Updated results of the phase II CAPTIVATE trial continue to show high response rates as well as high rates of undetectable minimal residual disease (MRD) with ibrutinib plus venetoclax as front-line treatment of chronic lymphocytic leukemia (CLL) in patients under the age of 70 years. The combination of front-line ibrutinib/venetoclax led to undetectable MRD in peripheral blood for 75% of patients and in bone marrow for 72%.

At the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, lead study author Constantine S. Tam, MBBS, PhD, of Peter MacCallum Cancer Center, St. Vincent’s Hospital, and The University of Melbourne, presented data from the prerandomization phase of the double-blind CAPTIVATE-MRD cohort. The abstract was also published in Blood.¹ Data from the MRD-guided randomization phase of the trial will be available in the future.

“These excellent results on depth of response reflect the synergism of this combination and support high rates of remission and undetectable MRD shown [with ibrutinib/ venetoclax] in other studies of CLL and mantle cell lymphoma.”

— Constantine S. Tam, MBBS, PhD

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“Ibrutinib/venetoclax represents an all-oral, once-daily, chemotherapy-free regimen that provides high rates of undetectable MRD in peripheral blood and bone marrow in the first-line treatment of CLL,” Dr. Tam said.

“These excellent results on depth of response reflect the synergism of this combination and support high rates of remission and undetectable MRD shown [with this regimen] in other studies of CLL and mantle cell lymphoma. The low treatment discontinuation rates due to adverse events (5%) and the ability of 90% of patients to complete treatment as planned really show that this combination approach is a viable option,” Dr. Tam noted.

CAPTIVATE Study Details

Patients with CLL and small lymphocytic lymphoma (SLL) who required treatment were enrolled in the phase II trial if they were < 70 years old and had an Eastern Cooperative Oncology Group performance status of 0 or 1. At baseline, the median age was 58 years. Cytogenetic abnormalities were as follows: del(17p) or TP53 mutation in 20%; del(11q) without del(17p) in 16%; complex karyotype in 19%; unmutated IGHV in 59%. Lymph nodes larger than 5 cm were present in 32%.

Ibrutinib was given at 420 mg/d as monotherapy for the first 3 cycles; then venetoclax was added in a 5-week ramp-up schedule with the dose escalated to 400 mg/d, for a total of 12 cycles of therapy. MRD was defined as < 0.01% CLL cells as measured by flow cytometry in the peripheral blood following 6 cycles of combination therapy and measured again after 12 cycles.

Dr. Tam presented data showing that after three cycles of ibrutinib lead-in, hospitalization for tumor-lysis syndrome was avoided in 76% of at-risk patients. Ninety percent of patients were categorized as high-risk for tumor-lysis syndrome at baseline, and among these patients, 90% transformed to medium- or low-risk, and 74% were not hospitalized after receiving venetoclax.

“No patients with a medium or low risk of tumor-lysis syndrome became high risk,” said Dr. Tam.

There were five treatment discontinuations prior to starting venetoclax—four due to adverse events and one due to Richter’s transformation. On combination therapy, seven patients discontinued treatment (four patients due to adverse events and one patient each due to disease progression, patient withdrawal, or investigator’s decision). Planned treatment with 12 cycles of ibrutinib/venetoclax was completed by 90%, and the median duration of treatment was 14.7 months. No deaths were reported.

MRD Evaluation

MRD was evaluated in the blood and bone marrow. In the intent-to-treat population (n = 164), 74% had undetectable MRD in peripheral blood and 68% had undetectable MRD in bone marrow, with 12 or fewer cycles of combination treatment.

“High rates of undetectable MRD were achieved irrespective of adverse clinical characteristics, including patients with del(17p) and TP53 abnormalities, unmutated IGHV, and those with a complex karyotype,” Dr. Tam told listeners.

“High rates of undetectable MRD were achieved irrespective of adverse clinical characteristics, including patients with del(17p) and TP53 abnormalities, unmutated IGHV, and those a with complex karyotype.”

— Constantine S. Tam, MBBS, PhD

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During the MRD-guided randomization phase of the trial, patients with undetectable MRD are being randomly assigned 1:1 to ibrutinib or placebo, and those with detectable MRD will be assigned to ibrutinib or ibrutinib/venetoclax. A separate cohort of 159 patients will receive time-limited therapy with 12 cycles of ibrutinib/venetoclax.

Safety

Ibrutinib’s adverse event profile has been well characterized. The most common adverse events with single-agent ibrutinib were diarrhea, fatigue, headache, nausea, upper respiratory tract infection, vomiting, hypertension, and thrombocytopena. Most grade 3 and 4 events were neutropenia.

With the combination of ibrutinib plus venetoclax, the most common adverse events were primarily grade 1 or 2. Grade 3 or 4 adverse events occurred mostly during the first three cycles of treatment and decreased to 15% over the last cycles. Grade 3 or 4 treatment-related adverse events occurred in 57%, and serious treatment-related adverse events were reported in 11%.

Grade 3 or 4 neutropenia was an adverse event “of interest.” Although laboratory-detected tumor-lysis syndrome was reported in three patients, no patient developed clinical tumor-lysis syndrome.

The rates of grade 3 or 4 atrial fibrillation, major bleeding, febrile neutropenia, and laboratory tumor-lysis syndrome were low. Treatment-related adverse events leading to discontinuation of therapy occurred in eight patients (5%). 

DISCLOSURE: Dr. Tam has received honoraria from AbbVie, BeiGene, Janssen-­Cilag, Novartis, and Pharmacyclics and has received institutional research funding from AbbVie and Janssen-Cilag.

REFERENCES

1. Tam CS, Siddiqi T, Allan JN, et al: Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Results from the MRD cohort of the phase II CAPTIVATE study. Blood 134(suppl 1):Abstract 35, 2019.

2. Wierda WG, Siddiqi T, Flinn I, et al: Phase II CAPTIVATE results of ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol 36(suppl 15):Abstract 7502, 2018.