Innovative oral regimen developed for 1st-line CLL treatment

Researchers developed an oral two-drug combination regimen for the first-line treatment of chronic lymphocytic leukemia (CLL), which outperformed the conventional chemotherapy plus an antibody injection. CLL occurs mostly in the elderly.

The researchers unveiled the results of the GLOW trial, evaluating the combo of Imbruvica and Venclexta in newly diagnosed CLL patients, at the online annual meeting of the European Hematology Association (EHA 2021).

Using Imbruvica (left) in combination with Venclexta significantly improved progression-free survival in newly diagnosed CLL patients, according to the results of the GLOW trial.

GLOW compared the fixed-duration oral combo of BTK inhibitor Imburvica (ingredient: ibrutinib) plus BCL-2 inhibitor Venclexta (venetoclax) with the existing chemotherapy chlorambucil plus anti-CD20 antibody Gazyba (obinutuzumab) for untreated CLL patients.

The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC), and secondary endpoints were undetectable minimal residual disease (uMRD) in the bone marrow and complete response (CR) through NGS analysis.

The research team randomly assigned 106 patients to the Imbruvica+Venclexta (I+V) group, and 105 to the chlorambucil+obinutuzumab (Clb+O) group. The results showed that patients treated with I+V improved PFS significantly, with a 78.4 percent lower risk of disease progression and death than the Clb+O group.

During the median follow-up period of 27.7 months, the median PFS in the Clb+O group was 21 months, whereas the I+V group had not yet reached the median value. The PFS improvement effect was consistent across subgroups, including those categorized by patients' severity and age, and the investigator-assessed PFS was similar to that of the IRC assessment.

Progression-free survival assessed by the independent review committee (Credit: EHA 2021)

The two-drug, fixed-duration oral treatment of Imbruvica and Venclexta reduced the chance of recurrence or death, compared to the existing chemotherapy and the antibody injection, even one year after the discontinuation of the medication, the results showed.

The uMRD ratio in bone marrow at three months after discontinuation of the fixed-duration treatment was 51.9 percent in the I+V group, significantly higher than 17.1 percent in the Clb+O group. The uMRD ratio in peripheral blood was 54.7 percent in the I+V group and 39 percent in the Clb+O group.

Also, 84.5 percent of the patients with I+V treatment who achieved uMRD in peripheral blood at three months after treatment discontinuation maintained it at 12 months. A high uMRD rate means a low risk of recurrence.

CR assessed by IRC was 38.7 percent in the I+V group vs. 11.4 percent in the Clb+O group. The investigator-evaluated CR was 45.3 percent and 13.3 percent, respectively.

The most commonly reported grade 3 or higher adverse events were neutropenia (34.9 percent), diarrhea (10.4 percent), and hypertension (7.5 percent) in the I+V group, and neutropenia (49.5 percent), thrombocytopenia (20 percent), pneumonia, and tumor lysis syndrome (TLS) (5.7 percent each) in the Clb+O group.

Arnon Kater, a hematology specialist at the Amsterdam Medical Centers, University of Amsterdam, said once-daily oral treatment I+V administered for a fixed period showed excellent PFS as the first-line CLL treatment regardless of CIRS score and other variables, compared to Clb+O.

“The combination of ibrutinib and venetoclax significantly improved the CR’s depth and duration, prolonging the time to the next treatment, and uMRD was mostly maintained even one year after discontinuation of the fixed period treatment,” he said.

The safety profile of ibrutinib plus venetoclax was consistent in the elderly group with complications. This indicates that fixed-duration ibrutinib plus venetoclax therapy may be an effective treatment strategy in elderly patients, he added.