ASH 2011

SAN DIEGO – The risk of a secondary malignancy doubled in patients with newly diagnosed multiple myeloma treated with melphalan plus thalidomide or lenalidomide in a retrospective, pooled analysis of 2,283 patients.

Incidence rates per 100 persons per year of follow-up were 0.95 with high-dose melphalan (Alkeran) followed by lenalidomide (Revlimid) maintenance and 1.05 with melphalan and thalidomide. In comparison, rates were 0.40 with cyclophosphamide, lenalidomide, and dexamethasone and 0.42 with melphalan and no immunomodulatory drugs, Dr. Antonio Palumbo reported at the annual meeting of the American Society of Hematology (ASH).

At 4 years of follow-up, second cancers were diagnosed in 48 (2.1%) of the 2,283 patients enrolled in nine experimental trials of the European Myeloma Network. There was consistent evidence of an increase in late events over time.

"I do not want to underestimate the issue," Dr. Palumbo said. "There is a signal, but the first conclusion is caution. When you come to 48 cancers versus 2,200 patients, by chance many things may happen."

He noted that the risk of multiple myeloma progression is between 10 and 15 times higher than the diagnosis of a second cancer, and suggested that the emphasis on second cancers may be overshadowing the risk of death due to toxic effects and infections.

Of the 48 secondary cancers, 8 of the 10 hematologic malignancies and 8 of the 38 solid tumors were fatal. In contrast, there were 124 toxic deaths (8.6%) and 49 infective deaths (3.4%) among 1,435 patients given the combination of melphalan-prednisone-thalidomide or bortezomib (Velcade)-melphalan-prednisone, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

"We take it for granted that with chemo we have some toxic effects," he said in an interview. "We should increase our alert of our combinations, and not focus solely on the second cancers."

Session co-moderator Dr. Meral Beksac, with Ankara (Turkey) University, said the Italian data suggest caution and greater vigilance regarding routine cancer screenings among multiple myeloma patients, but would not change her treatment approach.

"Dr. Palumbo has shown very beautifully that the benefits you achieve in terms of the long-term myeloma effect outweigh the risk of secondary malignancies," she said in an interview. "Personally, I think we must plan to avoid alkylating agents when we now have these better agents."

Preliminary data from three trials showing a fourfold increase in secondary cancers in multiple myeloma patients treated with lenalidomide as maintenance therapy or in combination with melphalan prompted investigations into the safety of lenalidomide in the United States and Europe in 2011.

The European Medicines Agency concluded in September that the benefits of lenalidomide continue to outweigh the risks within the approved setting of relapsed multiple myeloma, but recommended that a warning be added on the risk of second cancers. The U.S. Food and Drug Administration review is ongoing, and includes the risk for thalidomide, since lenalidomide is an analogue of thalidomide.

Although the development of acute myeloid leukemia (AML) following multiple myeloma was observed decades ago, the underlying mechanisms remain unclear. Swedish researchers recently reported that the risk of AML and myelodysplastic syndromes is 11.5-fold higher in multiple myeloma patients than in the general population, even before the introduction of novel agents (Blood 2011;118:4086-92). In addition, the risk of AML/MDS was eightfold higher in patients with monoclonal gammopathy of undetermined significance (MGUS), even though none of the MGUS patients developed multiple myeloma, according to session co-moderator Dr. Sigurdur Y. Kristinsson, who was a coauthor of the Swedish study.

"Even those people that never develop the disease have an increased risk of AML and MDS, so it shows that it’s not only the treatment that we’re giving, but it’s also an inherent susceptibility," Dr. Kristinsson, with the Karolinska Hospital and Institute in Stockholm, said in an interview.

Work is ongoing to identify multiple myeloma patients at an increased risk of second cancers, thereby allowing clinicians to tailor therapy to reduce risks. A separate poster presentation at the ASH meeting reported that higher risk of second cancers was associated with older age, male sex, and radiation and/or surgery among roughly 29,250 multiple myeloma patients in the Surveillance, Epidemiology, and End Results (SEER) database.

Subgroup analysis of the pooled Italian data did not identify specific subgroups at greater risk, Dr. Palumbo said. The incidence rate was higher at 1.13 per 100 person-years for patients given melphalan-lenalidomide vs. 0.76 per 100 person-years for patients treated with autologous stem cell transplantation and lenalidomide (median age 68 years vs. 59 years, respectively).

Speaking on behalf of the investigators, Dr. Palumbo reported employment with, serving as a consultant and on the speakers bureau of, having equity ownership in, and receiving research funding, patent royalties, and honoraria from Celgene, maker of lenalidomide. Dr. Beksac reported honoraria and speakers bureau activity with Celgene and Janssen Cilag. Dr. Kristinsson reported no conflicts of interest.

SAN DIEGO – The risk of a secondary malignancy doubled in patients with newly diagnosed multiple myeloma treated with melphalan plus thalidomide or lenalidomide in a retrospective, pooled analysis of 2,283 patients.

Incidence rates per 100 persons per year of follow-up were 0.95 with high-dose melphalan (Alkeran) followed by lenalidomide (Revlimid) maintenance and 1.05 with melphalan and thalidomide. In comparison, rates were 0.40 with cyclophosphamide, lenalidomide, and dexamethasone and 0.42 with melphalan and no immunomodulatory drugs, Dr. Antonio Palumbo reported at the annual meeting of the American Society of Hematology (ASH).

At 4 years of follow-up, second cancers were diagnosed in 48 (2.1%) of the 2,283 patients enrolled in nine experimental trials of the European Myeloma Network. There was consistent evidence of an increase in late events over time.

"I do not want to underestimate the issue," Dr. Palumbo said. "There is a signal, but the first conclusion is caution. When you come to 48 cancers versus 2,200 patients, by chance many things may happen."

He noted that the risk of multiple myeloma progression is between 10 and 15 times higher than the diagnosis of a second cancer, and suggested that the emphasis on second cancers may be overshadowing the risk of death due to toxic effects and infections.

Of the 48 secondary cancers, 8 of the 10 hematologic malignancies and 8 of the 38 solid tumors were fatal. In contrast, there were 124 toxic deaths (8.6%) and 49 infective deaths (3.4%) among 1,435 patients given the combination of melphalan-prednisone-thalidomide or bortezomib (Velcade)-melphalan-prednisone, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

"We take it for granted that with chemo we have some toxic effects," he said in an interview. "We should increase our alert of our combinations, and not focus solely on the second cancers."

Session co-moderator Dr. Meral Beksac, with Ankara (Turkey) University, said the Italian data suggest caution and greater vigilance regarding routine cancer screenings among multiple myeloma patients, but would not change her treatment approach.

"Dr. Palumbo has shown very beautifully that the benefits you achieve in terms of the long-term myeloma effect outweigh the risk of secondary malignancies," she said in an interview. "Personally, I think we must plan to avoid alkylating agents when we now have these better agents."

Preliminary data from three trials showing a fourfold increase in secondary cancers in multiple myeloma patients treated with lenalidomide as maintenance therapy or in combination with melphalan prompted investigations into the safety of lenalidomide in the United States and Europe in 2011.

The European Medicines Agency concluded in September that the benefits of lenalidomide continue to outweigh the risks within the approved setting of relapsed multiple myeloma, but recommended that a warning be added on the risk of second cancers. The U.S. Food and Drug Administration review is ongoing, and includes the risk for thalidomide, since lenalidomide is an analogue of thalidomide.

Although the development of acute myeloid leukemia (AML) following multiple myeloma was observed decades ago, the underlying mechanisms remain unclear. Swedish researchers recently reported that the risk of AML and myelodysplastic syndromes is 11.5-fold higher in multiple myeloma patients than in the general population, even before the introduction of novel agents (Blood 2011;118:4086-92). In addition, the risk of AML/MDS was eightfold higher in patients with monoclonal gammopathy of undetermined significance (MGUS), even though none of the MGUS patients developed multiple myeloma, according to session co-moderator Dr. Sigurdur Y. Kristinsson, who was a coauthor of the Swedish study.

"Even those people that never develop the disease have an increased risk of AML and MDS, so it shows that it’s not only the treatment that we’re giving, but it’s also an inherent susceptibility," Dr. Kristinsson, with the Karolinska Hospital and Institute in Stockholm, said in an interview.

Work is ongoing to identify multiple myeloma patients at an increased risk of second cancers, thereby allowing clinicians to tailor therapy to reduce risks. A separate poster presentation at the ASH meeting reported that higher risk of second cancers was associated with older age, male sex, and radiation and/or surgery among roughly 29,250 multiple myeloma patients in the Surveillance, Epidemiology, and End Results (SEER) database.

Subgroup analysis of the pooled Italian data did not identify specific subgroups at greater risk, Dr. Palumbo said. The incidence rate was higher at 1.13 per 100 person-years for patients given melphalan-lenalidomide vs. 0.76 per 100 person-years for patients treated with autologous stem cell transplantation and lenalidomide (median age 68 years vs. 59 years, respectively).

Speaking on behalf of the investigators, Dr. Palumbo reported employment with, serving as a consultant and on the speakers bureau of, having equity ownership in, and receiving research funding, patent royalties, and honoraria from Celgene, maker of lenalidomide. Dr. Beksac reported honoraria and speakers bureau activity with Celgene and Janssen Cilag. Dr. Kristinsson reported no conflicts of interest.

SAN DIEGO – The risk of a secondary malignancy doubled in patients with newly diagnosed multiple myeloma treated with melphalan plus thalidomide or lenalidomide in a retrospective, pooled analysis of 2,283 patients.

Incidence rates per 100 persons per year of follow-up were 0.95 with high-dose melphalan (Alkeran) followed by lenalidomide (Revlimid) maintenance and 1.05 with melphalan and thalidomide. In comparison, rates were 0.40 with cyclophosphamide, lenalidomide, and dexamethasone and 0.42 with melphalan and no immunomodulatory drugs, Dr. Antonio Palumbo reported at the annual meeting of the American Society of Hematology (ASH).

At 4 years of follow-up, second cancers were diagnosed in 48 (2.1%) of the 2,283 patients enrolled in nine experimental trials of the European Myeloma Network. There was consistent evidence of an increase in late events over time.

"I do not want to underestimate the issue," Dr. Palumbo said. "There is a signal, but the first conclusion is caution. When you come to 48 cancers versus 2,200 patients, by chance many things may happen."

He noted that the risk of multiple myeloma progression is between 10 and 15 times higher than the diagnosis of a second cancer, and suggested that the emphasis on second cancers may be overshadowing the risk of death due to toxic effects and infections.

Of the 48 secondary cancers, 8 of the 10 hematologic malignancies and 8 of the 38 solid tumors were fatal. In contrast, there were 124 toxic deaths (8.6%) and 49 infective deaths (3.4%) among 1,435 patients given the combination of melphalan-prednisone-thalidomide or bortezomib (Velcade)-melphalan-prednisone, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

"We take it for granted that with chemo we have some toxic effects," he said in an interview. "We should increase our alert of our combinations, and not focus solely on the second cancers."

Session co-moderator Dr. Meral Beksac, with Ankara (Turkey) University, said the Italian data suggest caution and greater vigilance regarding routine cancer screenings among multiple myeloma patients, but would not change her treatment approach.

"Dr. Palumbo has shown very beautifully that the benefits you achieve in terms of the long-term myeloma effect outweigh the risk of secondary malignancies," she said in an interview. "Personally, I think we must plan to avoid alkylating agents when we now have these better agents."

Preliminary data from three trials showing a fourfold increase in secondary cancers in multiple myeloma patients treated with lenalidomide as maintenance therapy or in combination with melphalan prompted investigations into the safety of lenalidomide in the United States and Europe in 2011.

The European Medicines Agency concluded in September that the benefits of lenalidomide continue to outweigh the risks within the approved setting of relapsed multiple myeloma, but recommended that a warning be added on the risk of second cancers. The U.S. Food and Drug Administration review is ongoing, and includes the risk for thalidomide, since lenalidomide is an analogue of thalidomide.

Although the development of acute myeloid leukemia (AML) following multiple myeloma was observed decades ago, the underlying mechanisms remain unclear. Swedish researchers recently reported that the risk of AML and myelodysplastic syndromes is 11.5-fold higher in multiple myeloma patients than in the general population, even before the introduction of novel agents (Blood 2011;118:4086-92). In addition, the risk of AML/MDS was eightfold higher in patients with monoclonal gammopathy of undetermined significance (MGUS), even though none of the MGUS patients developed multiple myeloma, according to session co-moderator Dr. Sigurdur Y. Kristinsson, who was a coauthor of the Swedish study.

"Even those people that never develop the disease have an increased risk of AML and MDS, so it shows that it’s not only the treatment that we’re giving, but it’s also an inherent susceptibility," Dr. Kristinsson, with the Karolinska Hospital and Institute in Stockholm, said in an interview.

Work is ongoing to identify multiple myeloma patients at an increased risk of second cancers, thereby allowing clinicians to tailor therapy to reduce risks. A separate poster presentation at the ASH meeting reported that higher risk of second cancers was associated with older age, male sex, and radiation and/or surgery among roughly 29,250 multiple myeloma patients in the Surveillance, Epidemiology, and End Results (SEER) database.

Subgroup analysis of the pooled Italian data did not identify specific subgroups at greater risk, Dr. Palumbo said. The incidence rate was higher at 1.13 per 100 person-years for patients given melphalan-lenalidomide vs. 0.76 per 100 person-years for patients treated with autologous stem cell transplantation and lenalidomide (median age 68 years vs. 59 years, respectively).

Speaking on behalf of the investigators, Dr. Palumbo reported employment with, serving as a consultant and on the speakers bureau of, having equity ownership in, and receiving research funding, patent royalties, and honoraria from Celgene, maker of lenalidomide. Dr. Beksac reported honoraria and speakers bureau activity with Celgene and Janssen Cilag. Dr. Kristinsson reported no conflicts of interest.

SAN DIEGO – More than 40% of patients with sickle cell disease return for acute care within 14 days following an emergency department treat-and-release visit, with young adults and those with public insurance having the highest rates of return.

Those are key findings from a large analysis of data from the 2005 and 2006 State Emergency Department Databases and State Inpatient Databases managed by the Healthcare Cost and Utilization Project, a federal, state, and industry partnership sponsored by the Agency for Healthcare Research and Quality.

"Patients with sickle cell disease who are discharged from the hospital have higher rates of rehospitalization than [patients with] almost any other chronic disease," lead study author Dr. David C. Brousseau said at the annual meeting of the American Society of Hematology. "Because of the high rate of rehospitalizations, many hospitals have been developing programs to decrease rehospitalization rates for sickle cell disease. This effort is primarily driven by two factors: the recent federal emphasis on rehospitalizations, and a desire to improve care, with the belief that rehospitalizations represent a deficiency in care quality, or at least an opportunity to improve care."

Previous studies have shown that about half of ED visits made by patients with sickle cell disease result in inpatient hospitalization, he continued, "yet little emphasis has been placed on what happens after an ED treat-and-release visit."

Dr. Brousseau and his associates conducted a retrospective cohort study of all sickle cell disease–related ED visits and hospitalizations during 2005 and 2006 in the states of Arizona, California, Florida, Massachusetts, Missouri, New York, South Carolina, and Tennessee. "One-third of patients with sickle cell disease in the United States reside in these eight states," said Dr. Brousseau, of the pediatrics department at the Medical College of Wisconsin and an emergency medicine specialist at Children’s Hospital of Wisconsin, Milwaukee.

The researchers hypothesized that patients with sickle cell disease who were treated and released from an ED would have high rates of 14-day return visits to both the ED and an inpatient unit. A 14-day window was chosen "to more accurately reflect a time period ... where a revisit would not be due to a new crisis," he said.

During the 2-year study period, 12,109 people with sickle cell disease made 39,775 index ED visits. The 14-day return visit rate was 42.1%, "meaning that 42.1% of all ED treat-and-release visits were followed within 14 days by a return visit to either the ED or the inpatient unit," Dr. Brousseau said. A higher proportion of the return visits were to the ED than to the inpatient unit (25.4% vs. 16.7%, respectively).

Analysis of data by patient age and insurance provider revealed that the highest proportion of return visits within 14 days was made by patients aged 18-30 years (49%) and by those who carried public insurance (46.5%).

The 7-day return rate was 31.6%. Of these, 18.6% were to the ED and 13% were to the inpatient unit.

The 14-day revisit rate to the same hospital was 31.2%. Children were more likely than adults to make return visits to the same hospital (84.3% vs. 72.7%, respectively).

"We conclude that an ED treat-and-release visit should serve as a trigger to focus enhanced outpatient care to prevent subsequent inpatient visits and to improve patient care," Dr. Brousseau said.

Dr. Brousseau said he had no relevant financial disclosures.

SAN DIEGO – More than 40% of patients with sickle cell disease return for acute care within 14 days following an emergency department treat-and-release visit, with young adults and those with public insurance having the highest rates of return.

Those are key findings from a large analysis of data from the 2005 and 2006 State Emergency Department Databases and State Inpatient Databases managed by the Healthcare Cost and Utilization Project, a federal, state, and industry partnership sponsored by the Agency for Healthcare Research and Quality.

"Patients with sickle cell disease who are discharged from the hospital have higher rates of rehospitalization than [patients with] almost any other chronic disease," lead study author Dr. David C. Brousseau said at the annual meeting of the American Society of Hematology. "Because of the high rate of rehospitalizations, many hospitals have been developing programs to decrease rehospitalization rates for sickle cell disease. This effort is primarily driven by two factors: the recent federal emphasis on rehospitalizations, and a desire to improve care, with the belief that rehospitalizations represent a deficiency in care quality, or at least an opportunity to improve care."

Previous studies have shown that about half of ED visits made by patients with sickle cell disease result in inpatient hospitalization, he continued, "yet little emphasis has been placed on what happens after an ED treat-and-release visit."

Dr. Brousseau and his associates conducted a retrospective cohort study of all sickle cell disease–related ED visits and hospitalizations during 2005 and 2006 in the states of Arizona, California, Florida, Massachusetts, Missouri, New York, South Carolina, and Tennessee. "One-third of patients with sickle cell disease in the United States reside in these eight states," said Dr. Brousseau, of the pediatrics department at the Medical College of Wisconsin and an emergency medicine specialist at Children’s Hospital of Wisconsin, Milwaukee.

The researchers hypothesized that patients with sickle cell disease who were treated and released from an ED would have high rates of 14-day return visits to both the ED and an inpatient unit. A 14-day window was chosen "to more accurately reflect a time period ... where a revisit would not be due to a new crisis," he said.

During the 2-year study period, 12,109 people with sickle cell disease made 39,775 index ED visits. The 14-day return visit rate was 42.1%, "meaning that 42.1% of all ED treat-and-release visits were followed within 14 days by a return visit to either the ED or the inpatient unit," Dr. Brousseau said. A higher proportion of the return visits were to the ED than to the inpatient unit (25.4% vs. 16.7%, respectively).

Analysis of data by patient age and insurance provider revealed that the highest proportion of return visits within 14 days was made by patients aged 18-30 years (49%) and by those who carried public insurance (46.5%).

The 7-day return rate was 31.6%. Of these, 18.6% were to the ED and 13% were to the inpatient unit.

The 14-day revisit rate to the same hospital was 31.2%. Children were more likely than adults to make return visits to the same hospital (84.3% vs. 72.7%, respectively).

"We conclude that an ED treat-and-release visit should serve as a trigger to focus enhanced outpatient care to prevent subsequent inpatient visits and to improve patient care," Dr. Brousseau said.

Dr. Brousseau said he had no relevant financial disclosures.

SAN DIEGO – More than 40% of patients with sickle cell disease return for acute care within 14 days following an emergency department treat-and-release visit, with young adults and those with public insurance having the highest rates of return.

Those are key findings from a large analysis of data from the 2005 and 2006 State Emergency Department Databases and State Inpatient Databases managed by the Healthcare Cost and Utilization Project, a federal, state, and industry partnership sponsored by the Agency for Healthcare Research and Quality.

"Patients with sickle cell disease who are discharged from the hospital have higher rates of rehospitalization than [patients with] almost any other chronic disease," lead study author Dr. David C. Brousseau said at the annual meeting of the American Society of Hematology. "Because of the high rate of rehospitalizations, many hospitals have been developing programs to decrease rehospitalization rates for sickle cell disease. This effort is primarily driven by two factors: the recent federal emphasis on rehospitalizations, and a desire to improve care, with the belief that rehospitalizations represent a deficiency in care quality, or at least an opportunity to improve care."

Previous studies have shown that about half of ED visits made by patients with sickle cell disease result in inpatient hospitalization, he continued, "yet little emphasis has been placed on what happens after an ED treat-and-release visit."

Dr. Brousseau and his associates conducted a retrospective cohort study of all sickle cell disease–related ED visits and hospitalizations during 2005 and 2006 in the states of Arizona, California, Florida, Massachusetts, Missouri, New York, South Carolina, and Tennessee. "One-third of patients with sickle cell disease in the United States reside in these eight states," said Dr. Brousseau, of the pediatrics department at the Medical College of Wisconsin and an emergency medicine specialist at Children’s Hospital of Wisconsin, Milwaukee.

The researchers hypothesized that patients with sickle cell disease who were treated and released from an ED would have high rates of 14-day return visits to both the ED and an inpatient unit. A 14-day window was chosen "to more accurately reflect a time period ... where a revisit would not be due to a new crisis," he said.

During the 2-year study period, 12,109 people with sickle cell disease made 39,775 index ED visits. The 14-day return visit rate was 42.1%, "meaning that 42.1% of all ED treat-and-release visits were followed within 14 days by a return visit to either the ED or the inpatient unit," Dr. Brousseau said. A higher proportion of the return visits were to the ED than to the inpatient unit (25.4% vs. 16.7%, respectively).

Analysis of data by patient age and insurance provider revealed that the highest proportion of return visits within 14 days was made by patients aged 18-30 years (49%) and by those who carried public insurance (46.5%).

The 7-day return rate was 31.6%. Of these, 18.6% were to the ED and 13% were to the inpatient unit.

The 14-day revisit rate to the same hospital was 31.2%. Children were more likely than adults to make return visits to the same hospital (84.3% vs. 72.7%, respectively).

"We conclude that an ED treat-and-release visit should serve as a trigger to focus enhanced outpatient care to prevent subsequent inpatient visits and to improve patient care," Dr. Brousseau said.

Dr. Brousseau said he had no relevant financial disclosures.

SAN DIEGO – Even before it has earned a name, the novel targeted agent designated PCI-32765 is earning an impressive reputation, first for its mettle against chronic lymphocytic leukemia, and now for its potent action against relapsed or refractory mantle cell lymphoma in early clinical data, reported investigators at the annual meeting of the American Society of Hematology.

Preliminary results of a phase II trial of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, show that the agent induced complete responses in 16% of 51 patients with relapsed/refractory mantle cell lymphoma (MCL) and partial responses in 53%, for a combined overall response rate of 69%, said Dr. Luhua (Michael) Wang from the division of lymphoma and myeloma at the University of Texas M.D. Anderson Cancer Center in Houston.

"We think, as a single oral agent in the relapse setting of mantle cell lymphoma, this is a high response rate so far. The efficacy is also observed in patients with bulky disease, and also in refractive disease. Most importantly, the efficacy is independent, so far, from the MIPI [MCL International Prognostic Index] score," he said.

Patients with a high-risk MIPI score had a 75% response rate, the same as that for patients with a low-risk score; intermediate-risk patients had a 65% response rate.

An additional 18% of patients overall had stable disease; only 14% experienced disease progression.

In an earlier presentation at the ASH meeting, Dr. Susan O’Brien, also from M.D. Anderson, reported that PCI-32765 was associated with an overall response rate of 70% at 10.2 months’ follow-up in patients with relapsed/refractory CLL.

In the mantle cell lymphoma study, the BTK-inhibitor induced good responses both in patients who had previously been treated with the proteasome inhibitor bortezomib (Velcade), with rates of 15% for complete responses and 50% for partial responses, and in those who were bortezomib naive, with a 16% complete response rate and 55% partial response rate.

"People are very interested in this agent," commented Dr. Mitchell R. Smith from the Fox Chase Cancer Center in Philadelphia, in an interview.

"It looks very active, but we don’t know a lot about long-term effects and how long responses will last. But when you think about hitting specific pathways, that’s our goal in treating these diseases. This hits a specific pathway, does it well, and there have been responses in many B-cell disorders," he said. Dr. Smith comoderated the session at which the data were presented, but was not involved in the study.

PCI-32765 is an oral inhibitor of BTK, an essential element of the B-cell antigen receptor-signaling pathway. It blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion, and has been shown in in vitro studies to block pERK, pJNK, and NF-kappaB pathways in MCL cell lines.

The trial, designated PCYC-1104-CA, is a multicenter open-label phase II study of PCI-32765 in 68 patients. Dr. Wang presented data from an efficacy analysis of 51 patients who had at least one post-baseline tumor assessment. The patients were divided into two groups: bortezomib-exposed (27 patients) and bortezomib naive (41 patients, 34 of whom had never received bortezomib, and 7 who had received less than 2 cycles).

The patients were treated with 560 mg PCI-32765 daily until disease progression.

Median time on study was 3.7 months among all patients. At the most recent follow-up, 71% of bortezomib-naive and 70% of bortezomib-exposed patients were still on study. Discontinuations were primarily for disease progression, and there was one on-study death, a patient who had previously received bortezomib.

Non-hematologic adverse events were generally mild, with the only grade 4 toxicity being abdominal pain in about 2% of patients.

Grade 3 neutropenia occurred in 2% overall of 61 patients available for a safety analysis, and grade 4 neutropenia was seen 3%. Grade 3 febrile neutropenia, anemia, and thrombocytopenias were each seen in 3% of patients (no grade 4), and grade 4 pancytopenia was seen in 2%.

The investigators saw a 57% overall response rate in patients with bulky disease, 67% in those with refractory disease, 77% among those who had received fewer than 3 prior lines of therapy, and 57% among those who had received 3 or more. In addition, the overall response rate was 71% in patients who had received high-intensity prior therapy, and 65% in those who had received standard-dose therapy.

Additional follow-up will be required before the investigators can determine duration of response and progression-free survival, and more clinical trials with PCI-32765 are in the planning stages, Dr. Wang said.

Pharmacyclics sponsored the study. Dr. Wang disclosed consulting, having equity ownership in, and receiving research funding from, Pharmacyclics. He also disclosed relationships with Celgene, Millennium, Novartis, and Onyx. Dr. Smith disclosed board membership and receiving research funding from Cephalon, and being on the speakers bureau for Celgene, Genentech, Spectrum, and Allos.

SAN DIEGO – Even before it has earned a name, the novel targeted agent designated PCI-32765 is earning an impressive reputation, first for its mettle against chronic lymphocytic leukemia, and now for its potent action against relapsed or refractory mantle cell lymphoma in early clinical data, reported investigators at the annual meeting of the American Society of Hematology.

Preliminary results of a phase II trial of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, show that the agent induced complete responses in 16% of 51 patients with relapsed/refractory mantle cell lymphoma (MCL) and partial responses in 53%, for a combined overall response rate of 69%, said Dr. Luhua (Michael) Wang from the division of lymphoma and myeloma at the University of Texas M.D. Anderson Cancer Center in Houston.

"We think, as a single oral agent in the relapse setting of mantle cell lymphoma, this is a high response rate so far. The efficacy is also observed in patients with bulky disease, and also in refractive disease. Most importantly, the efficacy is independent, so far, from the MIPI [MCL International Prognostic Index] score," he said.

Patients with a high-risk MIPI score had a 75% response rate, the same as that for patients with a low-risk score; intermediate-risk patients had a 65% response rate.

An additional 18% of patients overall had stable disease; only 14% experienced disease progression.

In an earlier presentation at the ASH meeting, Dr. Susan O’Brien, also from M.D. Anderson, reported that PCI-32765 was associated with an overall response rate of 70% at 10.2 months’ follow-up in patients with relapsed/refractory CLL.

In the mantle cell lymphoma study, the BTK-inhibitor induced good responses both in patients who had previously been treated with the proteasome inhibitor bortezomib (Velcade), with rates of 15% for complete responses and 50% for partial responses, and in those who were bortezomib naive, with a 16% complete response rate and 55% partial response rate.

"People are very interested in this agent," commented Dr. Mitchell R. Smith from the Fox Chase Cancer Center in Philadelphia, in an interview.

"It looks very active, but we don’t know a lot about long-term effects and how long responses will last. But when you think about hitting specific pathways, that’s our goal in treating these diseases. This hits a specific pathway, does it well, and there have been responses in many B-cell disorders," he said. Dr. Smith comoderated the session at which the data were presented, but was not involved in the study.

PCI-32765 is an oral inhibitor of BTK, an essential element of the B-cell antigen receptor-signaling pathway. It blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion, and has been shown in in vitro studies to block pERK, pJNK, and NF-kappaB pathways in MCL cell lines.

The trial, designated PCYC-1104-CA, is a multicenter open-label phase II study of PCI-32765 in 68 patients. Dr. Wang presented data from an efficacy analysis of 51 patients who had at least one post-baseline tumor assessment. The patients were divided into two groups: bortezomib-exposed (27 patients) and bortezomib naive (41 patients, 34 of whom had never received bortezomib, and 7 who had received less than 2 cycles).

The patients were treated with 560 mg PCI-32765 daily until disease progression.

Median time on study was 3.7 months among all patients. At the most recent follow-up, 71% of bortezomib-naive and 70% of bortezomib-exposed patients were still on study. Discontinuations were primarily for disease progression, and there was one on-study death, a patient who had previously received bortezomib.

Non-hematologic adverse events were generally mild, with the only grade 4 toxicity being abdominal pain in about 2% of patients.

Grade 3 neutropenia occurred in 2% overall of 61 patients available for a safety analysis, and grade 4 neutropenia was seen 3%. Grade 3 febrile neutropenia, anemia, and thrombocytopenias were each seen in 3% of patients (no grade 4), and grade 4 pancytopenia was seen in 2%.

The investigators saw a 57% overall response rate in patients with bulky disease, 67% in those with refractory disease, 77% among those who had received fewer than 3 prior lines of therapy, and 57% among those who had received 3 or more. In addition, the overall response rate was 71% in patients who had received high-intensity prior therapy, and 65% in those who had received standard-dose therapy.

Additional follow-up will be required before the investigators can determine duration of response and progression-free survival, and more clinical trials with PCI-32765 are in the planning stages, Dr. Wang said.

Pharmacyclics sponsored the study. Dr. Wang disclosed consulting, having equity ownership in, and receiving research funding from, Pharmacyclics. He also disclosed relationships with Celgene, Millennium, Novartis, and Onyx. Dr. Smith disclosed board membership and receiving research funding from Cephalon, and being on the speakers bureau for Celgene, Genentech, Spectrum, and Allos.

SAN DIEGO – Even before it has earned a name, the novel targeted agent designated PCI-32765 is earning an impressive reputation, first for its mettle against chronic lymphocytic leukemia, and now for its potent action against relapsed or refractory mantle cell lymphoma in early clinical data, reported investigators at the annual meeting of the American Society of Hematology.

Preliminary results of a phase II trial of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, show that the agent induced complete responses in 16% of 51 patients with relapsed/refractory mantle cell lymphoma (MCL) and partial responses in 53%, for a combined overall response rate of 69%, said Dr. Luhua (Michael) Wang from the division of lymphoma and myeloma at the University of Texas M.D. Anderson Cancer Center in Houston.

"We think, as a single oral agent in the relapse setting of mantle cell lymphoma, this is a high response rate so far. The efficacy is also observed in patients with bulky disease, and also in refractive disease. Most importantly, the efficacy is independent, so far, from the MIPI [MCL International Prognostic Index] score," he said.

Patients with a high-risk MIPI score had a 75% response rate, the same as that for patients with a low-risk score; intermediate-risk patients had a 65% response rate.

An additional 18% of patients overall had stable disease; only 14% experienced disease progression.

In an earlier presentation at the ASH meeting, Dr. Susan O’Brien, also from M.D. Anderson, reported that PCI-32765 was associated with an overall response rate of 70% at 10.2 months’ follow-up in patients with relapsed/refractory CLL.

In the mantle cell lymphoma study, the BTK-inhibitor induced good responses both in patients who had previously been treated with the proteasome inhibitor bortezomib (Velcade), with rates of 15% for complete responses and 50% for partial responses, and in those who were bortezomib naive, with a 16% complete response rate and 55% partial response rate.

"People are very interested in this agent," commented Dr. Mitchell R. Smith from the Fox Chase Cancer Center in Philadelphia, in an interview.

"It looks very active, but we don’t know a lot about long-term effects and how long responses will last. But when you think about hitting specific pathways, that’s our goal in treating these diseases. This hits a specific pathway, does it well, and there have been responses in many B-cell disorders," he said. Dr. Smith comoderated the session at which the data were presented, but was not involved in the study.

PCI-32765 is an oral inhibitor of BTK, an essential element of the B-cell antigen receptor-signaling pathway. It blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion, and has been shown in in vitro studies to block pERK, pJNK, and NF-kappaB pathways in MCL cell lines.

The trial, designated PCYC-1104-CA, is a multicenter open-label phase II study of PCI-32765 in 68 patients. Dr. Wang presented data from an efficacy analysis of 51 patients who had at least one post-baseline tumor assessment. The patients were divided into two groups: bortezomib-exposed (27 patients) and bortezomib naive (41 patients, 34 of whom had never received bortezomib, and 7 who had received less than 2 cycles).

The patients were treated with 560 mg PCI-32765 daily until disease progression.

Median time on study was 3.7 months among all patients. At the most recent follow-up, 71% of bortezomib-naive and 70% of bortezomib-exposed patients were still on study. Discontinuations were primarily for disease progression, and there was one on-study death, a patient who had previously received bortezomib.

Non-hematologic adverse events were generally mild, with the only grade 4 toxicity being abdominal pain in about 2% of patients.

Grade 3 neutropenia occurred in 2% overall of 61 patients available for a safety analysis, and grade 4 neutropenia was seen 3%. Grade 3 febrile neutropenia, anemia, and thrombocytopenias were each seen in 3% of patients (no grade 4), and grade 4 pancytopenia was seen in 2%.

The investigators saw a 57% overall response rate in patients with bulky disease, 67% in those with refractory disease, 77% among those who had received fewer than 3 prior lines of therapy, and 57% among those who had received 3 or more. In addition, the overall response rate was 71% in patients who had received high-intensity prior therapy, and 65% in those who had received standard-dose therapy.

Additional follow-up will be required before the investigators can determine duration of response and progression-free survival, and more clinical trials with PCI-32765 are in the planning stages, Dr. Wang said.

Pharmacyclics sponsored the study. Dr. Wang disclosed consulting, having equity ownership in, and receiving research funding from, Pharmacyclics. He also disclosed relationships with Celgene, Millennium, Novartis, and Onyx. Dr. Smith disclosed board membership and receiving research funding from Cephalon, and being on the speakers bureau for Celgene, Genentech, Spectrum, and Allos.

SAN DIEGO – Induction therapy with obinutuzumab, a bioengineered CD20 inhibitor, induced a slightly higher overall response rate in induction therapy than did rituximab in patients with relapsed, CD20-positive indolent B-cell non-Hodgkin’s lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

According to independent radiology reviewers who were blinded to treatment type, the overall response rate – a composite of complete responses (CR), CR-unconfirmed (CRu), and partial responses – was 44.6% at the end of induction among 74 patients with follicular lymphoma that was treated with obinutuzumab (Genentech’s GA101), compared with 26.7% of patients on rituximab (Rituxan) (P = .01), said Dr. Laurie H. Sehn, a medical oncologist at the University of British Columbia, Vancouver.

However, the overall response rate (ORR) by trial investigator ratings – the primary end point – showed a trend that was not significant, at 44.6% vs. 33.3% (P = .08). There is currently no difference in progression-free survival, said Dr. Sehn, on behalf of her colleagues in the phase II GAUSS trial, touted at the first head-to-head comparison of the two anti-CD20 antibodies.

Patients with other indolent lymphoma histologies were included in the trial, but Dr. Sehn reported full data on patients with follicular lymphomas only.

Obinutuzumab is considered to be a type II monoclonal antibody, shown in preclinical testing to have better ability than does rituximab to cause cell death and to invoke a cellular immune response, with lower complement-dependent cytotoxicity, Dr, Sehn said at a briefing on Dec. 11 in advance of presentation of the results on Dec. 12, 2011.

"As a single drug, rituximab really has had one of the most significant impacts in outcome in B-cell lymphomas in probably the last several decades, so there’s a real motivation to take it one step further and possibly develop a new anti-CD20 antibody that might work better than rituximab or one that may continue to work when rituximab stops working, so as to further improve outcomes," Dr, Sehn said.

A lymphoma specialist who was not involved in the GAUSS trial commented that despite rituximab’s significant benefits, new treatments still are needed, but whether obinutuzumab or another pretender is heir to rituximab’s throne is still unclear.

"We’ve been waiting for a better rituximab for some period of time. It has certainly been the major advance in the therapy of lymphomas in the last 10 to 12 years. The question is, can we do better? Genentech has made an attempt with obinutuzumab to improve the outcome for these patients who are still rituximab-sensitive," commented Dr. Ephraim P. Hochberg of the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"The results are not overwhelming: there’s certainly a trend toward better progression-free survival, there’s a trend toward a slightly improved response rate, and a trend toward a slightly improved complete response rate, but this doesn’t look to be the home run that we might have hoped for with this patient population," he said.

The GAUSS trial is an ongoing, open-label, phase II study. Patients with relapsed CD20+ NHL who had a prior response lasting at least 6 months to a rituximab-containing regimen were randomly assigned to receive either rituximab 375 mg/m² IV weekly for 4 weeks or obinutuzumab 1 g IV weekly for 4 weeks. At the end of the induction phase, patients were assessed and those without disease progression continued with maintenance therapy on the same drug and dose every 2 months for up to 2 years.

In addition to the primary end point results shown above, they found that the best overall response rates by investigator determination occurred in 66.2% of patients on obinutuzumab (35.1% CR/Cru, and 31.1% partial response), and 64% among those on rituximab (18.7% CR/Cru, and 45.3% PR; P = .39). By independent review, the best ORR was 60.8% with obinutuzumab (27% CR/Cru, 33.8% PR), and 46.7% with rituximab (20% and 26.7%; P = .04).*

There were no differences in progression-survival with 39.2% of patients on obinutuzumab having an event at a median time to event of 17.3 months, compared with 34.7% of patients on rituximab with a median time to event of 17.4 months.

In the obinutuzumab arm, 93% of patients had at least one adverse event vs. 81% in the rituximab arm. There were no adverse events leading to death within 28 months of the last dose of obinutuzumab compared with 2 patients on rituximab. Adverse events leading to withdrawal occurred in 8% and 10%, respectively. The proportion of patients having at least one adverse event in each group was identical, at 14%.

Phase III trials with obinutuzumab are underway.

The study was supported by Roche. Dr. Sehn and three coauthors disclosed consulting and receiving honoraria and/or research funding from Roche/Genentech. Two coauthors are Roche employees. Dr. Hochberg has received consulting fees or research support from the company.

*Correction, 12/15/2011: The best overall response rate by independent review was incorrectly stated for rituximab. This version has been updated.

SAN DIEGO – Induction therapy with obinutuzumab, a bioengineered CD20 inhibitor, induced a slightly higher overall response rate in induction therapy than did rituximab in patients with relapsed, CD20-positive indolent B-cell non-Hodgkin’s lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

According to independent radiology reviewers who were blinded to treatment type, the overall response rate – a composite of complete responses (CR), CR-unconfirmed (CRu), and partial responses – was 44.6% at the end of induction among 74 patients with follicular lymphoma that was treated with obinutuzumab (Genentech’s GA101), compared with 26.7% of patients on rituximab (Rituxan) (P = .01), said Dr. Laurie H. Sehn, a medical oncologist at the University of British Columbia, Vancouver.

However, the overall response rate (ORR) by trial investigator ratings – the primary end point – showed a trend that was not significant, at 44.6% vs. 33.3% (P = .08). There is currently no difference in progression-free survival, said Dr. Sehn, on behalf of her colleagues in the phase II GAUSS trial, touted at the first head-to-head comparison of the two anti-CD20 antibodies.

Patients with other indolent lymphoma histologies were included in the trial, but Dr. Sehn reported full data on patients with follicular lymphomas only.

Obinutuzumab is considered to be a type II monoclonal antibody, shown in preclinical testing to have better ability than does rituximab to cause cell death and to invoke a cellular immune response, with lower complement-dependent cytotoxicity, Dr, Sehn said at a briefing on Dec. 11 in advance of presentation of the results on Dec. 12, 2011.

"As a single drug, rituximab really has had one of the most significant impacts in outcome in B-cell lymphomas in probably the last several decades, so there’s a real motivation to take it one step further and possibly develop a new anti-CD20 antibody that might work better than rituximab or one that may continue to work when rituximab stops working, so as to further improve outcomes," Dr, Sehn said.

A lymphoma specialist who was not involved in the GAUSS trial commented that despite rituximab’s significant benefits, new treatments still are needed, but whether obinutuzumab or another pretender is heir to rituximab’s throne is still unclear.

"We’ve been waiting for a better rituximab for some period of time. It has certainly been the major advance in the therapy of lymphomas in the last 10 to 12 years. The question is, can we do better? Genentech has made an attempt with obinutuzumab to improve the outcome for these patients who are still rituximab-sensitive," commented Dr. Ephraim P. Hochberg of the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"The results are not overwhelming: there’s certainly a trend toward better progression-free survival, there’s a trend toward a slightly improved response rate, and a trend toward a slightly improved complete response rate, but this doesn’t look to be the home run that we might have hoped for with this patient population," he said.

The GAUSS trial is an ongoing, open-label, phase II study. Patients with relapsed CD20+ NHL who had a prior response lasting at least 6 months to a rituximab-containing regimen were randomly assigned to receive either rituximab 375 mg/m² IV weekly for 4 weeks or obinutuzumab 1 g IV weekly for 4 weeks. At the end of the induction phase, patients were assessed and those without disease progression continued with maintenance therapy on the same drug and dose every 2 months for up to 2 years.

In addition to the primary end point results shown above, they found that the best overall response rates by investigator determination occurred in 66.2% of patients on obinutuzumab (35.1% CR/Cru, and 31.1% partial response), and 64% among those on rituximab (18.7% CR/Cru, and 45.3% PR; P = .39). By independent review, the best ORR was 60.8% with obinutuzumab (27% CR/Cru, 33.8% PR), and 46.7% with rituximab (20% and 26.7%; P = .04).*

There were no differences in progression-survival with 39.2% of patients on obinutuzumab having an event at a median time to event of 17.3 months, compared with 34.7% of patients on rituximab with a median time to event of 17.4 months.

In the obinutuzumab arm, 93% of patients had at least one adverse event vs. 81% in the rituximab arm. There were no adverse events leading to death within 28 months of the last dose of obinutuzumab compared with 2 patients on rituximab. Adverse events leading to withdrawal occurred in 8% and 10%, respectively. The proportion of patients having at least one adverse event in each group was identical, at 14%.

Phase III trials with obinutuzumab are underway.

The study was supported by Roche. Dr. Sehn and three coauthors disclosed consulting and receiving honoraria and/or research funding from Roche/Genentech. Two coauthors are Roche employees. Dr. Hochberg has received consulting fees or research support from the company.

*Correction, 12/15/2011: The best overall response rate by independent review was incorrectly stated for rituximab. This version has been updated.

SAN DIEGO – Induction therapy with obinutuzumab, a bioengineered CD20 inhibitor, induced a slightly higher overall response rate in induction therapy than did rituximab in patients with relapsed, CD20-positive indolent B-cell non-Hodgkin’s lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

According to independent radiology reviewers who were blinded to treatment type, the overall response rate – a composite of complete responses (CR), CR-unconfirmed (CRu), and partial responses – was 44.6% at the end of induction among 74 patients with follicular lymphoma that was treated with obinutuzumab (Genentech’s GA101), compared with 26.7% of patients on rituximab (Rituxan) (P = .01), said Dr. Laurie H. Sehn, a medical oncologist at the University of British Columbia, Vancouver.

However, the overall response rate (ORR) by trial investigator ratings – the primary end point – showed a trend that was not significant, at 44.6% vs. 33.3% (P = .08). There is currently no difference in progression-free survival, said Dr. Sehn, on behalf of her colleagues in the phase II GAUSS trial, touted at the first head-to-head comparison of the two anti-CD20 antibodies.

Patients with other indolent lymphoma histologies were included in the trial, but Dr. Sehn reported full data on patients with follicular lymphomas only.

Obinutuzumab is considered to be a type II monoclonal antibody, shown in preclinical testing to have better ability than does rituximab to cause cell death and to invoke a cellular immune response, with lower complement-dependent cytotoxicity, Dr, Sehn said at a briefing on Dec. 11 in advance of presentation of the results on Dec. 12, 2011.

"As a single drug, rituximab really has had one of the most significant impacts in outcome in B-cell lymphomas in probably the last several decades, so there’s a real motivation to take it one step further and possibly develop a new anti-CD20 antibody that might work better than rituximab or one that may continue to work when rituximab stops working, so as to further improve outcomes," Dr, Sehn said.

A lymphoma specialist who was not involved in the GAUSS trial commented that despite rituximab’s significant benefits, new treatments still are needed, but whether obinutuzumab or another pretender is heir to rituximab’s throne is still unclear.

"We’ve been waiting for a better rituximab for some period of time. It has certainly been the major advance in the therapy of lymphomas in the last 10 to 12 years. The question is, can we do better? Genentech has made an attempt with obinutuzumab to improve the outcome for these patients who are still rituximab-sensitive," commented Dr. Ephraim P. Hochberg of the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"The results are not overwhelming: there’s certainly a trend toward better progression-free survival, there’s a trend toward a slightly improved response rate, and a trend toward a slightly improved complete response rate, but this doesn’t look to be the home run that we might have hoped for with this patient population," he said.

The GAUSS trial is an ongoing, open-label, phase II study. Patients with relapsed CD20+ NHL who had a prior response lasting at least 6 months to a rituximab-containing regimen were randomly assigned to receive either rituximab 375 mg/m² IV weekly for 4 weeks or obinutuzumab 1 g IV weekly for 4 weeks. At the end of the induction phase, patients were assessed and those without disease progression continued with maintenance therapy on the same drug and dose every 2 months for up to 2 years.

In addition to the primary end point results shown above, they found that the best overall response rates by investigator determination occurred in 66.2% of patients on obinutuzumab (35.1% CR/Cru, and 31.1% partial response), and 64% among those on rituximab (18.7% CR/Cru, and 45.3% PR; P = .39). By independent review, the best ORR was 60.8% with obinutuzumab (27% CR/Cru, 33.8% PR), and 46.7% with rituximab (20% and 26.7%; P = .04).*

There were no differences in progression-survival with 39.2% of patients on obinutuzumab having an event at a median time to event of 17.3 months, compared with 34.7% of patients on rituximab with a median time to event of 17.4 months.

In the obinutuzumab arm, 93% of patients had at least one adverse event vs. 81% in the rituximab arm. There were no adverse events leading to death within 28 months of the last dose of obinutuzumab compared with 2 patients on rituximab. Adverse events leading to withdrawal occurred in 8% and 10%, respectively. The proportion of patients having at least one adverse event in each group was identical, at 14%.

Phase III trials with obinutuzumab are underway.

The study was supported by Roche. Dr. Sehn and three coauthors disclosed consulting and receiving honoraria and/or research funding from Roche/Genentech. Two coauthors are Roche employees. Dr. Hochberg has received consulting fees or research support from the company.

*Correction, 12/15/2011: The best overall response rate by independent review was incorrectly stated for rituximab. This version has been updated.

SAN DIEGO – In the long run, standard chemotherapy alone is more effective than radiation in keeping patients with limited-stage nonbulky Hodgkin’s lymphoma alive, according to updated results from an intergroup trial in 405 patients.

At 12 years, 94% of patients receiving ABVD – doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velbe), and dacarbazine – chemotherapy were alive, compared with 87% receiving subtotal nodal radiation with or without chemotherapy (hazard ratio for death, 0.50; P = .04).

Although 5-year data showed that patients treated with radiation experienced greater disease control, the survival advantage with chemotherapy resulted from a lower rate of death from other causes, Dr. Ralph M. Meyer said at the annual meeting of the American Society of Hematology.

A total of 12 patients in the ABVD arm died: six due to Hodgkin’s, four to a second cancer, and two due to cardiac causes. In contrast, 10 of the 24 deaths in the radiation arm were due to a second cancer. There were two deaths due to cardiac events, four to Hodgkin’s, three fatal infections, and five other deaths.

Dr. Meyer acknowledged that interpretation of the results is bound to be controversial because subtotal nodal radiation is no longer current practice as it is considered excessive. Patients today with low-risk stage IA or IIA nonbulky disease typically receive two cycles of ABVD with 20 Gy of involved-field radiation therapy. Although modern technology has reduced radiation exposure, radiation therapy would still include the coronary artery, heart, and substantial areas of the subdiaphragmatic, he said at a press briefing.

What is clear from the National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study is that measures of disease control, like freedom from progressive disease, are not accurate surrogates for long-term overall survival in patients with stage I-II nonbulky Hodgkin’s lymphoma, said Dr. Meyer, director of the National Cancer Institute of Canada Clinical Trials Group.

"New proxies that predict for risks of late-treatment effects are needed," he said.

Trials are testing the use of PET scanning during therapy to identify patients who may receive chemotherapy alone. It is hypothesized that if PET scans are negative and patients are in remission after two cycles of chemotherapy, the cure rate will be high with further chemotherapy alone, whereas radiation therapy or some other form of chemotherapy should be considered if there is residual PET activity.

How the use of PET will alter current treatment management will be another contentious issue since results from ongoing trials are not expected for 2-3 years. Moreover, the trials are limited because they are using disease control and progression-free survival as end points, which the current trial has shown are not good proxies for overall survival, Dr. Meyer said.

"Thus it will cause issues and interpretation as to how to proceed with these results," he said.

Dr. Meyer and his associates randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma to receive ABVD chemotherapy alone or subtotal nodal radiation at a dose of 35 Gy in 20 daily fractions. Patients in the radiation group with a favorable risk profile received radiation only, while those with an unfavorable risk received two cycles of ABVD followed by radiation therapy. Median follow-up was 11.3 years.

At 12 years, freedom from disease progression was 92% with radiation vs. 87% with ABVD chemotherapy (HR, 1.91; P = .05,), Dr. Meyer said. Event-free survival was similar at 80% with radiation therapy and 85% with ABVD (HR, 0.88; P = .60).

The results were simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2011 [doi:10.1056/NEJMoa1111961]).

Dr. Meyer reported honoraria from Lilly and Celgene.

SAN DIEGO – In the long run, standard chemotherapy alone is more effective than radiation in keeping patients with limited-stage nonbulky Hodgkin’s lymphoma alive, according to updated results from an intergroup trial in 405 patients.

At 12 years, 94% of patients receiving ABVD – doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velbe), and dacarbazine – chemotherapy were alive, compared with 87% receiving subtotal nodal radiation with or without chemotherapy (hazard ratio for death, 0.50; P = .04).

Although 5-year data showed that patients treated with radiation experienced greater disease control, the survival advantage with chemotherapy resulted from a lower rate of death from other causes, Dr. Ralph M. Meyer said at the annual meeting of the American Society of Hematology.

A total of 12 patients in the ABVD arm died: six due to Hodgkin’s, four to a second cancer, and two due to cardiac causes. In contrast, 10 of the 24 deaths in the radiation arm were due to a second cancer. There were two deaths due to cardiac events, four to Hodgkin’s, three fatal infections, and five other deaths.

Dr. Meyer acknowledged that interpretation of the results is bound to be controversial because subtotal nodal radiation is no longer current practice as it is considered excessive. Patients today with low-risk stage IA or IIA nonbulky disease typically receive two cycles of ABVD with 20 Gy of involved-field radiation therapy. Although modern technology has reduced radiation exposure, radiation therapy would still include the coronary artery, heart, and substantial areas of the subdiaphragmatic, he said at a press briefing.

What is clear from the National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study is that measures of disease control, like freedom from progressive disease, are not accurate surrogates for long-term overall survival in patients with stage I-II nonbulky Hodgkin’s lymphoma, said Dr. Meyer, director of the National Cancer Institute of Canada Clinical Trials Group.

"New proxies that predict for risks of late-treatment effects are needed," he said.

Trials are testing the use of PET scanning during therapy to identify patients who may receive chemotherapy alone. It is hypothesized that if PET scans are negative and patients are in remission after two cycles of chemotherapy, the cure rate will be high with further chemotherapy alone, whereas radiation therapy or some other form of chemotherapy should be considered if there is residual PET activity.

How the use of PET will alter current treatment management will be another contentious issue since results from ongoing trials are not expected for 2-3 years. Moreover, the trials are limited because they are using disease control and progression-free survival as end points, which the current trial has shown are not good proxies for overall survival, Dr. Meyer said.

"Thus it will cause issues and interpretation as to how to proceed with these results," he said.

Dr. Meyer and his associates randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma to receive ABVD chemotherapy alone or subtotal nodal radiation at a dose of 35 Gy in 20 daily fractions. Patients in the radiation group with a favorable risk profile received radiation only, while those with an unfavorable risk received two cycles of ABVD followed by radiation therapy. Median follow-up was 11.3 years.

At 12 years, freedom from disease progression was 92% with radiation vs. 87% with ABVD chemotherapy (HR, 1.91; P = .05,), Dr. Meyer said. Event-free survival was similar at 80% with radiation therapy and 85% with ABVD (HR, 0.88; P = .60).

The results were simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2011 [doi:10.1056/NEJMoa1111961]).

Dr. Meyer reported honoraria from Lilly and Celgene.

SAN DIEGO – In the long run, standard chemotherapy alone is more effective than radiation in keeping patients with limited-stage nonbulky Hodgkin’s lymphoma alive, according to updated results from an intergroup trial in 405 patients.

At 12 years, 94% of patients receiving ABVD – doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velbe), and dacarbazine – chemotherapy were alive, compared with 87% receiving subtotal nodal radiation with or without chemotherapy (hazard ratio for death, 0.50; P = .04).

Although 5-year data showed that patients treated with radiation experienced greater disease control, the survival advantage with chemotherapy resulted from a lower rate of death from other causes, Dr. Ralph M. Meyer said at the annual meeting of the American Society of Hematology.

A total of 12 patients in the ABVD arm died: six due to Hodgkin’s, four to a second cancer, and two due to cardiac causes. In contrast, 10 of the 24 deaths in the radiation arm were due to a second cancer. There were two deaths due to cardiac events, four to Hodgkin’s, three fatal infections, and five other deaths.

Dr. Meyer acknowledged that interpretation of the results is bound to be controversial because subtotal nodal radiation is no longer current practice as it is considered excessive. Patients today with low-risk stage IA or IIA nonbulky disease typically receive two cycles of ABVD with 20 Gy of involved-field radiation therapy. Although modern technology has reduced radiation exposure, radiation therapy would still include the coronary artery, heart, and substantial areas of the subdiaphragmatic, he said at a press briefing.

What is clear from the National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study is that measures of disease control, like freedom from progressive disease, are not accurate surrogates for long-term overall survival in patients with stage I-II nonbulky Hodgkin’s lymphoma, said Dr. Meyer, director of the National Cancer Institute of Canada Clinical Trials Group.

"New proxies that predict for risks of late-treatment effects are needed," he said.

Trials are testing the use of PET scanning during therapy to identify patients who may receive chemotherapy alone. It is hypothesized that if PET scans are negative and patients are in remission after two cycles of chemotherapy, the cure rate will be high with further chemotherapy alone, whereas radiation therapy or some other form of chemotherapy should be considered if there is residual PET activity.

How the use of PET will alter current treatment management will be another contentious issue since results from ongoing trials are not expected for 2-3 years. Moreover, the trials are limited because they are using disease control and progression-free survival as end points, which the current trial has shown are not good proxies for overall survival, Dr. Meyer said.

"Thus it will cause issues and interpretation as to how to proceed with these results," he said.

Dr. Meyer and his associates randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma to receive ABVD chemotherapy alone or subtotal nodal radiation at a dose of 35 Gy in 20 daily fractions. Patients in the radiation group with a favorable risk profile received radiation only, while those with an unfavorable risk received two cycles of ABVD followed by radiation therapy. Median follow-up was 11.3 years.

At 12 years, freedom from disease progression was 92% with radiation vs. 87% with ABVD chemotherapy (HR, 1.91; P = .05,), Dr. Meyer said. Event-free survival was similar at 80% with radiation therapy and 85% with ABVD (HR, 0.88; P = .60).

The results were simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2011 [doi:10.1056/NEJMoa1111961]).

Dr. Meyer reported honoraria from Lilly and Celgene.

SAN DIEGO – Maintain with more rituximab or re-treat? For patients with low tumor burden follicular lymphomas, the answer seems to be that it doesn’t much matter, said investigators at the annual meeting of the American Society of Hematology.

Following 4 weeks of induction with rituximab monotherapy, time to treatment failure (TTTF), the primary end point, was virtually identical between patients randomized to 12 weeks of rituximab (Rituxan) maintenance (3.9 years) or rituximab re-treatment at progression (3.6 years, P = .80) in the E4402 RESORT (Rituximab Extended Schedule or Re-Treatment Trial) study.

One year after randomization, there were no significant differences in patient quality of life or stress burden between the treatment strategies, said Dr. Brad S. Kahl of the University of Wisconsin, Madison, on behalf of coinvestigators a briefing in advance of his presentation of the results at a late-breaking abstracts session on Dec. 13.

For the end point of time to first cytotoxic therapy, however, maintenance was significantly better, with 95% of patients not on chemotherapy at 3 years, compared with 86% for the re-treatment strategy (hazard ratio, 2.5; P = .027).

"Both strategies performed extremely well," Dr. Kahl said.

The re-treatment strategy was less costly: Patients in the maintenance arm received a mean of 15.8 total doses of rituximab, compared with a mean 4.5 doses in the re-treatment arm, Dr. Kahl noted. "To get this very small improvement in time to chemotherapy took roughly 4 times more drug in the maintenance arm," he said,

"Given that there was no difference in time to treatment failure, and given the excellent results with re-treatment or time to first chemotherapy, given a slightly better toxicity profile [with re-treatment], given a lack of a quality-of-life benefit for maintenance, and given the resource utilization strategy, the re-treatment strategy would be our recommended strategy when you\'re administering single-agent rituximab in this patient population," he said.

Maintenance does, however, provide a progression-free survival advantage for patients with high tumor burden follicular lymphoma following induction with a combination immunochemotherapy regimen, as shown in the PRIMA trial, in which 2-years of rituximab maintenance was associated with significantly better progression-free survival compared with observation alone (Lancet 2011;377:42-51 [doi:10.1016/S0140-6736(10)62175-7]).

But some patients with low tumor burden may still be anxious about "doing nothing," and for them maintenance is still an appropriate option, said Dr. Ephraim P. Hochberg from the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"In my practice, the patients who I think are going to be psychologically intolerant of relapse, or for whom relapse is a devastating personal event, those are patients for whom there is a benefit to maintenance rituximab that\'s not measured in this sort of analysis," he said in an interview. Dr. Hochberg was not involved in RESORT.

The RESORT trial enrolled 545 patients with non-Hodgkin’s lymphoma, 384 of whom (71%) had a follicular histology; patients with nonfollicular histologies are being analyzed separately. Among the 384 patients, 274 had a response to induction rituximab, and were then randomized to either re-treatment at progression (134) or to maintenance with rituximab 375 mg/m² every 12 weeks. Each strategy was continued until treatment failure.

Time to treatment failure was defined as progression within 6 months of the last rituximab infusion, no response to re-treatment, initiation of alternative therapy, or inability to complete the protocol therapy. Patients were evaluated every 3 months and had restaging CT scans every 6 months,

Grade 3 or 4 hematologic toxicities were seen in less than 5% of patients, and there were two on-study deaths, one in each treatment arm. Both strategies were "extremely well tolerated with minimal toxicities," Dr. Kahl said. There were more toxicities leading to a failure event in the maintenance arm, however.

"Our analysis so far shows that there is no quality-of-life benefit for the maintenance strategy relative to retreatment," he said.

The E4402 (RESORT) trial was sponsored by the Eastern Cooperative Oncology Group and the National Cancer Institute. Dr. Kahl disclosed being a consultant to Genentech and Roche, comarketer of rituximab. Two of his coauthors also are consultants to the company, and one is an employee. Dr. Hochberg has received consulting fees or research support from the company.

SAN DIEGO – Maintain with more rituximab or re-treat? For patients with low tumor burden follicular lymphomas, the answer seems to be that it doesn’t much matter, said investigators at the annual meeting of the American Society of Hematology.

Following 4 weeks of induction with rituximab monotherapy, time to treatment failure (TTTF), the primary end point, was virtually identical between patients randomized to 12 weeks of rituximab (Rituxan) maintenance (3.9 years) or rituximab re-treatment at progression (3.6 years, P = .80) in the E4402 RESORT (Rituximab Extended Schedule or Re-Treatment Trial) study.

One year after randomization, there were no significant differences in patient quality of life or stress burden between the treatment strategies, said Dr. Brad S. Kahl of the University of Wisconsin, Madison, on behalf of coinvestigators a briefing in advance of his presentation of the results at a late-breaking abstracts session on Dec. 13.

For the end point of time to first cytotoxic therapy, however, maintenance was significantly better, with 95% of patients not on chemotherapy at 3 years, compared with 86% for the re-treatment strategy (hazard ratio, 2.5; P = .027).

"Both strategies performed extremely well," Dr. Kahl said.

The re-treatment strategy was less costly: Patients in the maintenance arm received a mean of 15.8 total doses of rituximab, compared with a mean 4.5 doses in the re-treatment arm, Dr. Kahl noted. "To get this very small improvement in time to chemotherapy took roughly 4 times more drug in the maintenance arm," he said,

"Given that there was no difference in time to treatment failure, and given the excellent results with re-treatment or time to first chemotherapy, given a slightly better toxicity profile [with re-treatment], given a lack of a quality-of-life benefit for maintenance, and given the resource utilization strategy, the re-treatment strategy would be our recommended strategy when you\'re administering single-agent rituximab in this patient population," he said.

Maintenance does, however, provide a progression-free survival advantage for patients with high tumor burden follicular lymphoma following induction with a combination immunochemotherapy regimen, as shown in the PRIMA trial, in which 2-years of rituximab maintenance was associated with significantly better progression-free survival compared with observation alone (Lancet 2011;377:42-51 [doi:10.1016/S0140-6736(10)62175-7]).

But some patients with low tumor burden may still be anxious about "doing nothing," and for them maintenance is still an appropriate option, said Dr. Ephraim P. Hochberg from the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"In my practice, the patients who I think are going to be psychologically intolerant of relapse, or for whom relapse is a devastating personal event, those are patients for whom there is a benefit to maintenance rituximab that\'s not measured in this sort of analysis," he said in an interview. Dr. Hochberg was not involved in RESORT.

The RESORT trial enrolled 545 patients with non-Hodgkin’s lymphoma, 384 of whom (71%) had a follicular histology; patients with nonfollicular histologies are being analyzed separately. Among the 384 patients, 274 had a response to induction rituximab, and were then randomized to either re-treatment at progression (134) or to maintenance with rituximab 375 mg/m² every 12 weeks. Each strategy was continued until treatment failure.

Time to treatment failure was defined as progression within 6 months of the last rituximab infusion, no response to re-treatment, initiation of alternative therapy, or inability to complete the protocol therapy. Patients were evaluated every 3 months and had restaging CT scans every 6 months,

Grade 3 or 4 hematologic toxicities were seen in less than 5% of patients, and there were two on-study deaths, one in each treatment arm. Both strategies were "extremely well tolerated with minimal toxicities," Dr. Kahl said. There were more toxicities leading to a failure event in the maintenance arm, however.

"Our analysis so far shows that there is no quality-of-life benefit for the maintenance strategy relative to retreatment," he said.

The E4402 (RESORT) trial was sponsored by the Eastern Cooperative Oncology Group and the National Cancer Institute. Dr. Kahl disclosed being a consultant to Genentech and Roche, comarketer of rituximab. Two of his coauthors also are consultants to the company, and one is an employee. Dr. Hochberg has received consulting fees or research support from the company.

SAN DIEGO – Maintain with more rituximab or re-treat? For patients with low tumor burden follicular lymphomas, the answer seems to be that it doesn’t much matter, said investigators at the annual meeting of the American Society of Hematology.

Following 4 weeks of induction with rituximab monotherapy, time to treatment failure (TTTF), the primary end point, was virtually identical between patients randomized to 12 weeks of rituximab (Rituxan) maintenance (3.9 years) or rituximab re-treatment at progression (3.6 years, P = .80) in the E4402 RESORT (Rituximab Extended Schedule or Re-Treatment Trial) study.

One year after randomization, there were no significant differences in patient quality of life or stress burden between the treatment strategies, said Dr. Brad S. Kahl of the University of Wisconsin, Madison, on behalf of coinvestigators a briefing in advance of his presentation of the results at a late-breaking abstracts session on Dec. 13.

For the end point of time to first cytotoxic therapy, however, maintenance was significantly better, with 95% of patients not on chemotherapy at 3 years, compared with 86% for the re-treatment strategy (hazard ratio, 2.5; P = .027).

"Both strategies performed extremely well," Dr. Kahl said.

The re-treatment strategy was less costly: Patients in the maintenance arm received a mean of 15.8 total doses of rituximab, compared with a mean 4.5 doses in the re-treatment arm, Dr. Kahl noted. "To get this very small improvement in time to chemotherapy took roughly 4 times more drug in the maintenance arm," he said,

"Given that there was no difference in time to treatment failure, and given the excellent results with re-treatment or time to first chemotherapy, given a slightly better toxicity profile [with re-treatment], given a lack of a quality-of-life benefit for maintenance, and given the resource utilization strategy, the re-treatment strategy would be our recommended strategy when you\'re administering single-agent rituximab in this patient population," he said.

Maintenance does, however, provide a progression-free survival advantage for patients with high tumor burden follicular lymphoma following induction with a combination immunochemotherapy regimen, as shown in the PRIMA trial, in which 2-years of rituximab maintenance was associated with significantly better progression-free survival compared with observation alone (Lancet 2011;377:42-51 [doi:10.1016/S0140-6736(10)62175-7]).

But some patients with low tumor burden may still be anxious about "doing nothing," and for them maintenance is still an appropriate option, said Dr. Ephraim P. Hochberg from the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"In my practice, the patients who I think are going to be psychologically intolerant of relapse, or for whom relapse is a devastating personal event, those are patients for whom there is a benefit to maintenance rituximab that\'s not measured in this sort of analysis," he said in an interview. Dr. Hochberg was not involved in RESORT.

The RESORT trial enrolled 545 patients with non-Hodgkin’s lymphoma, 384 of whom (71%) had a follicular histology; patients with nonfollicular histologies are being analyzed separately. Among the 384 patients, 274 had a response to induction rituximab, and were then randomized to either re-treatment at progression (134) or to maintenance with rituximab 375 mg/m² every 12 weeks. Each strategy was continued until treatment failure.

Time to treatment failure was defined as progression within 6 months of the last rituximab infusion, no response to re-treatment, initiation of alternative therapy, or inability to complete the protocol therapy. Patients were evaluated every 3 months and had restaging CT scans every 6 months,

Grade 3 or 4 hematologic toxicities were seen in less than 5% of patients, and there were two on-study deaths, one in each treatment arm. Both strategies were "extremely well tolerated with minimal toxicities," Dr. Kahl said. There were more toxicities leading to a failure event in the maintenance arm, however.

"Our analysis so far shows that there is no quality-of-life benefit for the maintenance strategy relative to retreatment," he said.

The E4402 (RESORT) trial was sponsored by the Eastern Cooperative Oncology Group and the National Cancer Institute. Dr. Kahl disclosed being a consultant to Genentech and Roche, comarketer of rituximab. Two of his coauthors also are consultants to the company, and one is an employee. Dr. Hochberg has received consulting fees or research support from the company.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Researchers using massively parallel sequencing to characterize the spectrum of somatic mutations in chronic lymphocytic leukemia identified nine genes that are mutated at significant frequencies in the disease.

Of these nine "driver" genes, which were identified from DNA samples from normal tissues and tumors in 91 patients with chronic lymphocytic leukemia, four have previously established roles in the disease (TP53, ATM, MYD88, and NOTCH1), and five do not (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X), Dr. Lili Wang of the Dana-Farber Cancer Institute, Boston, and her colleagues reported online in the Dec. 12 issue of the New England Journal of Medicine. The findings were reported simultaneously at the annual meeting of the American Society of Hematology.

"Strikingly, the second most frequently mutated gene in our cohort was splicing factor 3b, subunit 1 (SF3B1), with missense mutations occurring in 14 of 91 patients (15%). SF3B1 is a component of the SF3B complex, which is associated with the U2 small nuclear ribonucleoprotein (snRNP), at the catalytic center of the spliceosome," the investigators said (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMoa1109016]).

The nine driver genes identified in this study appear in five core signaling pathways, and the genes each play different, though well-established roles in these pathways, such as DNA repair and cell-cycle control, Notch signaling, inflammatory pathways, and RNA splicing (in which SF3B1, in particular, was implicated). Furthermore, each driver mutation was found to be associated with different key abnormalities; for example, the findings indicate there may be an interaction between del(11q), which is associated with aggressive disease, and SF3B1 mutation in the pathogenesis of a clinical subgroup of chronic lymphocytic leukemia.

Overall, the investigators concluded that:

• Chronic lymphocytic leukemia has a lower rate of somatic mutation than most solid tumors.

• The rate of nonsynonymous mutation was not strongly affected by therapy.

• In addition to the expected mutations in cell-cycle and DNA-repair pathways, genetic alterations in Notch signaling, inflammatory pathways, and RNA splicing and processing also exist.

• Driver mutations showed striking associations with standard prognostic markers.

The latter suggests that "particular combinations of genetic alterations may act in concert to drive cancer," the investigators said.

The findings regarding the core spliceosome component SF3B1, which they described as a "major surprise," led to further analyses that suggested that SF3B1 mutations lead to "mistakes in the splicing of ... transcripts that affect the pathogenesis of chronic lymphocytic leukemia," they said, adding that ongoing studies will evaluate how mutations in SF3B1 alter its function in the processing of critical messenger RNAs.

The study, and in particular the findings regarding SF3B1 mutations, illustrate how identification of coding mutations in chronic lymphocytic leukemia can lead to the development of mechanistic hypotheses, novel prognostic markers, and potential therapeutic targets, Dr. Wang and her associates said.

They also noted the information provides a starting point for determining "which genes within chromosomal deletions and amplifications are essential, how each mutation alters cellular networks and phenotypes, which combinations of mutations are critical in the development of cancer, and how genetic events in the host may affect the importance of specific mutations and their combinations."

In an accompanying editorial, Dr. Benjamin Ebert and Olivier A. Bernard, Ph.D., commented that the study finding regarding mutations in genes involved in RNA splicing, although highly unexpected, converge remarkably with recent published findings from studies of myelodysplastic syndromes (N. Engl. J. Med. 2011;35:1384-95; Nature 2011;478:64-9).

SF3B1 mutations were found in 20% of patients with myelodysplastic syndromes, and in 65% of patients with refractory anemia and ring sideroblasts in one study (N. Engl. J. Med. 2011;35:1384-95).

"Moreover, mutations have been reported in multiple components of the spliceosome in 45%-85% of patients with myelodysplastic syndrome. SF3B1 mutations also occur in 1%-5% of samples from a wide range of tumor types, which indicates that mutations in RNA splicing factors are a widespread cause of oncogenic transformation," they added.

These and other findings, taken together, raise the "provocative possibility" that SF3B1 mutations may sometimes occur first in hematopoietic stem cells, with "additional mutations then being acquired in either the lymphoid or the myeloid lineages and causing chronic lymphocytic leukemia or myelodysplastic syndromes, respectively," Dr. Ebert of Brigham and Women’s Hospital, Boston, and Dr. Bernard, who is with INSERM at Institut Gustave Roussy, Villejuif, France, wrote (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMe1111584]).

The findings have implications for determining prognosis, and for identifying targets for treatment. For example, the identification of mutations in genes encoding the RNA splicing machinery raises the possibility that spliceosome could be a therapeutic target, they said.

This study was supported by grants from the National Institutes of Health, the National Cancer Institute, the Melton and Rosenbach Funds, the Blavatnik Family Foundation, the Howard Hughes Medical Institute (via an Early Career Physician-Scientist Award), and the Damon Runyon Cancer Research Foundation. Dr. Wang said she had no relevant financial disclosures. Some of the coauthors said they were consultants to numerous pharmaceutical companies or owned stock in pharmaceutical companies. Other than employment by INSERM on the part of Dr. Bernard, neither he nor Dr. Ebert had any relevant financial disclosures to report.

Researchers using massively parallel sequencing to characterize the spectrum of somatic mutations in chronic lymphocytic leukemia identified nine genes that are mutated at significant frequencies in the disease.

Of these nine "driver" genes, which were identified from DNA samples from normal tissues and tumors in 91 patients with chronic lymphocytic leukemia, four have previously established roles in the disease (TP53, ATM, MYD88, and NOTCH1), and five do not (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X), Dr. Lili Wang of the Dana-Farber Cancer Institute, Boston, and her colleagues reported online in the Dec. 12 issue of the New England Journal of Medicine. The findings were reported simultaneously at the annual meeting of the American Society of Hematology.

"Strikingly, the second most frequently mutated gene in our cohort was splicing factor 3b, subunit 1 (SF3B1), with missense mutations occurring in 14 of 91 patients (15%). SF3B1 is a component of the SF3B complex, which is associated with the U2 small nuclear ribonucleoprotein (snRNP), at the catalytic center of the spliceosome," the investigators said (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMoa1109016]).

The nine driver genes identified in this study appear in five core signaling pathways, and the genes each play different, though well-established roles in these pathways, such as DNA repair and cell-cycle control, Notch signaling, inflammatory pathways, and RNA splicing (in which SF3B1, in particular, was implicated). Furthermore, each driver mutation was found to be associated with different key abnormalities; for example, the findings indicate there may be an interaction between del(11q), which is associated with aggressive disease, and SF3B1 mutation in the pathogenesis of a clinical subgroup of chronic lymphocytic leukemia.

Overall, the investigators concluded that:

• Chronic lymphocytic leukemia has a lower rate of somatic mutation than most solid tumors.

• The rate of nonsynonymous mutation was not strongly affected by therapy.

• In addition to the expected mutations in cell-cycle and DNA-repair pathways, genetic alterations in Notch signaling, inflammatory pathways, and RNA splicing and processing also exist.

• Driver mutations showed striking associations with standard prognostic markers.

The latter suggests that "particular combinations of genetic alterations may act in concert to drive cancer," the investigators said.

The findings regarding the core spliceosome component SF3B1, which they described as a "major surprise," led to further analyses that suggested that SF3B1 mutations lead to "mistakes in the splicing of ... transcripts that affect the pathogenesis of chronic lymphocytic leukemia," they said, adding that ongoing studies will evaluate how mutations in SF3B1 alter its function in the processing of critical messenger RNAs.

The study, and in particular the findings regarding SF3B1 mutations, illustrate how identification of coding mutations in chronic lymphocytic leukemia can lead to the development of mechanistic hypotheses, novel prognostic markers, and potential therapeutic targets, Dr. Wang and her associates said.

They also noted the information provides a starting point for determining "which genes within chromosomal deletions and amplifications are essential, how each mutation alters cellular networks and phenotypes, which combinations of mutations are critical in the development of cancer, and how genetic events in the host may affect the importance of specific mutations and their combinations."

In an accompanying editorial, Dr. Benjamin Ebert and Olivier A. Bernard, Ph.D., commented that the study finding regarding mutations in genes involved in RNA splicing, although highly unexpected, converge remarkably with recent published findings from studies of myelodysplastic syndromes (N. Engl. J. Med. 2011;35:1384-95; Nature 2011;478:64-9).

SF3B1 mutations were found in 20% of patients with myelodysplastic syndromes, and in 65% of patients with refractory anemia and ring sideroblasts in one study (N. Engl. J. Med. 2011;35:1384-95).

"Moreover, mutations have been reported in multiple components of the spliceosome in 45%-85% of patients with myelodysplastic syndrome. SF3B1 mutations also occur in 1%-5% of samples from a wide range of tumor types, which indicates that mutations in RNA splicing factors are a widespread cause of oncogenic transformation," they added.

These and other findings, taken together, raise the "provocative possibility" that SF3B1 mutations may sometimes occur first in hematopoietic stem cells, with "additional mutations then being acquired in either the lymphoid or the myeloid lineages and causing chronic lymphocytic leukemia or myelodysplastic syndromes, respectively," Dr. Ebert of Brigham and Women’s Hospital, Boston, and Dr. Bernard, who is with INSERM at Institut Gustave Roussy, Villejuif, France, wrote (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMe1111584]).

The findings have implications for determining prognosis, and for identifying targets for treatment. For example, the identification of mutations in genes encoding the RNA splicing machinery raises the possibility that spliceosome could be a therapeutic target, they said.

This study was supported by grants from the National Institutes of Health, the National Cancer Institute, the Melton and Rosenbach Funds, the Blavatnik Family Foundation, the Howard Hughes Medical Institute (via an Early Career Physician-Scientist Award), and the Damon Runyon Cancer Research Foundation. Dr. Wang said she had no relevant financial disclosures. Some of the coauthors said they were consultants to numerous pharmaceutical companies or owned stock in pharmaceutical companies. Other than employment by INSERM on the part of Dr. Bernard, neither he nor Dr. Ebert had any relevant financial disclosures to report.

Researchers using massively parallel sequencing to characterize the spectrum of somatic mutations in chronic lymphocytic leukemia identified nine genes that are mutated at significant frequencies in the disease.

Of these nine "driver" genes, which were identified from DNA samples from normal tissues and tumors in 91 patients with chronic lymphocytic leukemia, four have previously established roles in the disease (TP53, ATM, MYD88, and NOTCH1), and five do not (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X), Dr. Lili Wang of the Dana-Farber Cancer Institute, Boston, and her colleagues reported online in the Dec. 12 issue of the New England Journal of Medicine. The findings were reported simultaneously at the annual meeting of the American Society of Hematology.

"Strikingly, the second most frequently mutated gene in our cohort was splicing factor 3b, subunit 1 (SF3B1), with missense mutations occurring in 14 of 91 patients (15%). SF3B1 is a component of the SF3B complex, which is associated with the U2 small nuclear ribonucleoprotein (snRNP), at the catalytic center of the spliceosome," the investigators said (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMoa1109016]).

The nine driver genes identified in this study appear in five core signaling pathways, and the genes each play different, though well-established roles in these pathways, such as DNA repair and cell-cycle control, Notch signaling, inflammatory pathways, and RNA splicing (in which SF3B1, in particular, was implicated). Furthermore, each driver mutation was found to be associated with different key abnormalities; for example, the findings indicate there may be an interaction between del(11q), which is associated with aggressive disease, and SF3B1 mutation in the pathogenesis of a clinical subgroup of chronic lymphocytic leukemia.

Overall, the investigators concluded that:

• Chronic lymphocytic leukemia has a lower rate of somatic mutation than most solid tumors.

• The rate of nonsynonymous mutation was not strongly affected by therapy.

• In addition to the expected mutations in cell-cycle and DNA-repair pathways, genetic alterations in Notch signaling, inflammatory pathways, and RNA splicing and processing also exist.

• Driver mutations showed striking associations with standard prognostic markers.

The latter suggests that "particular combinations of genetic alterations may act in concert to drive cancer," the investigators said.

The findings regarding the core spliceosome component SF3B1, which they described as a "major surprise," led to further analyses that suggested that SF3B1 mutations lead to "mistakes in the splicing of ... transcripts that affect the pathogenesis of chronic lymphocytic leukemia," they said, adding that ongoing studies will evaluate how mutations in SF3B1 alter its function in the processing of critical messenger RNAs.

The study, and in particular the findings regarding SF3B1 mutations, illustrate how identification of coding mutations in chronic lymphocytic leukemia can lead to the development of mechanistic hypotheses, novel prognostic markers, and potential therapeutic targets, Dr. Wang and her associates said.

They also noted the information provides a starting point for determining "which genes within chromosomal deletions and amplifications are essential, how each mutation alters cellular networks and phenotypes, which combinations of mutations are critical in the development of cancer, and how genetic events in the host may affect the importance of specific mutations and their combinations."

In an accompanying editorial, Dr. Benjamin Ebert and Olivier A. Bernard, Ph.D., commented that the study finding regarding mutations in genes involved in RNA splicing, although highly unexpected, converge remarkably with recent published findings from studies of myelodysplastic syndromes (N. Engl. J. Med. 2011;35:1384-95; Nature 2011;478:64-9).

SF3B1 mutations were found in 20% of patients with myelodysplastic syndromes, and in 65% of patients with refractory anemia and ring sideroblasts in one study (N. Engl. J. Med. 2011;35:1384-95).

"Moreover, mutations have been reported in multiple components of the spliceosome in 45%-85% of patients with myelodysplastic syndrome. SF3B1 mutations also occur in 1%-5% of samples from a wide range of tumor types, which indicates that mutations in RNA splicing factors are a widespread cause of oncogenic transformation," they added.

These and other findings, taken together, raise the "provocative possibility" that SF3B1 mutations may sometimes occur first in hematopoietic stem cells, with "additional mutations then being acquired in either the lymphoid or the myeloid lineages and causing chronic lymphocytic leukemia or myelodysplastic syndromes, respectively," Dr. Ebert of Brigham and Women’s Hospital, Boston, and Dr. Bernard, who is with INSERM at Institut Gustave Roussy, Villejuif, France, wrote (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMe1111584]).

The findings have implications for determining prognosis, and for identifying targets for treatment. For example, the identification of mutations in genes encoding the RNA splicing machinery raises the possibility that spliceosome could be a therapeutic target, they said.

This study was supported by grants from the National Institutes of Health, the National Cancer Institute, the Melton and Rosenbach Funds, the Blavatnik Family Foundation, the Howard Hughes Medical Institute (via an Early Career Physician-Scientist Award), and the Damon Runyon Cancer Research Foundation. Dr. Wang said she had no relevant financial disclosures. Some of the coauthors said they were consultants to numerous pharmaceutical companies or owned stock in pharmaceutical companies. Other than employment by INSERM on the part of Dr. Bernard, neither he nor Dr. Ebert had any relevant financial disclosures to report.