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ASH 2018: Dr. O'Connor Shares Insight on MCL and T-Cell Lymphoma Advances

Owen A. O'Connor, MD, PhD
Published: Friday, Jan 11, 2019



Owen A. O’Connor, MD, PhD, professor of medicine and experimental therapeutics, director, Center for Lymphoid Malignancies, co-program director, Lymphoid Development and Malignancy Program, NewYork-Presbyterian/Columbia University Medical Center, shares insight on mantle cell lymphoma (MCL) and T-cell lymphoma breakthroughs.

In the MCL space, BTK inhibitors continue to evolve in the relapsed/refractory setting, says O’Connor. The first-generation BTK inhibitor ibrutinib (Imbruvica) was first reported by Dr. Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, and 2018 brought acalabrutinib (Calquence) to prominence. O’Connor says this second-generation BTK inhibitor can be distinguished from ibrutinib because it is a little more selective of its target. New, long-term follow-up data for ibrutinib and acalabrutinib were presented at the 2018 ASH Annual Meeting, which continued to confirm very good durability of response and no change in the toxicity profiles.

He adds that the investigational agent zanubrutinib (BGB-3111-206), a third-generation BTK inhibitor, is thought to be more selective against the relevant kinases of the kinome. Results from a single-arm, open-label, multicenter phase II trial presented at the meeting showed that the agent was highly active in patients with relapsed/refractory MCL. The overall response rate (ORR) was 83.5% with the inhibitor and responses appeared to be durable. The 12-month progression-free survival (PFS) in zanubrutinib-treated patients was 90% and the 24-month PFS was 82%. At a median follow-up of 35.9 weeks, the median PFS had not been reached.

There was also a trial which evaluated the use of acalabrutinib in combination with bendamustine and rituximab (Rituxan). In the open-label phase 1b trial, patients who were either treatment-naïve or had relapsed/refractory disease, received oral acalabrutinib 100 mg twice daily, bendamustine at 90 mg/m2 intravenously on days 1 and 2, and rituximab at 375 mg/m2 on day 1 in each 28-day cycle. In the treatment-naïve arm, the ORR was 94% and the complete response (CR) rate was 72%, while the relapsed/refractory arm had an ORR of 85% and a CR rate of 65%. This appears to be a promising regimen, says O’Connor, who would like to see PCR monitoring in future research and if the addition of a BTK inhibitor can result in greater levels of not just complete remission, but PCR-negative complete remissions.

In T-cell lymphoma, a disease that has been neglected for quite some time, things are finally changing, O’Connor says. New data from the randomized phase III ECHELON-2 study, which evaluated the addition of the antibody drug conjugate (ADC) brentuximab vedotin (Adcetris) to chemotherapy in patients with CD30-expressing T-cell lymphoma, were also presented at the meeting.

The majority (75%) of the eligible population consisted of those with anaplastic large cell lymphoma (ALCL), the disease for which brentuximab received its early approval by the FDA and is characterized by 100% expression of CD30; only 25% of patients had non-ALCL. Although three-quarters of the population had ALCL and they’re more sensitive to brentuximab, the study was positive for both PFS and overall survival—the first time this has been observed, according to O’Connor. Although this trial raises the question of whether CD30 is important in predicting the response to treatment, O’Connor thinks the data show that for patients with a CD30-positive T cell lymphoma, this regimen is the new standard of care.

Another study presented at the meeting was the ACT-1 phase III trial which looked at adding alemtuzumab, a monoclonal anti-CD52 antibody to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. Specifically, the study compared the use of CHOP and that of A-CHOP, consolidated by stem cell transplant. In the early stages, the study, according to O’Connor, was wrought with various challenges, including toxicities. Although dose adjustments removed a lot of those toxicities, the final results were negative, showing no difference in PFS or OS in both arms.
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Owen A. O’Connor, MD, PhD, professor of medicine and experimental therapeutics, director, Center for Lymphoid Malignancies, co-program director, Lymphoid Development and Malignancy Program, NewYork-Presbyterian/Columbia University Medical Center, shares insight on mantle cell lymphoma (MCL) and T-cell lymphoma breakthroughs.

In the MCL space, BTK inhibitors continue to evolve in the relapsed/refractory setting, says O’Connor. The first-generation BTK inhibitor ibrutinib (Imbruvica) was first reported by Dr. Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, and 2018 brought acalabrutinib (Calquence) to prominence. O’Connor says this second-generation BTK inhibitor can be distinguished from ibrutinib because it is a little more selective of its target. New, long-term follow-up data for ibrutinib and acalabrutinib were presented at the 2018 ASH Annual Meeting, which continued to confirm very good durability of response and no change in the toxicity profiles.

He adds that the investigational agent zanubrutinib (BGB-3111-206), a third-generation BTK inhibitor, is thought to be more selective against the relevant kinases of the kinome. Results from a single-arm, open-label, multicenter phase II trial presented at the meeting showed that the agent was highly active in patients with relapsed/refractory MCL. The overall response rate (ORR) was 83.5% with the inhibitor and responses appeared to be durable. The 12-month progression-free survival (PFS) in zanubrutinib-treated patients was 90% and the 24-month PFS was 82%. At a median follow-up of 35.9 weeks, the median PFS had not been reached.

There was also a trial which evaluated the use of acalabrutinib in combination with bendamustine and rituximab (Rituxan). In the open-label phase 1b trial, patients who were either treatment-naïve or had relapsed/refractory disease, received oral acalabrutinib 100 mg twice daily, bendamustine at 90 mg/m2 intravenously on days 1 and 2, and rituximab at 375 mg/m2 on day 1 in each 28-day cycle. In the treatment-naïve arm, the ORR was 94% and the complete response (CR) rate was 72%, while the relapsed/refractory arm had an ORR of 85% and a CR rate of 65%. This appears to be a promising regimen, says O’Connor, who would like to see PCR monitoring in future research and if the addition of a BTK inhibitor can result in greater levels of not just complete remission, but PCR-negative complete remissions.

In T-cell lymphoma, a disease that has been neglected for quite some time, things are finally changing, O’Connor says. New data from the randomized phase III ECHELON-2 study, which evaluated the addition of the antibody drug conjugate (ADC) brentuximab vedotin (Adcetris) to chemotherapy in patients with CD30-expressing T-cell lymphoma, were also presented at the meeting.

The majority (75%) of the eligible population consisted of those with anaplastic large cell lymphoma (ALCL), the disease for which brentuximab received its early approval by the FDA and is characterized by 100% expression of CD30; only 25% of patients had non-ALCL. Although three-quarters of the population had ALCL and they’re more sensitive to brentuximab, the study was positive for both PFS and overall survival—the first time this has been observed, according to O’Connor. Although this trial raises the question of whether CD30 is important in predicting the response to treatment, O’Connor thinks the data show that for patients with a CD30-positive T cell lymphoma, this regimen is the new standard of care.

Another study presented at the meeting was the ACT-1 phase III trial which looked at adding alemtuzumab, a monoclonal anti-CD52 antibody to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. Specifically, the study compared the use of CHOP and that of A-CHOP, consolidated by stem cell transplant. In the early stages, the study, according to O’Connor, was wrought with various challenges, including toxicities. Although dose adjustments removed a lot of those toxicities, the final results were negative, showing no difference in PFS or OS in both arms.
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