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Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
Other adverse events of all grades occurring in 10% of patients or more for the combination and monotherapy arms, respectively, were: diarrhea (42% and 40%), fatigue (27% and 33%), insomnia (24% and 10%), nausea (22% and 21%), headache (20% and 28%), arthralgia (19% and 17%), cough (19% and 24%), abdominal pain (15% and 9%), stomatitis (15% and 9%), upper respiratory infection (15% and 12%), dizziness (15% and 22%), contusion (15% and 29%), anemia (14% and 17%), and peripheral edema (10% and 21%).
Neutropenia was higher in the experimental arm, 22% any grade, compared with 12% in the ibrutinib arm, although grade 3 or higher neutropenia was similar in the 2 arms. Other laboratory abnormalities were similar between the arms.
Efficacy
The best ORR in the combination arm was 78%, with 7% achieving CR compared with 45% in the monotherapy arm with no CRs (P<0.001).
Nineteen percent of the combination arm achieved MRD negativity in peripheral blood compared with 2% of the monotherapy arm (P<0.01).
The reduction in lymph node size was similar between the arms.
In contrast, lymphocytosis was very different between the arms.
“As has been reported multiple times with targeted B-cell receptor signaling inhibitors,” Dr Sharman said, “patients treated with ibrutinib experienced rapid increase in their lymphocytes, returning approximately to baseline by 3 months and decreasing thereafter.”
“By contrast,” he continued, “those patients treated with the additional antibody had much more rapid resolution of their lymphocytosis. This was true whether patients were considered rituximab refractory or not.”
The investigators performed an additional analysis of ORR, this time including patients who achieved partial response with lymphocytosis (PR-L). These patients were not included in the primary endpoint because the iwCLL 2008 criteria had not yet been updated to include PR-L.
The best overall response including active PR-L patients was 83% in the experimental arm and 59% in the ibrutinib monotherapy arm (P<0.01).
PFS showed a trend toward improvement in the patients treated with the combination, with a hazard ratio of 0.559, which was not of statistical significance at the time of analysis.
The investigators concluded that the study met its primary endpoint, with a greater response rate and a greater depth of response than ibrutinib alone.
And the addition of ublituximab did not alter the safety profile of ibrutinib monotherapy.
TG Therapeutics, Inc, funded the study. 
*Data in the abstract differ from the meeting presentation.
Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
Other adverse events of all grades occurring in 10% of patients or more for the combination and monotherapy arms, respectively, were: diarrhea (42% and 40%), fatigue (27% and 33%), insomnia (24% and 10%), nausea (22% and 21%), headache (20% and 28%), arthralgia (19% and 17%), cough (19% and 24%), abdominal pain (15% and 9%), stomatitis (15% and 9%), upper respiratory infection (15% and 12%), dizziness (15% and 22%), contusion (15% and 29%), anemia (14% and 17%), and peripheral edema (10% and 21%).
Neutropenia was higher in the experimental arm, 22% any grade, compared with 12% in the ibrutinib arm, although grade 3 or higher neutropenia was similar in the 2 arms. Other laboratory abnormalities were similar between the arms.
Efficacy
The best ORR in the combination arm was 78%, with 7% achieving CR compared with 45% in the monotherapy arm with no CRs (P<0.001).
Nineteen percent of the combination arm achieved MRD negativity in peripheral blood compared with 2% of the monotherapy arm (P<0.01).
The reduction in lymph node size was similar between the arms.
In contrast, lymphocytosis was very different between the arms.
“As has been reported multiple times with targeted B-cell receptor signaling inhibitors,” Dr Sharman said, “patients treated with ibrutinib experienced rapid increase in their lymphocytes, returning approximately to baseline by 3 months and decreasing thereafter.”
“By contrast,” he continued, “those patients treated with the additional antibody had much more rapid resolution of their lymphocytosis. This was true whether patients were considered rituximab refractory or not.”
The investigators performed an additional analysis of ORR, this time including patients who achieved partial response with lymphocytosis (PR-L). These patients were not included in the primary endpoint because the iwCLL 2008 criteria had not yet been updated to include PR-L.
The best overall response including active PR-L patients was 83% in the experimental arm and 59% in the ibrutinib monotherapy arm (P<0.01).
PFS showed a trend toward improvement in the patients treated with the combination, with a hazard ratio of 0.559, which was not of statistical significance at the time of analysis.
The investigators concluded that the study met its primary endpoint, with a greater response rate and a greater depth of response than ibrutinib alone.
And the addition of ublituximab did not alter the safety profile of ibrutinib monotherapy.
TG Therapeutics, Inc, funded the study.
*Data in the abstract differ from the meeting presentation.
Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
Other adverse events of all grades occurring in 10% of patients or more for the combination and monotherapy arms, respectively, were: diarrhea (42% and 40%), fatigue (27% and 33%), insomnia (24% and 10%), nausea (22% and 21%), headache (20% and 28%), arthralgia (19% and 17%), cough (19% and 24%), abdominal pain (15% and 9%), stomatitis (15% and 9%), upper respiratory infection (15% and 12%), dizziness (15% and 22%), contusion (15% and 29%), anemia (14% and 17%), and peripheral edema (10% and 21%).
Neutropenia was higher in the experimental arm, 22% any grade, compared with 12% in the ibrutinib arm, although grade 3 or higher neutropenia was similar in the 2 arms. Other laboratory abnormalities were similar between the arms.
Efficacy
The best ORR in the combination arm was 78%, with 7% achieving CR compared with 45% in the monotherapy arm with no CRs (P<0.001).
Nineteen percent of the combination arm achieved MRD negativity in peripheral blood compared with 2% of the monotherapy arm (P<0.01).
The reduction in lymph node size was similar between the arms.
In contrast, lymphocytosis was very different between the arms.
“As has been reported multiple times with targeted B-cell receptor signaling inhibitors,” Dr Sharman said, “patients treated with ibrutinib experienced rapid increase in their lymphocytes, returning approximately to baseline by 3 months and decreasing thereafter.”
“By contrast,” he continued, “those patients treated with the additional antibody had much more rapid resolution of their lymphocytosis. This was true whether patients were considered rituximab refractory or not.”
The investigators performed an additional analysis of ORR, this time including patients who achieved partial response with lymphocytosis (PR-L). These patients were not included in the primary endpoint because the iwCLL 2008 criteria had not yet been updated to include PR-L.
The best overall response including active PR-L patients was 83% in the experimental arm and 59% in the ibrutinib monotherapy arm (P<0.01).
PFS showed a trend toward improvement in the patients treated with the combination, with a hazard ratio of 0.559, which was not of statistical significance at the time of analysis.
The investigators concluded that the study met its primary endpoint, with a greater response rate and a greater depth of response than ibrutinib alone.
And the addition of ublituximab did not alter the safety profile of ibrutinib monotherapy.
TG Therapeutics, Inc, funded the study.
*Data in the abstract differ from the meeting presentation.