Clear difference when compared with chemotherapy in patients with CLL

ATLANTA—Twenty months after stopping therapy, patients diagnosed with chronic lymphocytic leukemia (CLL) who were treated with the combination of ibrutinib plus venetoclax showed a marked difference in the rate of undetectable minimal residual disease when compared with patients treated with chlorambucil plus obinutuzumab in the GLOW trial, researchers reported here.

After 34.1 months of follow-up, 51.9% of patients on the ibrutinib-based treatment had achieved undetectable minimal residual disease in analysis of bone marrow compared with 17.1% of patients treated with the chlorambucil-based therapy (P<0.0001), reported Tahla Munir, MBBS, consultant hematologist at Leeds Teaching Hospitals NHS Trust in the United Kingdom.

The story was much the same when peripheral blood was analyzed using next generation sequencing, he said. The undetectable minimal residual disease was achieved by 54.7% of the patients on ibrutinib and in 39% of patients on chlorambucil (P=0.0259), he said in his oral presentation at the 63rd annual meeting of the American Society of Hematology.

In almost every subgroup category, undetectable minimal residual disease was significantly more likely in the ibrutinib arm of the trial, he said. A key difference, however, was that people 65 years of age or older did better with ibrutinib plus venetoclax, while those individuals in the study under age 65 did not show a statistically significant advantage with ibrutinib plus venetoclax, though it trended in favor of the dual targeted therapy regimen.

“An all oral, once daily, fixed duration treatment with ibrutinib plus venetoclax achieved deeper and better sustained undetectable minimal residual disease responses versus chlorambucil plus obinutuzumab as assessed by next generation sequencing,” Munir said.

He explained that the analysis was conducted because minimal residual disease status had been established as a predictive marker for progression-free survival in CLL following chemoimmunotherapy as well as for fixed-duration treatment with venetoclax and an anti-CD20 antibody. “To date, this relationship has not been explored for the combination of ibrutinib plus venetoclax,” he said.

At the 30-month time point, 80.5% of patients who received the ibrutinib-based therapy had maintained progression-free survival compared with 35.8% of patients in the chemotherapy arm of the trial—a relative risk reduction of 78.8% (P<0.0001), Munir reported.

Overall survival did not reach statistical significance. There were 11 deaths in the ibrutinib-based arm of the study; 16 deaths occurred on chlorambucil-obinutuzumab, Munir reported.

The GLOW study recruited patients who were diagnosed with CLL who were naïve to treatment and were 65 years of age or older or 18-64 years old with issues with creatinine clearance or cumulative illness rating scale. The patients also had to be free of 17p deletion or known TP53 mutations. They were required to have ECOG performance status of 0-2 to be eligible for the study.

The 106 patients randomized to receive the ibrutinib-based therapy—410 mg daily for 3 cycles as a lead-in treatment followed by ibrutinib plus venetoclax for 12 cycles. Venetoclax was titrated from 20 mg daily to 400 mg daily over a five-week period. The research team treated the other 105 patients in the study with chlorambucil, delivered in a dose of 0.5 mg/kg on Day 1 and Day 15 for 6 cycles. The latter group also received obinutuzumab 1,000 mg on Day 1-2, Day 8, and Day 15 of cycle 1, and then on Day 1 of cycles 2-6.

In commenting on the study, Shuo Ma, MD, PhD, of Northwestern University School of Medicine, Chicago, told BreakingMED, “The GLOW study compared combination targeted therapy of ibrutinib and venetoclax when compared with chemotherapy and targeted therapy—chlorambucil and obinutuzumab—and the conventional chemotherapy regimen did not do as well. The targeted therapy appears to give a deeper response and a longer-acting response.

“The targeted therapy is not yet the new standard of care,” Ma added. “The combination has not gotten Food and Drug Administration approval as yet for chronic lymphocytic leukemia, because I think we are still waiting for the long-term data.

“There have been plenty of studies comparing targeted therapies against chemotherapy regimens, and these newer regimens are being used in the clinic even without formal approval,” she said. “However, there are still patients with different forms of chronic lymphocytic leukemia who respond well to standard chemotherapy.”

  1. Undetectable minimal residual disease—a marker of remission in CLL—was achieved by a higher percentage of patients on ibrutinib-venetoclax than on chlorambucil-obinutuzumab.

  2. These results were reported in a presentation at a medical meeting and should be considered with caution until published in a peer-reviewed journal.

Edward Susman, Contributing Writer, BreakingMED™

Munir disclosed membership on board of directors or advisory committee at Janssen, Abbvie, AstraZeneca, Morphosys, Alexion, Gilead, and Novartis and receiving honoraria from Janssen, Abbvie, AstraZeneca, Alexion, Apellis, Gilead, and Novartis.

Ma disclosed research funding, honoraria, or speaker’s bureau fees from Loxo, AstraZeneca, Juno, Beigene, Janssen, TG Therapeutics, and Pharmacyclics.

Cat ID: 118

Topic ID: 78,118,730,118,119,332,466,935,192,925,331