Follicular Lymphoma

 

 

Monoclonal antibodies

Credit: Linda Bartlett

 

KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).

The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.

The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.

Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.

Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.

The study is sponsored by TG Therapeutics, the company developing both drugs.

The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).

Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.

The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.

As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.

Adverse events

The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.

Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.

No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.

On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.

Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).

Activity in CLL/SLL

Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.

All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.

The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.

Activity in NHL

Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.

Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.

Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).

In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.

The RS patient also had SD following TGR-1202 and ublituximab.

“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.

“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”

 

 

Monoclonal antibodies

Credit: Linda Bartlett

 

KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).

The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.

The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.

Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.

Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.

The study is sponsored by TG Therapeutics, the company developing both drugs.

The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).

Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.

The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.

As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.

Adverse events

The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.

Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.

No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.

On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.

Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).

Activity in CLL/SLL

Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.

All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.

The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.

Activity in NHL

Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.

Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.

Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).

In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.

The RS patient also had SD following TGR-1202 and ublituximab.

“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.

“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”

 

 

Monoclonal antibodies

Credit: Linda Bartlett

 

KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).

The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.

The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.

Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.

Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.

The study is sponsored by TG Therapeutics, the company developing both drugs.

The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).

Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.

The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.

As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.

Adverse events

The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.

Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.

No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.

On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.

Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).

Activity in CLL/SLL

Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.

All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.

The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.

Activity in NHL

Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.

Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.

Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).

In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.

The RS patient also had SD following TGR-1202 and ublituximab.

“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.

“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”

 

 

Patient receiving chemotherapy

Credit: Rhoda Baer

 

Differences in treatment access and quality may explain why survival rates vary widely for European patients with hematologic malignancies, researchers have reported in The Lancet Oncology.

“The good news is that 5-year survival for most cancers of the blood has increased over the past 11 years, most likely reflecting the approval of new targeted drugs in the early 2000s . . . ,” said Milena Sant, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy.

“But there continue to be persistent differences between regions. For example, the uptake and use of new technologies and effective treatments has been far slower in eastern Europe than other regions. This might have contributed to the large differences in the management and outcomes of patients.”

Dr Sant and her colleagues uncovered these differences by analyzing data from 30 cancer registries covering all patients diagnosed in 20 European countries.*

The researchers compared changes in 5-year survival for 560,444 adults (aged 15 years and older) who were diagnosed with 11 lymphoid and myeloid cancers between 1997 and 2008, and followed up to the end of 2008.

Some cancers have shown particularly large increases in survival between 1997-1999 and 2006-2008, such as follicular lymphoma (59% to 74%), diffuse large B-cell lymphoma (42% to 55%), chronic myeloid leukemia (32% to 54%), and acute promyelocytic leukemia (50% to 62%).

The greatest improvements in survival have been in northern, central, and eastern Europe, even though adults in eastern Europe (where survival in 1997 was the lowest) continue to have lower survival for most hematologic malignancies than elsewhere.

Survival gains have been lower in southern Europe and the UK. For example, improvements in 5-year chronic myeloid leukemia survival in northern Europe (29% to 60%) and central Europe (34% to 65%) have been persistently higher than in the UK (35% to 56%) and southern Europe (37% to 55%).

Overall, the risk of death within 5 years from diagnosis fell significantly for all malignancies except myelodysplastic syndromes. But not all regions have seen such improvements.

For example, compared with the UK, the excess risk of death was significantly higher in eastern Europe than in other regions for most of the cancers investigated, but significantly lower in northern Europe.

The researchers said the most likely reasons for continuing geographical differences in survival are inequalities in the provision of care and in the availability and use of new treatments.

“We know that rituximab, imatinib, thalidomide, and bortezomib were first made available for general use in Europe in 1997, 2001, 1998, and 2003, respectively,” the researchers wrote.

“The years following general release of these drugs coincided with large increases in survival for chronic myeloid leukemia, diffuse large B-cell lymphoma, and follicular lymphoma, with a smaller but still significant survival increase for multiple myeloma plasmacytoma.”

However, they pointed out that the uptake and use of these drugs has not been uniform across Europe. For example, market uptake of rituximab, imatinib, and bortezomib was lower in eastern Europe than elsewhere and might explain the consistently lower survival in this region.

Writing in a linked comment article, Alastair Munro, MD, of the University of Dundee Medical School in Scotland, questioned whether improvements in survival can be attributed to drugs alone.

He said that better understanding of the conclusions from this study (called EUROCARE-5) requires additional information about changes affecting survival according to disease categories, the distribution of histological subtypes and their relation with the age distribution of the population, the distribution of stages at diagnosis, and the timing of active intervention for indolent tumors.

*The areas included in the study were northern Europe (Denmark, Iceland, and Norway), the UK (England, Northern Ireland, Scotland, and Wales), central Europe (Austria, France, Germany, Switzerland, and The Netherlands), eastern Europe (Bulgaria, Estonia, Lithuania, Poland, and Slovakia), and southern Europe (Italy, Malta, and Slovenia).

 

 

Patient receiving chemotherapy

Credit: Rhoda Baer

 

Differences in treatment access and quality may explain why survival rates vary widely for European patients with hematologic malignancies, researchers have reported in The Lancet Oncology.

“The good news is that 5-year survival for most cancers of the blood has increased over the past 11 years, most likely reflecting the approval of new targeted drugs in the early 2000s . . . ,” said Milena Sant, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy.

“But there continue to be persistent differences between regions. For example, the uptake and use of new technologies and effective treatments has been far slower in eastern Europe than other regions. This might have contributed to the large differences in the management and outcomes of patients.”

Dr Sant and her colleagues uncovered these differences by analyzing data from 30 cancer registries covering all patients diagnosed in 20 European countries.*

The researchers compared changes in 5-year survival for 560,444 adults (aged 15 years and older) who were diagnosed with 11 lymphoid and myeloid cancers between 1997 and 2008, and followed up to the end of 2008.

Some cancers have shown particularly large increases in survival between 1997-1999 and 2006-2008, such as follicular lymphoma (59% to 74%), diffuse large B-cell lymphoma (42% to 55%), chronic myeloid leukemia (32% to 54%), and acute promyelocytic leukemia (50% to 62%).

The greatest improvements in survival have been in northern, central, and eastern Europe, even though adults in eastern Europe (where survival in 1997 was the lowest) continue to have lower survival for most hematologic malignancies than elsewhere.

Survival gains have been lower in southern Europe and the UK. For example, improvements in 5-year chronic myeloid leukemia survival in northern Europe (29% to 60%) and central Europe (34% to 65%) have been persistently higher than in the UK (35% to 56%) and southern Europe (37% to 55%).

Overall, the risk of death within 5 years from diagnosis fell significantly for all malignancies except myelodysplastic syndromes. But not all regions have seen such improvements.

For example, compared with the UK, the excess risk of death was significantly higher in eastern Europe than in other regions for most of the cancers investigated, but significantly lower in northern Europe.

The researchers said the most likely reasons for continuing geographical differences in survival are inequalities in the provision of care and in the availability and use of new treatments.

“We know that rituximab, imatinib, thalidomide, and bortezomib were first made available for general use in Europe in 1997, 2001, 1998, and 2003, respectively,” the researchers wrote.

“The years following general release of these drugs coincided with large increases in survival for chronic myeloid leukemia, diffuse large B-cell lymphoma, and follicular lymphoma, with a smaller but still significant survival increase for multiple myeloma plasmacytoma.”

However, they pointed out that the uptake and use of these drugs has not been uniform across Europe. For example, market uptake of rituximab, imatinib, and bortezomib was lower in eastern Europe than elsewhere and might explain the consistently lower survival in this region.

Writing in a linked comment article, Alastair Munro, MD, of the University of Dundee Medical School in Scotland, questioned whether improvements in survival can be attributed to drugs alone.

He said that better understanding of the conclusions from this study (called EUROCARE-5) requires additional information about changes affecting survival according to disease categories, the distribution of histological subtypes and their relation with the age distribution of the population, the distribution of stages at diagnosis, and the timing of active intervention for indolent tumors.

*The areas included in the study were northern Europe (Denmark, Iceland, and Norway), the UK (England, Northern Ireland, Scotland, and Wales), central Europe (Austria, France, Germany, Switzerland, and The Netherlands), eastern Europe (Bulgaria, Estonia, Lithuania, Poland, and Slovakia), and southern Europe (Italy, Malta, and Slovenia).

 

 

Patient receiving chemotherapy

Credit: Rhoda Baer

 

Differences in treatment access and quality may explain why survival rates vary widely for European patients with hematologic malignancies, researchers have reported in The Lancet Oncology.

“The good news is that 5-year survival for most cancers of the blood has increased over the past 11 years, most likely reflecting the approval of new targeted drugs in the early 2000s . . . ,” said Milena Sant, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy.

“But there continue to be persistent differences between regions. For example, the uptake and use of new technologies and effective treatments has been far slower in eastern Europe than other regions. This might have contributed to the large differences in the management and outcomes of patients.”

Dr Sant and her colleagues uncovered these differences by analyzing data from 30 cancer registries covering all patients diagnosed in 20 European countries.*

The researchers compared changes in 5-year survival for 560,444 adults (aged 15 years and older) who were diagnosed with 11 lymphoid and myeloid cancers between 1997 and 2008, and followed up to the end of 2008.

Some cancers have shown particularly large increases in survival between 1997-1999 and 2006-2008, such as follicular lymphoma (59% to 74%), diffuse large B-cell lymphoma (42% to 55%), chronic myeloid leukemia (32% to 54%), and acute promyelocytic leukemia (50% to 62%).

The greatest improvements in survival have been in northern, central, and eastern Europe, even though adults in eastern Europe (where survival in 1997 was the lowest) continue to have lower survival for most hematologic malignancies than elsewhere.

Survival gains have been lower in southern Europe and the UK. For example, improvements in 5-year chronic myeloid leukemia survival in northern Europe (29% to 60%) and central Europe (34% to 65%) have been persistently higher than in the UK (35% to 56%) and southern Europe (37% to 55%).

Overall, the risk of death within 5 years from diagnosis fell significantly for all malignancies except myelodysplastic syndromes. But not all regions have seen such improvements.

For example, compared with the UK, the excess risk of death was significantly higher in eastern Europe than in other regions for most of the cancers investigated, but significantly lower in northern Europe.

The researchers said the most likely reasons for continuing geographical differences in survival are inequalities in the provision of care and in the availability and use of new treatments.

“We know that rituximab, imatinib, thalidomide, and bortezomib were first made available for general use in Europe in 1997, 2001, 1998, and 2003, respectively,” the researchers wrote.

“The years following general release of these drugs coincided with large increases in survival for chronic myeloid leukemia, diffuse large B-cell lymphoma, and follicular lymphoma, with a smaller but still significant survival increase for multiple myeloma plasmacytoma.”

However, they pointed out that the uptake and use of these drugs has not been uniform across Europe. For example, market uptake of rituximab, imatinib, and bortezomib was lower in eastern Europe than elsewhere and might explain the consistently lower survival in this region.

Writing in a linked comment article, Alastair Munro, MD, of the University of Dundee Medical School in Scotland, questioned whether improvements in survival can be attributed to drugs alone.

He said that better understanding of the conclusions from this study (called EUROCARE-5) requires additional information about changes affecting survival according to disease categories, the distribution of histological subtypes and their relation with the age distribution of the population, the distribution of stages at diagnosis, and the timing of active intervention for indolent tumors.

*The areas included in the study were northern Europe (Denmark, Iceland, and Norway), the UK (England, Northern Ireland, Scotland, and Wales), central Europe (Austria, France, Germany, Switzerland, and The Netherlands), eastern Europe (Bulgaria, Estonia, Lithuania, Poland, and Slovakia), and southern Europe (Italy, Malta, and Slovenia).

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

 

 

Farmer spraying pesticide

EPA/John Messina

 

After reviewing nearly 30 years’ worth of data, investigators have compiled a list of agricultural chemicals that appear to increase a person’s risk of developing non-Hodgkin lymphoma (NHL).

Meta-analyses suggested that occupational exposure to phenoxy herbicides, carbamate insecticides, organochlorine insecticides, and organophosphorus insecticides/herbicides can increase the risk of NHL.

The research also revealed associations between certain chemicals and specific NHL subtypes.

Leah Schinasi, PhD, and Maria E. Leon, PhD, of the International Agency for Research on Cancer in Lyon, France, described the analysis and its results in the International Journal of Environmental Research and Public Health.

The investigators reviewed epidemiological research spanning nearly 30 years and identified 44 relevant papers. The papers recounted studies conducted in the US, Canada, Europe, Australia, and New Zealand.

Drs Schinasi and Leon used these data to assess occupational exposure to 80 active ingredients and 21 chemical groups and clarify their role in the development of NHL. Most, but not all, of the studies looked at lifetime exposure to the chemicals in question.

The investigators performed a meta-analysis of the data and found associations between NHL and a range of insecticides and herbicides. But the strongest risk ratios (RRs) were for subtypes of NHL.

There was a positive association between exposure to the organophosphorus herbicide glyphosate and any NHL (RR=1.5), but the link was stronger for B-cell lymphoma in particular (RR=2.0).

Phenoxy herbicide exposure was associated with an increased risk of NHL in general (RR=1.4), B-cell lymphoma (RR=1.8), lymphocytic lymphoma (RR=1.8), and diffuse large B-cell lymphoma (RR=2.0). As for specific phenoxy herbicides, both MCPA (RR=1.5) and 2,4-D (RR=1.4) were associated with NHL.

Carbamate insecticides, as a group, appeared to confer an increased risk of NHL (RR=1.7). The individual insecticides carbaryl and carbofuran showed positive associations with NHL as well (RRs of 1.7 and 1.6, respectively).

There was a positive association with NHL for organophosphorus insecticides as a group (RR=1.6), as well as the individual insecticides chlorpyrifos (RR=1.6), diazinon (RR=1.6), dimethoate (RR=1.4), and malathion (RR=1.8).

Lastly, organochlorine insecticides appeared to confer an increased risk of NHL (RR=1.3). DDT was associated with NHL (RR=1.3), B-cell lymphoma (RR=1.4), diffuse large B-cell lymphoma (RR=1.2), and follicular lymphoma (RR=1.5). And lindane was associated with NHL in general (RR=1.6).

The investigators said this analysis represents one of the most comprehensive reviews on the topic of occupational exposure to agricultural chemicals in the scientific literature.

But it also suggests a need to study a wider variety of chemicals in more geographic areas, especially in low- and middle-income countries, as they were missing from the literature.

 

 

Farmer spraying pesticide

EPA/John Messina

 

After reviewing nearly 30 years’ worth of data, investigators have compiled a list of agricultural chemicals that appear to increase a person’s risk of developing non-Hodgkin lymphoma (NHL).

Meta-analyses suggested that occupational exposure to phenoxy herbicides, carbamate insecticides, organochlorine insecticides, and organophosphorus insecticides/herbicides can increase the risk of NHL.

The research also revealed associations between certain chemicals and specific NHL subtypes.

Leah Schinasi, PhD, and Maria E. Leon, PhD, of the International Agency for Research on Cancer in Lyon, France, described the analysis and its results in the International Journal of Environmental Research and Public Health.

The investigators reviewed epidemiological research spanning nearly 30 years and identified 44 relevant papers. The papers recounted studies conducted in the US, Canada, Europe, Australia, and New Zealand.

Drs Schinasi and Leon used these data to assess occupational exposure to 80 active ingredients and 21 chemical groups and clarify their role in the development of NHL. Most, but not all, of the studies looked at lifetime exposure to the chemicals in question.

The investigators performed a meta-analysis of the data and found associations between NHL and a range of insecticides and herbicides. But the strongest risk ratios (RRs) were for subtypes of NHL.

There was a positive association between exposure to the organophosphorus herbicide glyphosate and any NHL (RR=1.5), but the link was stronger for B-cell lymphoma in particular (RR=2.0).

Phenoxy herbicide exposure was associated with an increased risk of NHL in general (RR=1.4), B-cell lymphoma (RR=1.8), lymphocytic lymphoma (RR=1.8), and diffuse large B-cell lymphoma (RR=2.0). As for specific phenoxy herbicides, both MCPA (RR=1.5) and 2,4-D (RR=1.4) were associated with NHL.

Carbamate insecticides, as a group, appeared to confer an increased risk of NHL (RR=1.7). The individual insecticides carbaryl and carbofuran showed positive associations with NHL as well (RRs of 1.7 and 1.6, respectively).

There was a positive association with NHL for organophosphorus insecticides as a group (RR=1.6), as well as the individual insecticides chlorpyrifos (RR=1.6), diazinon (RR=1.6), dimethoate (RR=1.4), and malathion (RR=1.8).

Lastly, organochlorine insecticides appeared to confer an increased risk of NHL (RR=1.3). DDT was associated with NHL (RR=1.3), B-cell lymphoma (RR=1.4), diffuse large B-cell lymphoma (RR=1.2), and follicular lymphoma (RR=1.5). And lindane was associated with NHL in general (RR=1.6).

The investigators said this analysis represents one of the most comprehensive reviews on the topic of occupational exposure to agricultural chemicals in the scientific literature.

But it also suggests a need to study a wider variety of chemicals in more geographic areas, especially in low- and middle-income countries, as they were missing from the literature.

 

 

Farmer spraying pesticide

EPA/John Messina

 

After reviewing nearly 30 years’ worth of data, investigators have compiled a list of agricultural chemicals that appear to increase a person’s risk of developing non-Hodgkin lymphoma (NHL).

Meta-analyses suggested that occupational exposure to phenoxy herbicides, carbamate insecticides, organochlorine insecticides, and organophosphorus insecticides/herbicides can increase the risk of NHL.

The research also revealed associations between certain chemicals and specific NHL subtypes.

Leah Schinasi, PhD, and Maria E. Leon, PhD, of the International Agency for Research on Cancer in Lyon, France, described the analysis and its results in the International Journal of Environmental Research and Public Health.

The investigators reviewed epidemiological research spanning nearly 30 years and identified 44 relevant papers. The papers recounted studies conducted in the US, Canada, Europe, Australia, and New Zealand.

Drs Schinasi and Leon used these data to assess occupational exposure to 80 active ingredients and 21 chemical groups and clarify their role in the development of NHL. Most, but not all, of the studies looked at lifetime exposure to the chemicals in question.

The investigators performed a meta-analysis of the data and found associations between NHL and a range of insecticides and herbicides. But the strongest risk ratios (RRs) were for subtypes of NHL.

There was a positive association between exposure to the organophosphorus herbicide glyphosate and any NHL (RR=1.5), but the link was stronger for B-cell lymphoma in particular (RR=2.0).

Phenoxy herbicide exposure was associated with an increased risk of NHL in general (RR=1.4), B-cell lymphoma (RR=1.8), lymphocytic lymphoma (RR=1.8), and diffuse large B-cell lymphoma (RR=2.0). As for specific phenoxy herbicides, both MCPA (RR=1.5) and 2,4-D (RR=1.4) were associated with NHL.

Carbamate insecticides, as a group, appeared to confer an increased risk of NHL (RR=1.7). The individual insecticides carbaryl and carbofuran showed positive associations with NHL as well (RRs of 1.7 and 1.6, respectively).

There was a positive association with NHL for organophosphorus insecticides as a group (RR=1.6), as well as the individual insecticides chlorpyrifos (RR=1.6), diazinon (RR=1.6), dimethoate (RR=1.4), and malathion (RR=1.8).

Lastly, organochlorine insecticides appeared to confer an increased risk of NHL (RR=1.3). DDT was associated with NHL (RR=1.3), B-cell lymphoma (RR=1.4), diffuse large B-cell lymphoma (RR=1.2), and follicular lymphoma (RR=1.5). And lindane was associated with NHL in general (RR=1.6).

The investigators said this analysis represents one of the most comprehensive reviews on the topic of occupational exposure to agricultural chemicals in the scientific literature.

But it also suggests a need to study a wider variety of chemicals in more geographic areas, especially in low- and middle-income countries, as they were missing from the literature.

 

 

Syringe

 

The European Commission (EC) has approved a subcutaneous (SC) formulation of rituximab (MabThera) to treat patients with follicular lymphoma or diffuse large B-cell lymphoma.

This formulation allows for 5-minute administration, a significant decrease over the 2.5-hour infusion time required to administer intravenous (IV) rituximab.

The drug’s maker, Roche, plans to begin launching SC rituximab in a number of European markets this year.

The EC’s approval of this formulation was primarily based on data from the SABRINA trial, which was recently published in The Lancet Oncology and funded by Roche.

In this phase 3 trial, researchers compared 3-week cycles of fixed-dose, SC rituximab to IV rituximab. They enrolled 127 patients with previously untreated, grade 1-3a, CD20-positive follicular lymphoma.

Patients were randomized to receive IV rituximab (375 mg/m²) or SC rituximab (1400 mg). After randomization, they received 1 induction dose of IV rituximab in cycle 1 and then their allocated treatment for cycles 2 through 8. Patients with a complete or partial response continued their treatment as maintenance every 8 weeks.

The study’s primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the 2 groups at cycle 7.

Pharmacokinetic data were available for 75% of patients (48/64) in the IV arm and 86% of the patients (54/63) in the SC arm.

An analysis of these data suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio, 1.62).

The rate of adverse events was similar between the 2 arms, occurring in 88% (57/65) of patients in the IV arm and 92% (57/62) of patients in the SC arm. Grade 3 or higher adverse events occurred in 46% (n=30) and 47% (n=29) of patients, respectively.

The most common grade 3 or higher adverse event in both arms was neutropenia. It occurred in 22% (n=14) of patients in the IV arm and 26% (n=16) in the SC arm.

Adverse events related to administration were mostly grade 1-2. And they occurred more often in the SC arm than in the IV arm, in 50% (n=31) and 32% (n=21) of patients, respectively.

The researchers said these results suggest the SC formulation of rituximab is non-inferior to the IV formulation and poses no new safety concerns.

 

 

Syringe

 

The European Commission (EC) has approved a subcutaneous (SC) formulation of rituximab (MabThera) to treat patients with follicular lymphoma or diffuse large B-cell lymphoma.

This formulation allows for 5-minute administration, a significant decrease over the 2.5-hour infusion time required to administer intravenous (IV) rituximab.

The drug’s maker, Roche, plans to begin launching SC rituximab in a number of European markets this year.

The EC’s approval of this formulation was primarily based on data from the SABRINA trial, which was recently published in The Lancet Oncology and funded by Roche.

In this phase 3 trial, researchers compared 3-week cycles of fixed-dose, SC rituximab to IV rituximab. They enrolled 127 patients with previously untreated, grade 1-3a, CD20-positive follicular lymphoma.

Patients were randomized to receive IV rituximab (375 mg/m²) or SC rituximab (1400 mg). After randomization, they received 1 induction dose of IV rituximab in cycle 1 and then their allocated treatment for cycles 2 through 8. Patients with a complete or partial response continued their treatment as maintenance every 8 weeks.

The study’s primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the 2 groups at cycle 7.

Pharmacokinetic data were available for 75% of patients (48/64) in the IV arm and 86% of the patients (54/63) in the SC arm.

An analysis of these data suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio, 1.62).

The rate of adverse events was similar between the 2 arms, occurring in 88% (57/65) of patients in the IV arm and 92% (57/62) of patients in the SC arm. Grade 3 or higher adverse events occurred in 46% (n=30) and 47% (n=29) of patients, respectively.

The most common grade 3 or higher adverse event in both arms was neutropenia. It occurred in 22% (n=14) of patients in the IV arm and 26% (n=16) in the SC arm.

Adverse events related to administration were mostly grade 1-2. And they occurred more often in the SC arm than in the IV arm, in 50% (n=31) and 32% (n=21) of patients, respectively.

The researchers said these results suggest the SC formulation of rituximab is non-inferior to the IV formulation and poses no new safety concerns.

 

 

Syringe

 

The European Commission (EC) has approved a subcutaneous (SC) formulation of rituximab (MabThera) to treat patients with follicular lymphoma or diffuse large B-cell lymphoma.

This formulation allows for 5-minute administration, a significant decrease over the 2.5-hour infusion time required to administer intravenous (IV) rituximab.

The drug’s maker, Roche, plans to begin launching SC rituximab in a number of European markets this year.

The EC’s approval of this formulation was primarily based on data from the SABRINA trial, which was recently published in The Lancet Oncology and funded by Roche.

In this phase 3 trial, researchers compared 3-week cycles of fixed-dose, SC rituximab to IV rituximab. They enrolled 127 patients with previously untreated, grade 1-3a, CD20-positive follicular lymphoma.

Patients were randomized to receive IV rituximab (375 mg/m²) or SC rituximab (1400 mg). After randomization, they received 1 induction dose of IV rituximab in cycle 1 and then their allocated treatment for cycles 2 through 8. Patients with a complete or partial response continued their treatment as maintenance every 8 weeks.

The study’s primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the 2 groups at cycle 7.

Pharmacokinetic data were available for 75% of patients (48/64) in the IV arm and 86% of the patients (54/63) in the SC arm.

An analysis of these data suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio, 1.62).

The rate of adverse events was similar between the 2 arms, occurring in 88% (57/65) of patients in the IV arm and 92% (57/62) of patients in the SC arm. Grade 3 or higher adverse events occurred in 46% (n=30) and 47% (n=29) of patients, respectively.

The most common grade 3 or higher adverse event in both arms was neutropenia. It occurred in 22% (n=14) of patients in the IV arm and 26% (n=16) in the SC arm.

Adverse events related to administration were mostly grade 1-2. And they occurred more often in the SC arm than in the IV arm, in 50% (n=31) and 32% (n=21) of patients, respectively.

The researchers said these results suggest the SC formulation of rituximab is non-inferior to the IV formulation and poses no new safety concerns.

 

 

Micrograph showing FL

 

Single-agent treatment with the HDAC inhibitor vorinostat can be effective in certain patients with indolent non-Hodgkin lymphoma (NHL), according to research published in the British Journal of Haematology.

In the phase 2 study, vorinostat prompted a 49% overall response rate among 39 patients with relapsed or refractory follicular lymphoma (FL).

However, none of the 4 patients with previously treated mantle cell lymphoma (MCL) achieved a response.

Michinori Ogura, MD, PhD, of Nagoya Daini Red Cross Hospital in Japan, and his colleagues set out to analyze the effects of vorinostat in 56 patients with indolent NHL. Six patients were excluded from the final analysis, as their diseases could not be classified.

Thirty-nine patients had FL, 4 had extranodal marginal zone lymphoma (MZL) of MALT type, 4 had MCL, 2 had small B-cell lymphoma not otherwise specified (NOS), and 1 had small lymphocytic lymphoma.

The median age was 60 years (range, 33-75), and the median number of prior therapies was 2 (range, 1-4). These therapies included rituximab (n=40), alkylating agents (n=7), purine analogs (n=5), and radioimmunotherapy (n=3).

The patients received vorinostat for a median of 8 months. The planned dosage was 200 mg twice daily for 14 consecutive days in a 21-day cycle.

At the first data cutoff point (1 year from the last patient’s enrollment), 18 patients remained on treatment. Thirty-eight had discontinued due to disease progression (n=25), drug-related adverse events (n=9), or withdrawn consent (n=4).

The overall response rate was 49% among FL patients. Ten percent (n=4) achieved a complete response, 8% (n=3) achieved an unconfirmed complete response, and 31% (n=12) achieved a partial response.

None of the patients with MCL responded, but 3 of the 7 (43%) patients with other indolent NHLs achieved a response.

That included 2 patients with small B-cell lymphoma NOS and 1 with extranodal MZL of MALT type. One of the patients with small B-cell lymphoma NOS achieved a complete response.

Approximately 81% of all 56 patients remained alive at 2 years after the last patients had enrolled (the second data cutoff point).

At that point, the median overall survival had not been reached. And the median progression-free survival was 26 months among the FL patients who responded.

There were no treatment-related deaths. The most common drug-related events (in all 56 patients) were thrombocytopenia (93%), diarrhea (68%), neutropenia (68%), decreased appetite (63%), nausea (61%), leukopenia (55%), and fatigue (52%).

Eighty percent of patients (n=45) experienced grade 3/4 adverse events, the most common of which were thrombocytopenia (23% grade 3; 25% grade 4) and neutropenia (36% grade 3; 5% grade 4).

However, all of the patients with thrombocytopenia or neutropenia recovered after they received adequate supportive care and their vorinostat dose was reduced or treatment was interrupted or discontinued.

Taking these results together, the researchers concluded that vorinostat offers sustained antitumor activity and has an acceptable safety profile for patients with relapsed or refractory FL. The team noted, however, that because this was a single-arm study with limited data, a comparative study is needed.

 

 

Micrograph showing FL

 

Single-agent treatment with the HDAC inhibitor vorinostat can be effective in certain patients with indolent non-Hodgkin lymphoma (NHL), according to research published in the British Journal of Haematology.

In the phase 2 study, vorinostat prompted a 49% overall response rate among 39 patients with relapsed or refractory follicular lymphoma (FL).

However, none of the 4 patients with previously treated mantle cell lymphoma (MCL) achieved a response.

Michinori Ogura, MD, PhD, of Nagoya Daini Red Cross Hospital in Japan, and his colleagues set out to analyze the effects of vorinostat in 56 patients with indolent NHL. Six patients were excluded from the final analysis, as their diseases could not be classified.

Thirty-nine patients had FL, 4 had extranodal marginal zone lymphoma (MZL) of MALT type, 4 had MCL, 2 had small B-cell lymphoma not otherwise specified (NOS), and 1 had small lymphocytic lymphoma.

The median age was 60 years (range, 33-75), and the median number of prior therapies was 2 (range, 1-4). These therapies included rituximab (n=40), alkylating agents (n=7), purine analogs (n=5), and radioimmunotherapy (n=3).

The patients received vorinostat for a median of 8 months. The planned dosage was 200 mg twice daily for 14 consecutive days in a 21-day cycle.

At the first data cutoff point (1 year from the last patient’s enrollment), 18 patients remained on treatment. Thirty-eight had discontinued due to disease progression (n=25), drug-related adverse events (n=9), or withdrawn consent (n=4).

The overall response rate was 49% among FL patients. Ten percent (n=4) achieved a complete response, 8% (n=3) achieved an unconfirmed complete response, and 31% (n=12) achieved a partial response.

None of the patients with MCL responded, but 3 of the 7 (43%) patients with other indolent NHLs achieved a response.

That included 2 patients with small B-cell lymphoma NOS and 1 with extranodal MZL of MALT type. One of the patients with small B-cell lymphoma NOS achieved a complete response.

Approximately 81% of all 56 patients remained alive at 2 years after the last patients had enrolled (the second data cutoff point).

At that point, the median overall survival had not been reached. And the median progression-free survival was 26 months among the FL patients who responded.

There were no treatment-related deaths. The most common drug-related events (in all 56 patients) were thrombocytopenia (93%), diarrhea (68%), neutropenia (68%), decreased appetite (63%), nausea (61%), leukopenia (55%), and fatigue (52%).

Eighty percent of patients (n=45) experienced grade 3/4 adverse events, the most common of which were thrombocytopenia (23% grade 3; 25% grade 4) and neutropenia (36% grade 3; 5% grade 4).

However, all of the patients with thrombocytopenia or neutropenia recovered after they received adequate supportive care and their vorinostat dose was reduced or treatment was interrupted or discontinued.

Taking these results together, the researchers concluded that vorinostat offers sustained antitumor activity and has an acceptable safety profile for patients with relapsed or refractory FL. The team noted, however, that because this was a single-arm study with limited data, a comparative study is needed.

 

 

Micrograph showing FL

 

Single-agent treatment with the HDAC inhibitor vorinostat can be effective in certain patients with indolent non-Hodgkin lymphoma (NHL), according to research published in the British Journal of Haematology.

In the phase 2 study, vorinostat prompted a 49% overall response rate among 39 patients with relapsed or refractory follicular lymphoma (FL).

However, none of the 4 patients with previously treated mantle cell lymphoma (MCL) achieved a response.

Michinori Ogura, MD, PhD, of Nagoya Daini Red Cross Hospital in Japan, and his colleagues set out to analyze the effects of vorinostat in 56 patients with indolent NHL. Six patients were excluded from the final analysis, as their diseases could not be classified.

Thirty-nine patients had FL, 4 had extranodal marginal zone lymphoma (MZL) of MALT type, 4 had MCL, 2 had small B-cell lymphoma not otherwise specified (NOS), and 1 had small lymphocytic lymphoma.

The median age was 60 years (range, 33-75), and the median number of prior therapies was 2 (range, 1-4). These therapies included rituximab (n=40), alkylating agents (n=7), purine analogs (n=5), and radioimmunotherapy (n=3).

The patients received vorinostat for a median of 8 months. The planned dosage was 200 mg twice daily for 14 consecutive days in a 21-day cycle.

At the first data cutoff point (1 year from the last patient’s enrollment), 18 patients remained on treatment. Thirty-eight had discontinued due to disease progression (n=25), drug-related adverse events (n=9), or withdrawn consent (n=4).

The overall response rate was 49% among FL patients. Ten percent (n=4) achieved a complete response, 8% (n=3) achieved an unconfirmed complete response, and 31% (n=12) achieved a partial response.

None of the patients with MCL responded, but 3 of the 7 (43%) patients with other indolent NHLs achieved a response.

That included 2 patients with small B-cell lymphoma NOS and 1 with extranodal MZL of MALT type. One of the patients with small B-cell lymphoma NOS achieved a complete response.

Approximately 81% of all 56 patients remained alive at 2 years after the last patients had enrolled (the second data cutoff point).

At that point, the median overall survival had not been reached. And the median progression-free survival was 26 months among the FL patients who responded.

There were no treatment-related deaths. The most common drug-related events (in all 56 patients) were thrombocytopenia (93%), diarrhea (68%), neutropenia (68%), decreased appetite (63%), nausea (61%), leukopenia (55%), and fatigue (52%).

Eighty percent of patients (n=45) experienced grade 3/4 adverse events, the most common of which were thrombocytopenia (23% grade 3; 25% grade 4) and neutropenia (36% grade 3; 5% grade 4).

However, all of the patients with thrombocytopenia or neutropenia recovered after they received adequate supportive care and their vorinostat dose was reduced or treatment was interrupted or discontinued.

Taking these results together, the researchers concluded that vorinostat offers sustained antitumor activity and has an acceptable safety profile for patients with relapsed or refractory FL. The team noted, however, that because this was a single-arm study with limited data, a comparative study is needed.

 

 

Lab mouse

 

Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.

Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.

The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.

The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.

The research was published in The Journal of Clinical Investigation.

“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.

“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”

Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.

The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.

“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”

“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”

Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.

To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.

They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.

On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.

According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.

 

 

Lab mouse

 

Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.

Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.

The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.

The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.

The research was published in The Journal of Clinical Investigation.

“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.

“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”

Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.

The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.

“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”

“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”

Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.

To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.

They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.

On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.

According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.

 

 

Lab mouse

 

Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.

Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.

The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.

The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.

The research was published in The Journal of Clinical Investigation.

“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.

“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”

Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.

The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.

“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”

“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”

Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.

To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.

They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.

On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.

According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.

 

 

Pill production

Credit: FDA

 

Results of a phase 1 study suggest the PI3K delta inhibitor idelalisib can produce durable responses in certain patients with relapsed or refractory disease.

The drug elicited a response rate of 72% in patients with chronic lymphocytic leukemia (CLL), 47% in indolent non-Hodgkin lymphoma (iNHL), and 40% in mantle cell lymphoma(MCL).

The median duration of response was 16.2 months among CLL patients, 18.4 months among iNHL patients, and 2.7 months among those with MCL.

“Considering the high number of previous therapies that these patients had received, higher than we sometimes see in comparable studies, the efficacy of idelalisib that we observed was remarkable,” said study author Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

In 3 papers published in Blood, Dr Flinn and his colleagues presented data from this phase 1 study of idelalisib. After an initial study involving all trial participants, the patients were separated into CLL, iNHL, and MCL disease cohorts.

Solid survival rates in CLL

The researchers evaluated idelalisib in 54 patients with relapsed or refractory CLL. The patients had received a median of 5 prior treatments (range, 2-14).

They had a median age of 63 years (range 37-82), 80% had bulky lymphadenopathy, 70% had treatment-refractory disease, 91% had unmutated IGHV, and 24% had del17p and/or TP53 mutation.

In the primary study, the patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for 48 weeks. If they continued to derive clinical benefit, patients could continue treatment on an extension study.

Fifty-four percent of patients discontinued treatment during the primary study period. Twenty-eight percent stopped because of disease progression, 9% due to adverse events (AEs), and 6% due to early deaths resulting from AEs.

Grade 3 or higher AEs included pneumonia (20%), neutropenic fever (11%), diarrhea (6%), pyrexia (4%), cough (4%), and fatigue (2%). Common grade 3 or higher lab abnormalities included neutropenia (43%), anemia (11%), and thrombocytopenia (17%).

The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 criteria and 33% meeting the criteria of partial response in the presence of treatment-induced lymphocytosis.

The median duration of response was 16.2 months, the median progression-free survival (PFS) was 15.8 months, and the median overall survival was not reached.

Longer response duration in iNHL

The researchers evaluated idelalisib in 64 patients with iNHL. Lymphoma types included follicular lymphoma (59%), small lymphocytic lymphoma (17%), marginal zone lymphoma (9%), and lymphoplasmacytic lymphoma (14%).

Patients had a median age of 64 years (range, 32-91), 53% had bulky disease, and 58% had refractory disease. They had received a median of 4 prior therapies (range, 1-10).

The patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily. After 48 weeks, patients still benefitting from treatment (30%) were enrolled in an extension study.

The remaining 70% of patients discontinued treatment during the primary study. Nineteen percent of these patients discontinued due to AEs.

Grade 3 or higher AEs included pneumonia (17%), diarrhea (9%), peripheral edema (3%), fatigue (3%), rash (3%), pyrexia (3%), nausea (2%), and cough (2%). Grade 3 or higher lab abnormalities included AST elevation (20%), ALT elevation (23%), neutropenia (23%), thrombocytopenia (11%), and anemia (5%).

The overall response rate was 47%, with 1 patient (1.6%) achieving a complete response. The median duration of response was 18.4 months, and the median PFS was 7.6 months.

Short response, survival duration in MCL

The researchers evaluated idelalisib in 40 patients with relapsed or refractory MCL. The median age was 69 years (range, 52-83). Patients had received a median of 4 prior therapies (range, 1-14), and 43% were refractory to their most recent treatment.

Patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for a median of 3.5 months (range, 0.7-30.7). Six patients (15%) continued treatment for more than 48 weeks, although only 1 patient remains on treatment at present.

The 34 patients who discontinued the primary study did so because of progressive disease (60%), AEs (20%), withdrawn consent (3%), or investigator request (3%). Of the 6 patients who entered the extension trial, 4 ultimately discontinued due to progressive disease and 1 due to AEs.

Grade 3 or higher AEs included diarrhea (18%), decreased appetite (15%), pneumonia (10%), nausea (5%), fatigue (3%), and rash (3%). Grade 3 or higher lab abnormalities included ALT/AST elevations (20%), neutropenia (10%), thrombocytopenia (5%), and anemia (3%).

The overall response rate was 40%, with 5% of patients achieving a complete response. The median duration of response was 2.7 months, and the median PFS was 3.7 months.

Despite the modest duration of survival observed in these patients, the researchers believe the strong initial response to idelalisib suggests the drug could still prove useful in patients with MCL.

“[I]delalisib is unlikely to receive designation as a single-agent therapy in mantle cell lymphoma due to the short duration of response,” said study author Brad S. Kahl, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“The path forward will likely include administering it in combination with other agents or developing second-generation PI3 kinase inhibitors.”

 

 

Pill production

Credit: FDA

 

Results of a phase 1 study suggest the PI3K delta inhibitor idelalisib can produce durable responses in certain patients with relapsed or refractory disease.

The drug elicited a response rate of 72% in patients with chronic lymphocytic leukemia (CLL), 47% in indolent non-Hodgkin lymphoma (iNHL), and 40% in mantle cell lymphoma(MCL).

The median duration of response was 16.2 months among CLL patients, 18.4 months among iNHL patients, and 2.7 months among those with MCL.

“Considering the high number of previous therapies that these patients had received, higher than we sometimes see in comparable studies, the efficacy of idelalisib that we observed was remarkable,” said study author Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

In 3 papers published in Blood, Dr Flinn and his colleagues presented data from this phase 1 study of idelalisib. After an initial study involving all trial participants, the patients were separated into CLL, iNHL, and MCL disease cohorts.

Solid survival rates in CLL

The researchers evaluated idelalisib in 54 patients with relapsed or refractory CLL. The patients had received a median of 5 prior treatments (range, 2-14).

They had a median age of 63 years (range 37-82), 80% had bulky lymphadenopathy, 70% had treatment-refractory disease, 91% had unmutated IGHV, and 24% had del17p and/or TP53 mutation.

In the primary study, the patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for 48 weeks. If they continued to derive clinical benefit, patients could continue treatment on an extension study.

Fifty-four percent of patients discontinued treatment during the primary study period. Twenty-eight percent stopped because of disease progression, 9% due to adverse events (AEs), and 6% due to early deaths resulting from AEs.

Grade 3 or higher AEs included pneumonia (20%), neutropenic fever (11%), diarrhea (6%), pyrexia (4%), cough (4%), and fatigue (2%). Common grade 3 or higher lab abnormalities included neutropenia (43%), anemia (11%), and thrombocytopenia (17%).

The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 criteria and 33% meeting the criteria of partial response in the presence of treatment-induced lymphocytosis.

The median duration of response was 16.2 months, the median progression-free survival (PFS) was 15.8 months, and the median overall survival was not reached.

Longer response duration in iNHL

The researchers evaluated idelalisib in 64 patients with iNHL. Lymphoma types included follicular lymphoma (59%), small lymphocytic lymphoma (17%), marginal zone lymphoma (9%), and lymphoplasmacytic lymphoma (14%).

Patients had a median age of 64 years (range, 32-91), 53% had bulky disease, and 58% had refractory disease. They had received a median of 4 prior therapies (range, 1-10).

The patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily. After 48 weeks, patients still benefitting from treatment (30%) were enrolled in an extension study.

The remaining 70% of patients discontinued treatment during the primary study. Nineteen percent of these patients discontinued due to AEs.

Grade 3 or higher AEs included pneumonia (17%), diarrhea (9%), peripheral edema (3%), fatigue (3%), rash (3%), pyrexia (3%), nausea (2%), and cough (2%). Grade 3 or higher lab abnormalities included AST elevation (20%), ALT elevation (23%), neutropenia (23%), thrombocytopenia (11%), and anemia (5%).

The overall response rate was 47%, with 1 patient (1.6%) achieving a complete response. The median duration of response was 18.4 months, and the median PFS was 7.6 months.

Short response, survival duration in MCL

The researchers evaluated idelalisib in 40 patients with relapsed or refractory MCL. The median age was 69 years (range, 52-83). Patients had received a median of 4 prior therapies (range, 1-14), and 43% were refractory to their most recent treatment.

Patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for a median of 3.5 months (range, 0.7-30.7). Six patients (15%) continued treatment for more than 48 weeks, although only 1 patient remains on treatment at present.

The 34 patients who discontinued the primary study did so because of progressive disease (60%), AEs (20%), withdrawn consent (3%), or investigator request (3%). Of the 6 patients who entered the extension trial, 4 ultimately discontinued due to progressive disease and 1 due to AEs.

Grade 3 or higher AEs included diarrhea (18%), decreased appetite (15%), pneumonia (10%), nausea (5%), fatigue (3%), and rash (3%). Grade 3 or higher lab abnormalities included ALT/AST elevations (20%), neutropenia (10%), thrombocytopenia (5%), and anemia (3%).

The overall response rate was 40%, with 5% of patients achieving a complete response. The median duration of response was 2.7 months, and the median PFS was 3.7 months.

Despite the modest duration of survival observed in these patients, the researchers believe the strong initial response to idelalisib suggests the drug could still prove useful in patients with MCL.

“[I]delalisib is unlikely to receive designation as a single-agent therapy in mantle cell lymphoma due to the short duration of response,” said study author Brad S. Kahl, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“The path forward will likely include administering it in combination with other agents or developing second-generation PI3 kinase inhibitors.”

 

 

Pill production

Credit: FDA

 

Results of a phase 1 study suggest the PI3K delta inhibitor idelalisib can produce durable responses in certain patients with relapsed or refractory disease.

The drug elicited a response rate of 72% in patients with chronic lymphocytic leukemia (CLL), 47% in indolent non-Hodgkin lymphoma (iNHL), and 40% in mantle cell lymphoma(MCL).

The median duration of response was 16.2 months among CLL patients, 18.4 months among iNHL patients, and 2.7 months among those with MCL.

“Considering the high number of previous therapies that these patients had received, higher than we sometimes see in comparable studies, the efficacy of idelalisib that we observed was remarkable,” said study author Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

In 3 papers published in Blood, Dr Flinn and his colleagues presented data from this phase 1 study of idelalisib. After an initial study involving all trial participants, the patients were separated into CLL, iNHL, and MCL disease cohorts.

Solid survival rates in CLL

The researchers evaluated idelalisib in 54 patients with relapsed or refractory CLL. The patients had received a median of 5 prior treatments (range, 2-14).

They had a median age of 63 years (range 37-82), 80% had bulky lymphadenopathy, 70% had treatment-refractory disease, 91% had unmutated IGHV, and 24% had del17p and/or TP53 mutation.

In the primary study, the patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for 48 weeks. If they continued to derive clinical benefit, patients could continue treatment on an extension study.

Fifty-four percent of patients discontinued treatment during the primary study period. Twenty-eight percent stopped because of disease progression, 9% due to adverse events (AEs), and 6% due to early deaths resulting from AEs.

Grade 3 or higher AEs included pneumonia (20%), neutropenic fever (11%), diarrhea (6%), pyrexia (4%), cough (4%), and fatigue (2%). Common grade 3 or higher lab abnormalities included neutropenia (43%), anemia (11%), and thrombocytopenia (17%).

The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 criteria and 33% meeting the criteria of partial response in the presence of treatment-induced lymphocytosis.

The median duration of response was 16.2 months, the median progression-free survival (PFS) was 15.8 months, and the median overall survival was not reached.

Longer response duration in iNHL

The researchers evaluated idelalisib in 64 patients with iNHL. Lymphoma types included follicular lymphoma (59%), small lymphocytic lymphoma (17%), marginal zone lymphoma (9%), and lymphoplasmacytic lymphoma (14%).

Patients had a median age of 64 years (range, 32-91), 53% had bulky disease, and 58% had refractory disease. They had received a median of 4 prior therapies (range, 1-10).

The patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily. After 48 weeks, patients still benefitting from treatment (30%) were enrolled in an extension study.

The remaining 70% of patients discontinued treatment during the primary study. Nineteen percent of these patients discontinued due to AEs.

Grade 3 or higher AEs included pneumonia (17%), diarrhea (9%), peripheral edema (3%), fatigue (3%), rash (3%), pyrexia (3%), nausea (2%), and cough (2%). Grade 3 or higher lab abnormalities included AST elevation (20%), ALT elevation (23%), neutropenia (23%), thrombocytopenia (11%), and anemia (5%).

The overall response rate was 47%, with 1 patient (1.6%) achieving a complete response. The median duration of response was 18.4 months, and the median PFS was 7.6 months.

Short response, survival duration in MCL

The researchers evaluated idelalisib in 40 patients with relapsed or refractory MCL. The median age was 69 years (range, 52-83). Patients had received a median of 4 prior therapies (range, 1-14), and 43% were refractory to their most recent treatment.

Patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for a median of 3.5 months (range, 0.7-30.7). Six patients (15%) continued treatment for more than 48 weeks, although only 1 patient remains on treatment at present.

The 34 patients who discontinued the primary study did so because of progressive disease (60%), AEs (20%), withdrawn consent (3%), or investigator request (3%). Of the 6 patients who entered the extension trial, 4 ultimately discontinued due to progressive disease and 1 due to AEs.

Grade 3 or higher AEs included diarrhea (18%), decreased appetite (15%), pneumonia (10%), nausea (5%), fatigue (3%), and rash (3%). Grade 3 or higher lab abnormalities included ALT/AST elevations (20%), neutropenia (10%), thrombocytopenia (5%), and anemia (3%).

The overall response rate was 40%, with 5% of patients achieving a complete response. The median duration of response was 2.7 months, and the median PFS was 3.7 months.

Despite the modest duration of survival observed in these patients, the researchers believe the strong initial response to idelalisib suggests the drug could still prove useful in patients with MCL.

“[I]delalisib is unlikely to receive designation as a single-agent therapy in mantle cell lymphoma due to the short duration of response,” said study author Brad S. Kahl, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“The path forward will likely include administering it in combination with other agents or developing second-generation PI3 kinase inhibitors.”