BTK Inhibitor Draws High Response Rate in CLL

SAN DIEGO – A novel targeted agent was associated with high objective response rates at 10 months in patients with relapsed/refractory, heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

At 10.2 months’ median follow-up, objective responses (combined complete and partial responses) were seen in 70% of 27 CLL/SLL patients assigned to a 420-mg daily dose of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK). Objective responses were seen at 6.5 months’ follow-up in 44% of 34 patients on an 840 mg daily dose, reported Dr. Susan O’Brien, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The researchers had previously reported a 48% objective response rate at 6.2 months median follow-up.

Among patients who did not have a complete or partial response, a nodal partial response was noted in 19% of those in the 420-mg cohort and in 35% of those in the 840-mg group. A nodal partial response was defined as a reduction of greater than 50% in aggregate lymph node size, but with residual lymphocytosis.

Progression-free survival at 6 months is 92% in the 27 patients in the 420-mg cohort, and 90% in the 34 patients in the 840-mg group.

Although it’s still too early to tell which dose will be more effective, the evidence to date suggests that the 420-mg dose completely inhibits activity of the targeted kinase. Thus, the 840-mg dose may not be necessary, Dr. O'Brien said.

Further, PC-32765 does not cause myelosuppression, a trait noted with imatinib (Gleevec) and other tyrosine kinase inhibitors that are effective in other leukemia subtypes.

"This is a big deal in CLL because all of the treatments that we have are pretty much chemo-based or antibody-based treatments. The biggest complication in treating CLL with pretty much every therapy we have is myelosuppression and infection, and of course these people are [already] immune suppressed. To have an agent that’s not myelosuppressive and this effective is very exciting," she said in a briefing prior to her presentation of the results at a session on Tuesday, Dec.13.

A leukemia specialist who was not involved in the study said that the results are particularly impressive given the nature of the patient population.

Patients also tolerated the drug well. The incidence of serious adverse events potentially related to PCI-32765 was 10%. The most common adverse event was diarrhea, which was generally mild, easily controlled, and self-limited, Dr. O’Brien said.

PCI-32765 binds selectively and irreversibly to BTK, an essential element of the B-cell antigen receptor signaling pathway, thereby blocking receptor signaling, inducing cell death via apoptosis, and inhibiting cellular migration and adhesion of malignant B cells.

"To have an agent that’s not myelo-suppressive and this effective is very exciting."

The investigators enrolled both treatment-naive patients with CLL and those who had relapsed/refractory disease following at least two prior therapies, including fludarabine. The patients were treated with PCI-32765 administered daily for 28-day cycles until disease progression. Treatment-naive patients and 27 patients with relapsed/refractory disease were assigned to the 420-mg dose; 34 patients with relapsed/refractory disease were assigned to the 840-mg dose.

In all, 72% of patients had one or more poor-risk molecular features. Of this group, 31% had the 17p deletion, 33% had the 11q deletion, and 57% had IgV_H un-mutated.

Two patients dropped out of the trial because of adverse events (dose group not specified), and six patients (two in the 420-mg group, four in the 840-mg group) required a dose reduction.

The most frequently reported grade 1 or 2 adverse events were diarrhea, fatigue, nausea, and ecchymosis. Serious adverse events were reported in 38% of patients. Serious events potentially related to the drug occurred in 10% of all patients.

The investigators noted that, in a majority of patients "a characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of therapy, followed by resolution over time."

At last follow-up, 22 of 27 patients on the 420-mg dose and 28 of 34 on the 840-mg dose were still on therapy. Phase-III trials are planned.

The trial was funded by Pharmacyclics. Dr. O’Brien disclosed serving on the board of directors or advisory committee, and has received research funding from the company. All of her coauthors disclosed either receiving research funding or consulting fees from the company, or being employees and receiving equity ownership in Phamacyclics.

SAN DIEGO – A novel targeted agent was associated with high objective response rates at 10 months in patients with relapsed/refractory, heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

At 10.2 months’ median follow-up, objective responses (combined complete and partial responses) were seen in 70% of 27 CLL/SLL patients assigned to a 420-mg daily dose of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK). Objective responses were seen at 6.5 months’ follow-up in 44% of 34 patients on an 840 mg daily dose, reported Dr. Susan O’Brien, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The researchers had previously reported a 48% objective response rate at 6.2 months median follow-up.

Among patients who did not have a complete or partial response, a nodal partial response was noted in 19% of those in the 420-mg cohort and in 35% of those in the 840-mg group. A nodal partial response was defined as a reduction of greater than 50% in aggregate lymph node size, but with residual lymphocytosis.

Progression-free survival at 6 months is 92% in the 27 patients in the 420-mg cohort, and 90% in the 34 patients in the 840-mg group.

Although it’s still too early to tell which dose will be more effective, the evidence to date suggests that the 420-mg dose completely inhibits activity of the targeted kinase. Thus, the 840-mg dose may not be necessary, Dr. O'Brien said.

Further, PC-32765 does not cause myelosuppression, a trait noted with imatinib (Gleevec) and other tyrosine kinase inhibitors that are effective in other leukemia subtypes.

"This is a big deal in CLL because all of the treatments that we have are pretty much chemo-based or antibody-based treatments. The biggest complication in treating CLL with pretty much every therapy we have is myelosuppression and infection, and of course these people are [already] immune suppressed. To have an agent that’s not myelosuppressive and this effective is very exciting," she said in a briefing prior to her presentation of the results at a session on Tuesday, Dec.13.

A leukemia specialist who was not involved in the study said that the results are particularly impressive given the nature of the patient population.

Patients also tolerated the drug well. The incidence of serious adverse events potentially related to PCI-32765 was 10%. The most common adverse event was diarrhea, which was generally mild, easily controlled, and self-limited, Dr. O’Brien said.

PCI-32765 binds selectively and irreversibly to BTK, an essential element of the B-cell antigen receptor signaling pathway, thereby blocking receptor signaling, inducing cell death via apoptosis, and inhibiting cellular migration and adhesion of malignant B cells.

"To have an agent that’s not myelo-suppressive and this effective is very exciting."

The investigators enrolled both treatment-naive patients with CLL and those who had relapsed/refractory disease following at least two prior therapies, including fludarabine. The patients were treated with PCI-32765 administered daily for 28-day cycles until disease progression. Treatment-naive patients and 27 patients with relapsed/refractory disease were assigned to the 420-mg dose; 34 patients with relapsed/refractory disease were assigned to the 840-mg dose.

In all, 72% of patients had one or more poor-risk molecular features. Of this group, 31% had the 17p deletion, 33% had the 11q deletion, and 57% had IgV_H un-mutated.

Two patients dropped out of the trial because of adverse events (dose group not specified), and six patients (two in the 420-mg group, four in the 840-mg group) required a dose reduction.

The most frequently reported grade 1 or 2 adverse events were diarrhea, fatigue, nausea, and ecchymosis. Serious adverse events were reported in 38% of patients. Serious events potentially related to the drug occurred in 10% of all patients.

The investigators noted that, in a majority of patients "a characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of therapy, followed by resolution over time."

At last follow-up, 22 of 27 patients on the 420-mg dose and 28 of 34 on the 840-mg dose were still on therapy. Phase-III trials are planned.

The trial was funded by Pharmacyclics. Dr. O’Brien disclosed serving on the board of directors or advisory committee, and has received research funding from the company. All of her coauthors disclosed either receiving research funding or consulting fees from the company, or being employees and receiving equity ownership in Phamacyclics.

SAN DIEGO – A novel targeted agent was associated with high objective response rates at 10 months in patients with relapsed/refractory, heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

At 10.2 months’ median follow-up, objective responses (combined complete and partial responses) were seen in 70% of 27 CLL/SLL patients assigned to a 420-mg daily dose of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK). Objective responses were seen at 6.5 months’ follow-up in 44% of 34 patients on an 840 mg daily dose, reported Dr. Susan O’Brien, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The researchers had previously reported a 48% objective response rate at 6.2 months median follow-up.

Among patients who did not have a complete or partial response, a nodal partial response was noted in 19% of those in the 420-mg cohort and in 35% of those in the 840-mg group. A nodal partial response was defined as a reduction of greater than 50% in aggregate lymph node size, but with residual lymphocytosis.

Progression-free survival at 6 months is 92% in the 27 patients in the 420-mg cohort, and 90% in the 34 patients in the 840-mg group.

Although it’s still too early to tell which dose will be more effective, the evidence to date suggests that the 420-mg dose completely inhibits activity of the targeted kinase. Thus, the 840-mg dose may not be necessary, Dr. O'Brien said.

Further, PC-32765 does not cause myelosuppression, a trait noted with imatinib (Gleevec) and other tyrosine kinase inhibitors that are effective in other leukemia subtypes.

"This is a big deal in CLL because all of the treatments that we have are pretty much chemo-based or antibody-based treatments. The biggest complication in treating CLL with pretty much every therapy we have is myelosuppression and infection, and of course these people are [already] immune suppressed. To have an agent that’s not myelosuppressive and this effective is very exciting," she said in a briefing prior to her presentation of the results at a session on Tuesday, Dec.13.

A leukemia specialist who was not involved in the study said that the results are particularly impressive given the nature of the patient population.

Patients also tolerated the drug well. The incidence of serious adverse events potentially related to PCI-32765 was 10%. The most common adverse event was diarrhea, which was generally mild, easily controlled, and self-limited, Dr. O’Brien said.

PCI-32765 binds selectively and irreversibly to BTK, an essential element of the B-cell antigen receptor signaling pathway, thereby blocking receptor signaling, inducing cell death via apoptosis, and inhibiting cellular migration and adhesion of malignant B cells.

"To have an agent that’s not myelo-suppressive and this effective is very exciting."

The investigators enrolled both treatment-naive patients with CLL and those who had relapsed/refractory disease following at least two prior therapies, including fludarabine. The patients were treated with PCI-32765 administered daily for 28-day cycles until disease progression. Treatment-naive patients and 27 patients with relapsed/refractory disease were assigned to the 420-mg dose; 34 patients with relapsed/refractory disease were assigned to the 840-mg dose.

In all, 72% of patients had one or more poor-risk molecular features. Of this group, 31% had the 17p deletion, 33% had the 11q deletion, and 57% had IgV_H un-mutated.

Two patients dropped out of the trial because of adverse events (dose group not specified), and six patients (two in the 420-mg group, four in the 840-mg group) required a dose reduction.

The most frequently reported grade 1 or 2 adverse events were diarrhea, fatigue, nausea, and ecchymosis. Serious adverse events were reported in 38% of patients. Serious events potentially related to the drug occurred in 10% of all patients.

The investigators noted that, in a majority of patients "a characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of therapy, followed by resolution over time."

At last follow-up, 22 of 27 patients on the 420-mg dose and 28 of 34 on the 840-mg dose were still on therapy. Phase-III trials are planned.

The trial was funded by Pharmacyclics. Dr. O’Brien disclosed serving on the board of directors or advisory committee, and has received research funding from the company. All of her coauthors disclosed either receiving research funding or consulting fees from the company, or being employees and receiving equity ownership in Phamacyclics.