase 3 trial of [this combination] vs. acalabrutinib in combination with venetoclax vs. chemoimmunotherapy in approximately 780 patients with previously untreated CLL is now accruing.”– by John DeRosier
Reference:
Lampson BL, et al. Abstract 32; Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Lampson reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Stuart Goldberg, MD
This trial provided a combination of effective treatment options for the patient with newly diagnosed CLL, so it’s no surprise that we saw high response rates.
However, using three-drug combinations brings up the issue of value. The Bruton tyrosine kinase (BTK)-targeted therapies thus far have been designed to be lifelong treatments. Many patients will enter durable remission and will be on treatments that cost over $100,000 a year for many years. The question now becomes if we treat our patients with a BTK inhibitor, a BCL-2 inhibitor and a monoclonal agent upfront, can we obtain deep enough remissions to stop therapy? Will the initial costs of expensive treatment for a defined period be recovered by many years of treatment-free remission? This is critical as CLL is the most common type of leukemia in the United States and the economic impact of this strategy could be huge.
This study suggests that combination therapies can be effective with acceptable toxicities, but longer economic follow-up will be needed to justify this aggressive initial approach.
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