Experimental Ibrutinib Could Change Treatment of CLL

ATLANTA – The experimental oral therapy ibrutinib produces dramatic responses but dodges the significant toxicity seen in conventional treatments for chronic lymphocytic leukemia and small lymphocytic lymphoma.

In one of two phase II trials, the overall response rate was 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The outcome was similar in patients with high-risk relapsed or refractory disease, with the possible exception of those with chromosome 17p deletion. However, with more than half responding, these patients still do better with ibrutinib than with any other therapy explored to date, said Dr. John C. Byrd, director of hematology at Ohio State Comprehensive Cancer Center in Columbus.

"Ibrutinib offers great potential to significantly change the treatment landscape of CLL," he said at a press briefing at the annual meeting of the American Society of Hematology.

In the second trial, combining ibrutinib with the anti-CD20 antibody rituximab (Rituxan) pushed the overall response rate to 83% in high-risk CLL and SLL, said Dr. Jan A. Burger, of the University of Texas M.D. Anderson Cancer Center in Houston.

He noted that several ongoing phase III trials are underway that should accelerate the development of ibrutinib for high-risk patients, who have a high unmet need for alternative treatments.

Ibrutinib is currently not available, even under compassionate use. Despite this, the drug is generating much enthusiasm among clinicians and patients, with some traveling great distances to get into these ongoing trials despite only a 50-50 chance of receiving the drug, said press briefing moderator Dr. Claire Dearden, head of the CLL unit at the Royal Marsden NHS Foundation Trust in London.

"It’s orally active, it’s well tolerated, it’s not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.

Ibrutinib, formerly known as PCI-32765, is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK) to enter clinical development. BTK is essential for B-cell receptor signaling, chemokine-mediated migration and adhesion, and toll-like receptor signaling.

96% Survival Estimates at 22 Months

Dr. Byrd reported new and updated results from 31 patients with treatment naive CLL or SLL, 61 with relapsed or refractory disease, and 24 with high-risk relapsed or refractory disease (defined as progression within 24 months of starting a regimen containing at least a nucleoside analogue or bendamustine in combination with a monoclonal antibody or failure to respond to such a regimen).

Patients were given ibrutinib 420 mg or 840 mg daily 2 hours before food until disease progression or intolerable toxicity. Their median age was 72.

After follow-up ranging from 14.7 months to 22.1 months, complete responses occurred in 10% of treatment-naive patients and 2% of relapsed or refractory patients, Dr. Byrd said. Partial responses occurred in 58% and 68%.

At 22 months, progression-free and overall survival estimates were both 96% among previously untreated patients. To put these results in perspective, he said, that with standard cytotoxic chemotherapy, one would expect this number to be 70% or less if patients are young and 50% or less if elderly. "So these are really dramatic results," he added.

In the relapsed or refractory group, progression-free survival was 76% and overall survival 85%.

Longer follow-up is needed to determine whether the remissions are durable once ibrutinib is stopped – something currently being studied more than a decade after clinicians began using another kinase inhibitor, imatinib (Gleevec), to treat chronic myeloid leukemia, Dr. Byrd said.

He reported 3 grade 3 and no grade 4 infections in treatment-naive patients, and 26 grade 3 infections and 4 grade 4 events in relapsed/refractory patients.

Nearly All Still on Study in Combination Trial

In the second trial, 40 patients received continuous ibrutinib 420 mg daily plus weekly rituximab 365 mg/m² for 4 weeks, followed by daily ibrutinib plus monthly rituximab until month 6, followed by single-agent ibrutinib. High-risk CLL/SLL was defined as deletion 17p, TP53 mutation, deletion 11q, or less than 3 years remission after first-line chemo-immunotherapy. More than half of patients (58%) had stage IV disease.

After 3-6 months’ follow-up, there were 1 complete response, 32 partial responses, and 3 partial responses with lymphocytosis, Dr. Burger said. In all, 84% of patients experienced more than a 50% reduction in lymph node size.

At the time of the analysis, 95% of all patients and 90% with del 17p continued on therapy without disease progression.

Two patients came off study; one with pneumonia and an intracranial abscess, who died, and another who discontinued due to mucositis/ulcers after four cycles.

Severe toxicities were uncommon in both studies, particularly the considerable immunosuppression and serious infections associated with standard chemo-immunotherapy, the investigators said. The most common event was diarrhea, which was experienced by 54% of patients receiving ibrutinib monotherapy and was largely grade 1 or 2 and resolved after the first couple of cycles, Dr. Byrd said.

Other events included fatigue (29%), upper respiratory infection (29%), rash (28%), nausea (26%) and bone pain (25%). Rates were similar in the combination therapy trial, with bruising also seen in both trials

One of the ongoing phase III trials is the 350-patient RESONATE study evaluating ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL or SLL.

Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Co-authors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.

ATLANTA – The experimental oral therapy ibrutinib produces dramatic responses but dodges the significant toxicity seen in conventional treatments for chronic lymphocytic leukemia and small lymphocytic lymphoma.

In one of two phase II trials, the overall response rate was 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The outcome was similar in patients with high-risk relapsed or refractory disease, with the possible exception of those with chromosome 17p deletion. However, with more than half responding, these patients still do better with ibrutinib than with any other therapy explored to date, said Dr. John C. Byrd, director of hematology at Ohio State Comprehensive Cancer Center in Columbus.

"Ibrutinib offers great potential to significantly change the treatment landscape of CLL," he said at a press briefing at the annual meeting of the American Society of Hematology.

In the second trial, combining ibrutinib with the anti-CD20 antibody rituximab (Rituxan) pushed the overall response rate to 83% in high-risk CLL and SLL, said Dr. Jan A. Burger, of the University of Texas M.D. Anderson Cancer Center in Houston.

He noted that several ongoing phase III trials are underway that should accelerate the development of ibrutinib for high-risk patients, who have a high unmet need for alternative treatments.

Ibrutinib is currently not available, even under compassionate use. Despite this, the drug is generating much enthusiasm among clinicians and patients, with some traveling great distances to get into these ongoing trials despite only a 50-50 chance of receiving the drug, said press briefing moderator Dr. Claire Dearden, head of the CLL unit at the Royal Marsden NHS Foundation Trust in London.

"It’s orally active, it’s well tolerated, it’s not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.

Ibrutinib, formerly known as PCI-32765, is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK) to enter clinical development. BTK is essential for B-cell receptor signaling, chemokine-mediated migration and adhesion, and toll-like receptor signaling.

96% Survival Estimates at 22 Months

Dr. Byrd reported new and updated results from 31 patients with treatment naive CLL or SLL, 61 with relapsed or refractory disease, and 24 with high-risk relapsed or refractory disease (defined as progression within 24 months of starting a regimen containing at least a nucleoside analogue or bendamustine in combination with a monoclonal antibody or failure to respond to such a regimen).

Patients were given ibrutinib 420 mg or 840 mg daily 2 hours before food until disease progression or intolerable toxicity. Their median age was 72.

After follow-up ranging from 14.7 months to 22.1 months, complete responses occurred in 10% of treatment-naive patients and 2% of relapsed or refractory patients, Dr. Byrd said. Partial responses occurred in 58% and 68%.

At 22 months, progression-free and overall survival estimates were both 96% among previously untreated patients. To put these results in perspective, he said, that with standard cytotoxic chemotherapy, one would expect this number to be 70% or less if patients are young and 50% or less if elderly. "So these are really dramatic results," he added.

In the relapsed or refractory group, progression-free survival was 76% and overall survival 85%.

Longer follow-up is needed to determine whether the remissions are durable once ibrutinib is stopped – something currently being studied more than a decade after clinicians began using another kinase inhibitor, imatinib (Gleevec), to treat chronic myeloid leukemia, Dr. Byrd said.

He reported 3 grade 3 and no grade 4 infections in treatment-naive patients, and 26 grade 3 infections and 4 grade 4 events in relapsed/refractory patients.

Nearly All Still on Study in Combination Trial

In the second trial, 40 patients received continuous ibrutinib 420 mg daily plus weekly rituximab 365 mg/m² for 4 weeks, followed by daily ibrutinib plus monthly rituximab until month 6, followed by single-agent ibrutinib. High-risk CLL/SLL was defined as deletion 17p, TP53 mutation, deletion 11q, or less than 3 years remission after first-line chemo-immunotherapy. More than half of patients (58%) had stage IV disease.

After 3-6 months’ follow-up, there were 1 complete response, 32 partial responses, and 3 partial responses with lymphocytosis, Dr. Burger said. In all, 84% of patients experienced more than a 50% reduction in lymph node size.

At the time of the analysis, 95% of all patients and 90% with del 17p continued on therapy without disease progression.

Two patients came off study; one with pneumonia and an intracranial abscess, who died, and another who discontinued due to mucositis/ulcers after four cycles.

Severe toxicities were uncommon in both studies, particularly the considerable immunosuppression and serious infections associated with standard chemo-immunotherapy, the investigators said. The most common event was diarrhea, which was experienced by 54% of patients receiving ibrutinib monotherapy and was largely grade 1 or 2 and resolved after the first couple of cycles, Dr. Byrd said.

Other events included fatigue (29%), upper respiratory infection (29%), rash (28%), nausea (26%) and bone pain (25%). Rates were similar in the combination therapy trial, with bruising also seen in both trials

One of the ongoing phase III trials is the 350-patient RESONATE study evaluating ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL or SLL.

Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Co-authors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.

ATLANTA – The experimental oral therapy ibrutinib produces dramatic responses but dodges the significant toxicity seen in conventional treatments for chronic lymphocytic leukemia and small lymphocytic lymphoma.

In one of two phase II trials, the overall response rate was 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The outcome was similar in patients with high-risk relapsed or refractory disease, with the possible exception of those with chromosome 17p deletion. However, with more than half responding, these patients still do better with ibrutinib than with any other therapy explored to date, said Dr. John C. Byrd, director of hematology at Ohio State Comprehensive Cancer Center in Columbus.

"Ibrutinib offers great potential to significantly change the treatment landscape of CLL," he said at a press briefing at the annual meeting of the American Society of Hematology.

In the second trial, combining ibrutinib with the anti-CD20 antibody rituximab (Rituxan) pushed the overall response rate to 83% in high-risk CLL and SLL, said Dr. Jan A. Burger, of the University of Texas M.D. Anderson Cancer Center in Houston.

He noted that several ongoing phase III trials are underway that should accelerate the development of ibrutinib for high-risk patients, who have a high unmet need for alternative treatments.

Ibrutinib is currently not available, even under compassionate use. Despite this, the drug is generating much enthusiasm among clinicians and patients, with some traveling great distances to get into these ongoing trials despite only a 50-50 chance of receiving the drug, said press briefing moderator Dr. Claire Dearden, head of the CLL unit at the Royal Marsden NHS Foundation Trust in London.

"It’s orally active, it’s well tolerated, it’s not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.

Ibrutinib, formerly known as PCI-32765, is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK) to enter clinical development. BTK is essential for B-cell receptor signaling, chemokine-mediated migration and adhesion, and toll-like receptor signaling.

96% Survival Estimates at 22 Months

Dr. Byrd reported new and updated results from 31 patients with treatment naive CLL or SLL, 61 with relapsed or refractory disease, and 24 with high-risk relapsed or refractory disease (defined as progression within 24 months of starting a regimen containing at least a nucleoside analogue or bendamustine in combination with a monoclonal antibody or failure to respond to such a regimen).

Patients were given ibrutinib 420 mg or 840 mg daily 2 hours before food until disease progression or intolerable toxicity. Their median age was 72.

After follow-up ranging from 14.7 months to 22.1 months, complete responses occurred in 10% of treatment-naive patients and 2% of relapsed or refractory patients, Dr. Byrd said. Partial responses occurred in 58% and 68%.

At 22 months, progression-free and overall survival estimates were both 96% among previously untreated patients. To put these results in perspective, he said, that with standard cytotoxic chemotherapy, one would expect this number to be 70% or less if patients are young and 50% or less if elderly. "So these are really dramatic results," he added.

In the relapsed or refractory group, progression-free survival was 76% and overall survival 85%.

Longer follow-up is needed to determine whether the remissions are durable once ibrutinib is stopped – something currently being studied more than a decade after clinicians began using another kinase inhibitor, imatinib (Gleevec), to treat chronic myeloid leukemia, Dr. Byrd said.

He reported 3 grade 3 and no grade 4 infections in treatment-naive patients, and 26 grade 3 infections and 4 grade 4 events in relapsed/refractory patients.

Nearly All Still on Study in Combination Trial

In the second trial, 40 patients received continuous ibrutinib 420 mg daily plus weekly rituximab 365 mg/m² for 4 weeks, followed by daily ibrutinib plus monthly rituximab until month 6, followed by single-agent ibrutinib. High-risk CLL/SLL was defined as deletion 17p, TP53 mutation, deletion 11q, or less than 3 years remission after first-line chemo-immunotherapy. More than half of patients (58%) had stage IV disease.

After 3-6 months’ follow-up, there were 1 complete response, 32 partial responses, and 3 partial responses with lymphocytosis, Dr. Burger said. In all, 84% of patients experienced more than a 50% reduction in lymph node size.

At the time of the analysis, 95% of all patients and 90% with del 17p continued on therapy without disease progression.

Two patients came off study; one with pneumonia and an intracranial abscess, who died, and another who discontinued due to mucositis/ulcers after four cycles.

Severe toxicities were uncommon in both studies, particularly the considerable immunosuppression and serious infections associated with standard chemo-immunotherapy, the investigators said. The most common event was diarrhea, which was experienced by 54% of patients receiving ibrutinib monotherapy and was largely grade 1 or 2 and resolved after the first couple of cycles, Dr. Byrd said.

Other events included fatigue (29%), upper respiratory infection (29%), rash (28%), nausea (26%) and bone pain (25%). Rates were similar in the combination therapy trial, with bruising also seen in both trials

One of the ongoing phase III trials is the 350-patient RESONATE study evaluating ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL or SLL.

Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Co-authors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.