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ASH 2018: Dr. Wierda Discusses Pivotal Updates in CLL

William G. Wierda, MD
Published: Friday, Jan 11, 2019



William G. Wierda, MD, professor of medicine, executive medical director of Leukemia, The University of Texas MD Anderson Cancer Center, discusses pivotal updates in the field of chronic lymphocytic leukemia (CLL) that were presented at the 2018 ASH Annual Meeting.

There were 3 particularly important randomized trials presented at the meeting, Wierda says. First, there was a study looking at ibrutinib (Imbruvica) and rituximab (Rituxan) versus the standard fludarabine, cyclophosphamide, and rituximab (FCR) regimen in previously untreated patients who were fit enough to receive FCR.

Following a median follow-up of 33.4 months, results showed a 65% reduction in the risk of progression or death with ibrutinib/rituximab versus FCR (HR, 0.35; 95% CI, 0.22-0.50; P <.00001). Additionally, the combination of ibrutinib and rituximab reduced the risk of death by 83% versus FCR (HR, 0.17; 95% CI, 0.05-0.54; P <.0003).

This study is significant, Wierda says, because it was the only one to show an overall survival (OS) benefit with ibrutinib. While a positive progression-free survival (PFS) endpoint was expected, researchers will have to evaluate the deaths in the FCR arm to understand the clinical significance of this endpoint, he adds. A statistically significant PFS benefit was not seen in patients with IGHV mutations, but there was a trend observed (HR, 0.435; 95% CI, 0.140-0.1350; P = .07). Other large trials, similar to this one, have reported data of a plateau with patients who have IGHV-mutated disease; therefore, FCR could still be a potential treatment for this population.

A second study presented was a 3-arm ALLIANCE trial of ibrutinib monotherapy, ibrutinib plus rituximab, or bendamustine plus rituximab (BR). BR is tolerated well by both older and younger patients. There was an improvement in progression-free survival (PFS) in both arms involving ibrutinib, Wierda notes. Results showed that there was no difference in terms of OS nor PFS, specifically between the 2 ibrutinib arms. The data do not indicate an improvement in outcomes with the addition of an anti-CD20 agent to ibrutinib-based therapy, if giving indefinite continuous treatment.

Additionally, the MURANO study was the first phase III randomized trial to evaluate the combination of venetoclax and rituximab compared with BR in 389 patients with relapsed/refractory CLL. Patients were administered venetoclax for up to 2 years and rituximab for the first 6 months, or 6 cycles of bendamustine plus rituximab for the duration of 6 months. Previously presented data showed an improvement of PFS with the addition of venetoclax, but researchers still questioned the durability of these responses.

Follow-up data presented at ASH 2018 show a sustained durable PFS in the 130 patients who discontinued venetoclax. Specifically, patients on the venetoclax arm had a 63% undetectable minimal residual disease (uMRD) rate versus 15% for the bendamustine arm. At 2 years, uMRD status was maintained in 48% of venetoclax-treated patients versus 2% of those on the bendamustine arm.

Lastly, Wierda led an analysis of trials exploring MRD status with venetoclax in patients with relapsed/refractory CLL. Results showed that patients who achieved an uMRD status in the blood had a longer PFS, which was shown at 12-month and 24-month follow-up.

Additionally, researchers previously have had trouble understanding the mechanisms of resistance to ventoclax. Results of an analysis conducted at the meeting showed that a recurrent mutation in BCL2 is linked to resistance to venetoclax in patients with CLL.

Regarding chimeric antigen receptor (CAR) T-cell therapy, preliminary data in CLL have been somewhat limited, as well as limited responses—which have been around 20% to 30%. Researchers sought to conduct trials to enhance the complete remission rate, such as the addition of ibrutinib to CAR T-cell products.

Overall, Wierda explained that the CLL abstracts at this year’s meeting is a call to shift the standard of care for patients; there is also a further exploration of small molecule inhibitors.
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William G. Wierda, MD, professor of medicine, executive medical director of Leukemia, The University of Texas MD Anderson Cancer Center, discusses pivotal updates in the field of chronic lymphocytic leukemia (CLL) that were presented at the 2018 ASH Annual Meeting.

There were 3 particularly important randomized trials presented at the meeting, Wierda says. First, there was a study looking at ibrutinib (Imbruvica) and rituximab (Rituxan) versus the standard fludarabine, cyclophosphamide, and rituximab (FCR) regimen in previously untreated patients who were fit enough to receive FCR.

Following a median follow-up of 33.4 months, results showed a 65% reduction in the risk of progression or death with ibrutinib/rituximab versus FCR (HR, 0.35; 95% CI, 0.22-0.50; P <.00001). Additionally, the combination of ibrutinib and rituximab reduced the risk of death by 83% versus FCR (HR, 0.17; 95% CI, 0.05-0.54; P <.0003).

This study is significant, Wierda says, because it was the only one to show an overall survival (OS) benefit with ibrutinib. While a positive progression-free survival (PFS) endpoint was expected, researchers will have to evaluate the deaths in the FCR arm to understand the clinical significance of this endpoint, he adds. A statistically significant PFS benefit was not seen in patients with IGHV mutations, but there was a trend observed (HR, 0.435; 95% CI, 0.140-0.1350; P = .07). Other large trials, similar to this one, have reported data of a plateau with patients who have IGHV-mutated disease; therefore, FCR could still be a potential treatment for this population.

A second study presented was a 3-arm ALLIANCE trial of ibrutinib monotherapy, ibrutinib plus rituximab, or bendamustine plus rituximab (BR). BR is tolerated well by both older and younger patients. There was an improvement in progression-free survival (PFS) in both arms involving ibrutinib, Wierda notes. Results showed that there was no difference in terms of OS nor PFS, specifically between the 2 ibrutinib arms. The data do not indicate an improvement in outcomes with the addition of an anti-CD20 agent to ibrutinib-based therapy, if giving indefinite continuous treatment.

Additionally, the MURANO study was the first phase III randomized trial to evaluate the combination of venetoclax and rituximab compared with BR in 389 patients with relapsed/refractory CLL. Patients were administered venetoclax for up to 2 years and rituximab for the first 6 months, or 6 cycles of bendamustine plus rituximab for the duration of 6 months. Previously presented data showed an improvement of PFS with the addition of venetoclax, but researchers still questioned the durability of these responses.

Follow-up data presented at ASH 2018 show a sustained durable PFS in the 130 patients who discontinued venetoclax. Specifically, patients on the venetoclax arm had a 63% undetectable minimal residual disease (uMRD) rate versus 15% for the bendamustine arm. At 2 years, uMRD status was maintained in 48% of venetoclax-treated patients versus 2% of those on the bendamustine arm.

Lastly, Wierda led an analysis of trials exploring MRD status with venetoclax in patients with relapsed/refractory CLL. Results showed that patients who achieved an uMRD status in the blood had a longer PFS, which was shown at 12-month and 24-month follow-up.

Additionally, researchers previously have had trouble understanding the mechanisms of resistance to ventoclax. Results of an analysis conducted at the meeting showed that a recurrent mutation in BCL2 is linked to resistance to venetoclax in patients with CLL.

Regarding chimeric antigen receptor (CAR) T-cell therapy, preliminary data in CLL have been somewhat limited, as well as limited responses—which have been around 20% to 30%. Researchers sought to conduct trials to enhance the complete remission rate, such as the addition of ibrutinib to CAR T-cell products.

Overall, Wierda explained that the CLL abstracts at this year’s meeting is a call to shift the standard of care for patients; there is also a further exploration of small molecule inhibitors.
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