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Venetoclax plus ibrutinib linked to high likelihood of undetectable minimal residual disease in CLL
ORLANDO — The addition of venetoclax to ibrutinib as a consolidation therapy appeared associated with high rates of undetectable minimal residual disease in bone marrow and complete response within 12 months among patients with high-risk chronic lymphocytic leukemia, according to phase 2 study results presented at ASH Annual Meeting and Exposition.
The combination also appeared well-tolerated among this patient population.
“Achieving complete response with undetectable minimal residual disease (MRD) is rare — although not unheard of — with ibrutinib (Imbruvica; AbbVie, Janssen) alone and typically takes many years of treatment,” Philip A. Thompson, MBBS, assistant professor and hematologist/oncologist in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, told Healio. “For this reason, almost all patients need indefinite treatment, which increases risks for adverse effects, including potentially serious and life-threatening cardiac arrhythmias and bleeding.”
Patients with complex karyotype or deletion 17p have the highest risk for relapse, and previous studies have suggested that patients with deletion 11q or persistently elevated beta-2-microglobulin also have increased risk for relapse.
“For these reasons, we are very interested in developing time-limited therapy that can achieve deep remissions and limit the risk of developing resistance to treatment,” Thompson said.
Venetoclax (Venclexta; AbbVie, Genentech), a BCL-2 inhibitor, in combination with ibrutinib has demonstrated high efficacy and tolerability among patients with CLL in the first-line and relapsed/refractory settings.
Thompson and colleagues designed the response-adapted trial to evaluate the combination among patients with high-risk CLL. They reported results of the first 26 patients treated in the trial, which so far has enrolled 35 patients.
Patients received at least 1 year of ibrutinib therapy for CLL (median duration prior to venetoclax, 31.2 months), either in the first-line setting or for relapsed or refractory disease; had detectable disease without meeting International Workshop on CLL criteria for progression; and had one or more high-risk features for disease progression, including deletion 17p (n = 13), complex karyotype (n = 9), deletion 11q (n = 9), elevated beta-2-microglobulin or TP53 mutation (n = 11).
Patients continued on ibrutinib at 140 mg to 420 mg per day and received venetoclax starting at 20 mg per day and increasing weekly to the target dose of 400 mg per day. Treatment can continue for up to 2 years, with bone marrow evaluation for MRD using standard four-color flow cytometry and CT scans for restaging every 6 months.
The trial permitted patients to stop venetoclax if they achieve complete response with undetectable MRD on two consecutive evaluations. They may, however, continue ibrutinib at the discretion of the treating physician.
Patients who do not achieve complete response or have detectable MRD at the last restaging will receive ibrutinib maintenance therapy.
Achievement of undetectable MRD after 12 months of combination therapy served as the study’s primary endpoint.
Results showed that eight patients achieved undetectable MRD at 6 months, and 10 patients achieved it at 12 months. Researchers observed complete responses among nine patients at 6 months and seven patients at 12 months.
Two patients stopped treatment after achieving complete response and undetectable MRD at the 6- and 12-month evaluations. Twenty-one patients remain on therapy.
Common adverse events, regardless of attribution, included diarrhea (n = 14), neutropenia (n = 9), nausea (n = 8) and fatigue (n = 8).
Fourteen serious adverse events included localized nonmelanoma skin cancers (n = 6), metastatic melanoma (n = 1), localized bladder transitional cell carcinoma (n = 1), metastatic mucinous adenocarcinoma of the lung (n = 1), pyelonephritis (n = 1), skin abscess (n = 1), accidental overdose of ibrutinib (n = 1) and cholecystitis (n = 1). No other cancers were determined to be treatment-related.
Eight patients received a permanent venetoclax dose reduction due to neutropenia (n = 5) or diarrhea (n = 3), whereas seven patients received a permanently reduced dose of ibrutinib.
No patients developed CLL progression or stopped treatment because of toxicity.
“I certainly think [this combination] is likely to become a standard of care for patients with CLL,” Thompson said. “There are several ongoing front-line trials that I believe will lead to widespread use of this regimen, including the GLOW/CLL3011 study, which is comparing obinutuzumab [Gazyva, Genentech] and chlorambucil to ibrutinib and venetoclax. The modest efficacy of the comparator arm in this trial will likely lead to FDA approval but will not prove superiority of ibrutinib and venetoclax to ibrutinib monotherapy or venetoclax in combination with obinutuzumab.
“For this reason, I am looking forward to seeing results of the CLL17 study comparing ibrutinib monotherapy to venetoclax [in combination with] obinutuzumab and ibrutinib [in combination with] venetoclax,” he added. – by John DeRosier
Reference:
Thompson PA, et al. Abstract 358. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: AbbVie provided funding and venetoclax for the study. Thompson reports consultant/advisory roles with and honoraria from Genentech and Gilead, research funding from Pharmacyclics and Pfizer, and a consultant/advisory role with and research funding from Amgen. Please see the abstract for all other researchers’ relevant financial disclosures.