HIV budding from

a cultured lymphocyte

Credit: CDC

SAN FRANCISCO—Patients with HIV-related lymphoma (HRL) should not be excluded from clinical trials of autologous stem cell transplant (ASCT) due to their HIV status, new research suggests.

Investigators found no significant difference in rates of treatment failure, disease progression, or survival between transplant-treated historical controls who had lymphoma but not HIV and patients with HRL who received the modified BEAM regimen followed by ASCT on a phase 2 trial.

This suggests patients with chemotherapy-sensitive, relapsed/refractory HRL can be treated successfully with the modified BEAM regimen, said study investigator Joseph Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.

“Patients with treatment-responsive HIV infection and HIV-related lymphoma should be considered candidates for autologous transplant if they meet standard transplant criteria,” he added. “And we would argue that exclusion from clinical trials on the basis of HIV infection alone is no longer justified.”

Dr Alvarnas presented this viewpoint and the research to support it at the 2014 ASH Annual Meeting as abstract 674.

The trial enrolled 43 patients with treatable HIV-1 infection, adequate organ function, and aggressive lymphoma. Three patients were excluded because they could not undergo transplant due to lymphoma progression.

Of the 40 remaining patients, 5 were female, and their median age was 46.9 years (range, 22.5-62.2). They had diffuse large B-cell lymphoma (n=16), plasmablastic lymphoma (n=2), Burkitt/Burkitt-like lymphoma (n=7), and Hodgkin lymphoma (n=15).

The pre-ASCT HIV viral load was undetectable in 31 patients. In the patients with detectable HIV, the median viral load pre-ASCT was 84 copies/μL (range, 50-17,455). The median CD4 count was 250.5/µL (range, 39-797).

Before transplant, 30 patients (75%) were in complete remission, 8 (20%) were in partial remission, and 2 (5%) had relapsed/progressive disease.

The patients underwent ASCT after conditioning with the modified BEAM regimen—carmustine at 300 mg/m² (day -6), etoposide at 100 mg/m² twice daily (days -5 to -2), cytarabine at 100 mg/m² (days -5 to -2), and melphalan at 140 mg/m² (day -1).

Combination antiretroviral therapy (cART) was held during the preparative regimen and resumed after the resolution of gastrointestinal toxicity. The investigators switched efavirenz to an alternative agent 2 or more weeks prior to the planned interruption of cART, as the drug has a long half-life. And AZT was prohibited due to its myelosuppressive effects.

Treatment results

The median follow-up was 24 months. At 100 days post-transplant, the investigators assessed 39 patients for response. One patient was not evaluable due to early death.

Thirty-six of the patients (92.3%) were in complete remission, 1 (2.6%) was in partial remission, and 2 (5.1%) had relapsed or progressive disease.

Fifteen patients reported grade 3 or higher toxicities within a year of transplant. Of the 13 unexpected grade 3-5 adverse events (reported in 9 patients), 5 were infection/sepsis, 1 was acute appendicitis, 1 was acute coronary syndrome, 2 were deep vein thromboses, 2 were gastrointestinal toxicities, and 2 were metabolic abnormalities.

Seventeen patients reported at least 1 infectious episode, 42 events in total, 9 of which were severe. Fourteen patients required readmission to the hospital after transplant.

Within a year of transplant, 5 patients had died—3 from recurrent/persistent disease, 1 due to a fungal infection, and 1 from cardiac arrest. Two additional patients died after the 1-year mark—1 of recurrent/persistent disease and 1 of heart failure.

At 12 months, the rate of overall survival was 86.6%, progression-free survival was 82.3%, progression was 12.5%, and non-relapse mortality was 5.2%.

“In order to place this within context, we had the opportunity to compare our patient experience with 151 matched controls [without HIV] from CIBMTR,” Dr Alvarnas said. “Ninety-three percent of these patients were actually transplanted within 2 years so that they were the time-concordant group, and they were matched for performance score, disease, and disease stage.”

The investigators found no significant difference between their patient group and the HIV-free controls with regard to overall mortality (P=0.56), treatment failure (P=0.10), progression (P=0.06), and treatment-related mortality (P=0.97).

Likewise, there was no significant difference in overall survival between the HRL patients and controls—86.6% and 87.7%, respectively (P=0.56). And the same was true of progression-free survival—82.3% and 69.5%, respectively (P=0.10).

HIV budding from

a cultured lymphocyte

Credit: CDC

SAN FRANCISCO—Patients with HIV-related lymphoma (HRL) should not be excluded from clinical trials of autologous stem cell transplant (ASCT) due to their HIV status, new research suggests.

Investigators found no significant difference in rates of treatment failure, disease progression, or survival between transplant-treated historical controls who had lymphoma but not HIV and patients with HRL who received the modified BEAM regimen followed by ASCT on a phase 2 trial.

This suggests patients with chemotherapy-sensitive, relapsed/refractory HRL can be treated successfully with the modified BEAM regimen, said study investigator Joseph Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.

“Patients with treatment-responsive HIV infection and HIV-related lymphoma should be considered candidates for autologous transplant if they meet standard transplant criteria,” he added. “And we would argue that exclusion from clinical trials on the basis of HIV infection alone is no longer justified.”

Dr Alvarnas presented this viewpoint and the research to support it at the 2014 ASH Annual Meeting as abstract 674.

The trial enrolled 43 patients with treatable HIV-1 infection, adequate organ function, and aggressive lymphoma. Three patients were excluded because they could not undergo transplant due to lymphoma progression.

Of the 40 remaining patients, 5 were female, and their median age was 46.9 years (range, 22.5-62.2). They had diffuse large B-cell lymphoma (n=16), plasmablastic lymphoma (n=2), Burkitt/Burkitt-like lymphoma (n=7), and Hodgkin lymphoma (n=15).

The pre-ASCT HIV viral load was undetectable in 31 patients. In the patients with detectable HIV, the median viral load pre-ASCT was 84 copies/μL (range, 50-17,455). The median CD4 count was 250.5/µL (range, 39-797).

Before transplant, 30 patients (75%) were in complete remission, 8 (20%) were in partial remission, and 2 (5%) had relapsed/progressive disease.

The patients underwent ASCT after conditioning with the modified BEAM regimen—carmustine at 300 mg/m² (day -6), etoposide at 100 mg/m² twice daily (days -5 to -2), cytarabine at 100 mg/m² (days -5 to -2), and melphalan at 140 mg/m² (day -1).

Combination antiretroviral therapy (cART) was held during the preparative regimen and resumed after the resolution of gastrointestinal toxicity. The investigators switched efavirenz to an alternative agent 2 or more weeks prior to the planned interruption of cART, as the drug has a long half-life. And AZT was prohibited due to its myelosuppressive effects.

Treatment results

The median follow-up was 24 months. At 100 days post-transplant, the investigators assessed 39 patients for response. One patient was not evaluable due to early death.

Thirty-six of the patients (92.3%) were in complete remission, 1 (2.6%) was in partial remission, and 2 (5.1%) had relapsed or progressive disease.

Fifteen patients reported grade 3 or higher toxicities within a year of transplant. Of the 13 unexpected grade 3-5 adverse events (reported in 9 patients), 5 were infection/sepsis, 1 was acute appendicitis, 1 was acute coronary syndrome, 2 were deep vein thromboses, 2 were gastrointestinal toxicities, and 2 were metabolic abnormalities.

Seventeen patients reported at least 1 infectious episode, 42 events in total, 9 of which were severe. Fourteen patients required readmission to the hospital after transplant.

Within a year of transplant, 5 patients had died—3 from recurrent/persistent disease, 1 due to a fungal infection, and 1 from cardiac arrest. Two additional patients died after the 1-year mark—1 of recurrent/persistent disease and 1 of heart failure.

At 12 months, the rate of overall survival was 86.6%, progression-free survival was 82.3%, progression was 12.5%, and non-relapse mortality was 5.2%.

“In order to place this within context, we had the opportunity to compare our patient experience with 151 matched controls [without HIV] from CIBMTR,” Dr Alvarnas said. “Ninety-three percent of these patients were actually transplanted within 2 years so that they were the time-concordant group, and they were matched for performance score, disease, and disease stage.”

The investigators found no significant difference between their patient group and the HIV-free controls with regard to overall mortality (P=0.56), treatment failure (P=0.10), progression (P=0.06), and treatment-related mortality (P=0.97).

Likewise, there was no significant difference in overall survival between the HRL patients and controls—86.6% and 87.7%, respectively (P=0.56). And the same was true of progression-free survival—82.3% and 69.5%, respectively (P=0.10).

HIV budding from

a cultured lymphocyte

Credit: CDC

SAN FRANCISCO—Patients with HIV-related lymphoma (HRL) should not be excluded from clinical trials of autologous stem cell transplant (ASCT) due to their HIV status, new research suggests.

Investigators found no significant difference in rates of treatment failure, disease progression, or survival between transplant-treated historical controls who had lymphoma but not HIV and patients with HRL who received the modified BEAM regimen followed by ASCT on a phase 2 trial.

This suggests patients with chemotherapy-sensitive, relapsed/refractory HRL can be treated successfully with the modified BEAM regimen, said study investigator Joseph Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.

“Patients with treatment-responsive HIV infection and HIV-related lymphoma should be considered candidates for autologous transplant if they meet standard transplant criteria,” he added. “And we would argue that exclusion from clinical trials on the basis of HIV infection alone is no longer justified.”

Dr Alvarnas presented this viewpoint and the research to support it at the 2014 ASH Annual Meeting as abstract 674.

The trial enrolled 43 patients with treatable HIV-1 infection, adequate organ function, and aggressive lymphoma. Three patients were excluded because they could not undergo transplant due to lymphoma progression.

Of the 40 remaining patients, 5 were female, and their median age was 46.9 years (range, 22.5-62.2). They had diffuse large B-cell lymphoma (n=16), plasmablastic lymphoma (n=2), Burkitt/Burkitt-like lymphoma (n=7), and Hodgkin lymphoma (n=15).

The pre-ASCT HIV viral load was undetectable in 31 patients. In the patients with detectable HIV, the median viral load pre-ASCT was 84 copies/μL (range, 50-17,455). The median CD4 count was 250.5/µL (range, 39-797).

Before transplant, 30 patients (75%) were in complete remission, 8 (20%) were in partial remission, and 2 (5%) had relapsed/progressive disease.

The patients underwent ASCT after conditioning with the modified BEAM regimen—carmustine at 300 mg/m² (day -6), etoposide at 100 mg/m² twice daily (days -5 to -2), cytarabine at 100 mg/m² (days -5 to -2), and melphalan at 140 mg/m² (day -1).

Combination antiretroviral therapy (cART) was held during the preparative regimen and resumed after the resolution of gastrointestinal toxicity. The investigators switched efavirenz to an alternative agent 2 or more weeks prior to the planned interruption of cART, as the drug has a long half-life. And AZT was prohibited due to its myelosuppressive effects.

Treatment results

The median follow-up was 24 months. At 100 days post-transplant, the investigators assessed 39 patients for response. One patient was not evaluable due to early death.

Thirty-six of the patients (92.3%) were in complete remission, 1 (2.6%) was in partial remission, and 2 (5.1%) had relapsed or progressive disease.

Fifteen patients reported grade 3 or higher toxicities within a year of transplant. Of the 13 unexpected grade 3-5 adverse events (reported in 9 patients), 5 were infection/sepsis, 1 was acute appendicitis, 1 was acute coronary syndrome, 2 were deep vein thromboses, 2 were gastrointestinal toxicities, and 2 were metabolic abnormalities.

Seventeen patients reported at least 1 infectious episode, 42 events in total, 9 of which were severe. Fourteen patients required readmission to the hospital after transplant.

Within a year of transplant, 5 patients had died—3 from recurrent/persistent disease, 1 due to a fungal infection, and 1 from cardiac arrest. Two additional patients died after the 1-year mark—1 of recurrent/persistent disease and 1 of heart failure.

At 12 months, the rate of overall survival was 86.6%, progression-free survival was 82.3%, progression was 12.5%, and non-relapse mortality was 5.2%.

“In order to place this within context, we had the opportunity to compare our patient experience with 151 matched controls [without HIV] from CIBMTR,” Dr Alvarnas said. “Ninety-three percent of these patients were actually transplanted within 2 years so that they were the time-concordant group, and they were matched for performance score, disease, and disease stage.”

The investigators found no significant difference between their patient group and the HIV-free controls with regard to overall mortality (P=0.56), treatment failure (P=0.10), progression (P=0.06), and treatment-related mortality (P=0.97).

Likewise, there was no significant difference in overall survival between the HRL patients and controls—86.6% and 87.7%, respectively (P=0.56). And the same was true of progression-free survival—82.3% and 69.5%, respectively (P=0.10).

 

 

Monoclonal antibodies

Credit: Linda Bartlett

 

SAN FRANCISCO—Maintenance therapy with the anti-CD20 monoclonal antibody ofatumumab improves progression-free survival (PFS), but not overall survival (OS), in patients with relapsed chronic lymphocytic leukemia (CLL), according to an interim analysis of the PROLONG study.

The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance (P<0.0001).

But there was no significant difference in the median OS, which was not reached in either treatment arm.

Marinus H.J. van Oers, MD, PhD, of the Academisch Medisch Centrum and HOVON in Amsterdam, The Netherlands, reported these results at the 2014 ASH Annual Meeting (abstract 21*). The study was sponsored by GlaxoSmithKline, makers of ofatumumab.

“[A]s of 2014, still we cannot say that we are able to cure CLL,” Dr van Oers noted. “And CLL is characterized by decreasing response duration with subsequent lines of treatment. In this respect, but also a number of other respects, there are similarities in biological behavior between CLL and follicular lymphoma.”

“There is definitely a role—although it’s somewhat debated—for maintenance treatment in follicular lymphoma. Therefore, it is rational to explore safe and effective maintenance treatment in CLL as well.”

To that end, Dr van Oers and his colleagues compared ofatumumab maintenance to observation in patients who were in remission after induction treatment for relapsed CLL. The team enrolled 474 patients who were in complete or partial remission after their 2nd- or 3rd-line treatment for CLL.

Patients were randomized to observation (n=236) or to receive ofatumumab (n=238) at 300 mg, followed 1 week later by 1000 mg every 8 weeks for up to 2 years. Patients on ofatumumab also received premedication with acetaminophen, antihistamine, and glucocorticoid.

The patients were stratified by the number and type of prior therapy, as well as remission status after induction treatment, and baseline characteristics were similar between the two treatment arms.

“The median age was about 65, and about 30% of patients were older than 70 years,” Dr van Oers noted. “[There was] a male preponderance, as you would expect, and the time since diagnosis was somewhere between 5 and 6 years.”

“Most patients were in [partial response], actually 80%, and most patients had received 2 prior regimens, about 70%. As for prior treatments, 80% of patients had received effective immuno-chemotherapy.”

“In both arms, there were only a few patients with unfavorable cytogenetics—11q and 17p deletion. [As for] β2 microglobulin, two-thirds [of patients in both arms] had low levels. And, in both arms, there were almost twice as many IGVH-mutated as unmutated patients.”

Patient outcomes

The median follow-up was 19.1 months. The study’s primary endpoint was PFS, which was defined as the time from randomization to the date of disease progression or death from any cause.

The median PFS was significantly longer in the ofatumumab arm than in the observation arm, at 29.4 months and 15.2 months, respectively (hazard ratio [HR]=0.50; P<0.0001).

Similarly, the time to the start of patients’ next therapy was significantly longer in the ofatumumab arm than in the in observation arm—a median of 38 months and 31.1 months, respectively (HR=0.66, P=0.108).

However, there was no significant difference in OS, which was not reached in either arm (HR=0.85, P=0.4877).

Adverse events (AEs) occurred in 86% of patients in the ofatumumab arm and 72% of patients in the observation arm (P<0.001). Sixty percent of AEs were considered related to ofatumumab. None of the AEs led to study withdrawal.

Grade 3 or higher AEs occurred in 46% of patients in the ofatumumab arm and 28% in the observation arm. They included neutropenia (24% and 10%, respectively; P<0.001), infections (13% and 8%, respectively), thrombocytopenia (2% and 3%, respectively), and infusion-related reactions (1% and 0%, respectively).

There were 5 deaths in the observation arm—1 due to progression and 4 due to causes other than progression, infection, or secondary malignancy. There were 2 deaths in the ofatumumab arm—1 due to infection/sepsis and 1 due to an “other” cause.

“So based on this planned interim analysis, we can conclude that ofatumumab maintenance in relapsed CLL results in a highly significant and clinically meaningful improvement of progression-free survival,” Dr van Oers said in closing.

“It significantly prolongs time to next treatment, it’s well-tolerated, and it’s associated with an adverse event profile which is quite characteristic of anti-CD20 monoclonal antibodies.”

*Information in the abstract differs from that presented at the meeting.

 

 

Monoclonal antibodies

Credit: Linda Bartlett

 

SAN FRANCISCO—Maintenance therapy with the anti-CD20 monoclonal antibody ofatumumab improves progression-free survival (PFS), but not overall survival (OS), in patients with relapsed chronic lymphocytic leukemia (CLL), according to an interim analysis of the PROLONG study.

The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance (P<0.0001).

But there was no significant difference in the median OS, which was not reached in either treatment arm.

Marinus H.J. van Oers, MD, PhD, of the Academisch Medisch Centrum and HOVON in Amsterdam, The Netherlands, reported these results at the 2014 ASH Annual Meeting (abstract 21*). The study was sponsored by GlaxoSmithKline, makers of ofatumumab.

“[A]s of 2014, still we cannot say that we are able to cure CLL,” Dr van Oers noted. “And CLL is characterized by decreasing response duration with subsequent lines of treatment. In this respect, but also a number of other respects, there are similarities in biological behavior between CLL and follicular lymphoma.”

“There is definitely a role—although it’s somewhat debated—for maintenance treatment in follicular lymphoma. Therefore, it is rational to explore safe and effective maintenance treatment in CLL as well.”

To that end, Dr van Oers and his colleagues compared ofatumumab maintenance to observation in patients who were in remission after induction treatment for relapsed CLL. The team enrolled 474 patients who were in complete or partial remission after their 2nd- or 3rd-line treatment for CLL.

Patients were randomized to observation (n=236) or to receive ofatumumab (n=238) at 300 mg, followed 1 week later by 1000 mg every 8 weeks for up to 2 years. Patients on ofatumumab also received premedication with acetaminophen, antihistamine, and glucocorticoid.

The patients were stratified by the number and type of prior therapy, as well as remission status after induction treatment, and baseline characteristics were similar between the two treatment arms.

“The median age was about 65, and about 30% of patients were older than 70 years,” Dr van Oers noted. “[There was] a male preponderance, as you would expect, and the time since diagnosis was somewhere between 5 and 6 years.”

“Most patients were in [partial response], actually 80%, and most patients had received 2 prior regimens, about 70%. As for prior treatments, 80% of patients had received effective immuno-chemotherapy.”

“In both arms, there were only a few patients with unfavorable cytogenetics—11q and 17p deletion. [As for] β2 microglobulin, two-thirds [of patients in both arms] had low levels. And, in both arms, there were almost twice as many IGVH-mutated as unmutated patients.”

Patient outcomes

The median follow-up was 19.1 months. The study’s primary endpoint was PFS, which was defined as the time from randomization to the date of disease progression or death from any cause.

The median PFS was significantly longer in the ofatumumab arm than in the observation arm, at 29.4 months and 15.2 months, respectively (hazard ratio [HR]=0.50; P<0.0001).

Similarly, the time to the start of patients’ next therapy was significantly longer in the ofatumumab arm than in the in observation arm—a median of 38 months and 31.1 months, respectively (HR=0.66, P=0.108).

However, there was no significant difference in OS, which was not reached in either arm (HR=0.85, P=0.4877).

Adverse events (AEs) occurred in 86% of patients in the ofatumumab arm and 72% of patients in the observation arm (P<0.001). Sixty percent of AEs were considered related to ofatumumab. None of the AEs led to study withdrawal.

Grade 3 or higher AEs occurred in 46% of patients in the ofatumumab arm and 28% in the observation arm. They included neutropenia (24% and 10%, respectively; P<0.001), infections (13% and 8%, respectively), thrombocytopenia (2% and 3%, respectively), and infusion-related reactions (1% and 0%, respectively).

There were 5 deaths in the observation arm—1 due to progression and 4 due to causes other than progression, infection, or secondary malignancy. There were 2 deaths in the ofatumumab arm—1 due to infection/sepsis and 1 due to an “other” cause.

“So based on this planned interim analysis, we can conclude that ofatumumab maintenance in relapsed CLL results in a highly significant and clinically meaningful improvement of progression-free survival,” Dr van Oers said in closing.

“It significantly prolongs time to next treatment, it’s well-tolerated, and it’s associated with an adverse event profile which is quite characteristic of anti-CD20 monoclonal antibodies.”

*Information in the abstract differs from that presented at the meeting.

 

 

Monoclonal antibodies

Credit: Linda Bartlett

 

SAN FRANCISCO—Maintenance therapy with the anti-CD20 monoclonal antibody ofatumumab improves progression-free survival (PFS), but not overall survival (OS), in patients with relapsed chronic lymphocytic leukemia (CLL), according to an interim analysis of the PROLONG study.

The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance (P<0.0001).

But there was no significant difference in the median OS, which was not reached in either treatment arm.

Marinus H.J. van Oers, MD, PhD, of the Academisch Medisch Centrum and HOVON in Amsterdam, The Netherlands, reported these results at the 2014 ASH Annual Meeting (abstract 21*). The study was sponsored by GlaxoSmithKline, makers of ofatumumab.

“[A]s of 2014, still we cannot say that we are able to cure CLL,” Dr van Oers noted. “And CLL is characterized by decreasing response duration with subsequent lines of treatment. In this respect, but also a number of other respects, there are similarities in biological behavior between CLL and follicular lymphoma.”

“There is definitely a role—although it’s somewhat debated—for maintenance treatment in follicular lymphoma. Therefore, it is rational to explore safe and effective maintenance treatment in CLL as well.”

To that end, Dr van Oers and his colleagues compared ofatumumab maintenance to observation in patients who were in remission after induction treatment for relapsed CLL. The team enrolled 474 patients who were in complete or partial remission after their 2nd- or 3rd-line treatment for CLL.

Patients were randomized to observation (n=236) or to receive ofatumumab (n=238) at 300 mg, followed 1 week later by 1000 mg every 8 weeks for up to 2 years. Patients on ofatumumab also received premedication with acetaminophen, antihistamine, and glucocorticoid.

The patients were stratified by the number and type of prior therapy, as well as remission status after induction treatment, and baseline characteristics were similar between the two treatment arms.

“The median age was about 65, and about 30% of patients were older than 70 years,” Dr van Oers noted. “[There was] a male preponderance, as you would expect, and the time since diagnosis was somewhere between 5 and 6 years.”

“Most patients were in [partial response], actually 80%, and most patients had received 2 prior regimens, about 70%. As for prior treatments, 80% of patients had received effective immuno-chemotherapy.”

“In both arms, there were only a few patients with unfavorable cytogenetics—11q and 17p deletion. [As for] β2 microglobulin, two-thirds [of patients in both arms] had low levels. And, in both arms, there were almost twice as many IGVH-mutated as unmutated patients.”

Patient outcomes

The median follow-up was 19.1 months. The study’s primary endpoint was PFS, which was defined as the time from randomization to the date of disease progression or death from any cause.

The median PFS was significantly longer in the ofatumumab arm than in the observation arm, at 29.4 months and 15.2 months, respectively (hazard ratio [HR]=0.50; P<0.0001).

Similarly, the time to the start of patients’ next therapy was significantly longer in the ofatumumab arm than in the in observation arm—a median of 38 months and 31.1 months, respectively (HR=0.66, P=0.108).

However, there was no significant difference in OS, which was not reached in either arm (HR=0.85, P=0.4877).

Adverse events (AEs) occurred in 86% of patients in the ofatumumab arm and 72% of patients in the observation arm (P<0.001). Sixty percent of AEs were considered related to ofatumumab. None of the AEs led to study withdrawal.

Grade 3 or higher AEs occurred in 46% of patients in the ofatumumab arm and 28% in the observation arm. They included neutropenia (24% and 10%, respectively; P<0.001), infections (13% and 8%, respectively), thrombocytopenia (2% and 3%, respectively), and infusion-related reactions (1% and 0%, respectively).

There were 5 deaths in the observation arm—1 due to progression and 4 due to causes other than progression, infection, or secondary malignancy. There were 2 deaths in the ofatumumab arm—1 due to infection/sepsis and 1 due to an “other” cause.

“So based on this planned interim analysis, we can conclude that ofatumumab maintenance in relapsed CLL results in a highly significant and clinically meaningful improvement of progression-free survival,” Dr van Oers said in closing.

“It significantly prolongs time to next treatment, it’s well-tolerated, and it’s associated with an adverse event profile which is quite characteristic of anti-CD20 monoclonal antibodies.”

*Information in the abstract differs from that presented at the meeting.

Lab mouse

Sepsis may have an Achilles heel that would allow for more effective treatment of the condition, according to research published in The FASEB Journal.

The study showed that CD39, an enzyme capable of clearing high levels of adenosine triphosphate (ATP) from the bloodstream, significantly improved survival of mice with severe sepsis.

Based on this finding, the researchers speculate that CD39 may also be used in other diseases associated with inflammation.

“Although we have come a long way in the treatment of sepsis since it was first described by Hippocrates in the fourth century BC, about 250,000 Americans still die from sepsis each year,” said study author Gyorgy Hasko, PhD, of Rutgers New Jersey Medical School in Newark.

“A drug that could cure patients with sepsis would not only save the lives of many, it would also decrease the enormous costs associated with treating septic patients in the intensive care unit and would help unburden the healthcare system.”

To make their discovery, Dr Hasko and his colleagues compared mice lacking the CD39 gene to wild-type mice. When sepsis was induced in both sets of mice, those without CD39 had worse survival.

With this information in hand, the researchers then performed another experiment with two more groups of normal mice that were septic.

The first group was injected with CD39 and the other with placebo. The mice that received CD39 had improved survival compared to those injected with placebo.

“Finding a more effective treatment for sepsis would be a major step forward since far too many people still die from overwhelming microbial infection,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “If CD39 proves to be as critical a factor in humans as in mice, this is a major discovery.”

Lab mouse

Sepsis may have an Achilles heel that would allow for more effective treatment of the condition, according to research published in The FASEB Journal.

The study showed that CD39, an enzyme capable of clearing high levels of adenosine triphosphate (ATP) from the bloodstream, significantly improved survival of mice with severe sepsis.

Based on this finding, the researchers speculate that CD39 may also be used in other diseases associated with inflammation.

“Although we have come a long way in the treatment of sepsis since it was first described by Hippocrates in the fourth century BC, about 250,000 Americans still die from sepsis each year,” said study author Gyorgy Hasko, PhD, of Rutgers New Jersey Medical School in Newark.

“A drug that could cure patients with sepsis would not only save the lives of many, it would also decrease the enormous costs associated with treating septic patients in the intensive care unit and would help unburden the healthcare system.”

To make their discovery, Dr Hasko and his colleagues compared mice lacking the CD39 gene to wild-type mice. When sepsis was induced in both sets of mice, those without CD39 had worse survival.

With this information in hand, the researchers then performed another experiment with two more groups of normal mice that were septic.

The first group was injected with CD39 and the other with placebo. The mice that received CD39 had improved survival compared to those injected with placebo.

“Finding a more effective treatment for sepsis would be a major step forward since far too many people still die from overwhelming microbial infection,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “If CD39 proves to be as critical a factor in humans as in mice, this is a major discovery.”

Lab mouse

Sepsis may have an Achilles heel that would allow for more effective treatment of the condition, according to research published in The FASEB Journal.

The study showed that CD39, an enzyme capable of clearing high levels of adenosine triphosphate (ATP) from the bloodstream, significantly improved survival of mice with severe sepsis.

Based on this finding, the researchers speculate that CD39 may also be used in other diseases associated with inflammation.

“Although we have come a long way in the treatment of sepsis since it was first described by Hippocrates in the fourth century BC, about 250,000 Americans still die from sepsis each year,” said study author Gyorgy Hasko, PhD, of Rutgers New Jersey Medical School in Newark.

“A drug that could cure patients with sepsis would not only save the lives of many, it would also decrease the enormous costs associated with treating septic patients in the intensive care unit and would help unburden the healthcare system.”

To make their discovery, Dr Hasko and his colleagues compared mice lacking the CD39 gene to wild-type mice. When sepsis was induced in both sets of mice, those without CD39 had worse survival.

With this information in hand, the researchers then performed another experiment with two more groups of normal mice that were septic.

The first group was injected with CD39 and the other with placebo. The mice that received CD39 had improved survival compared to those injected with placebo.

“Finding a more effective treatment for sepsis would be a major step forward since far too many people still die from overwhelming microbial infection,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “If CD39 proves to be as critical a factor in humans as in mice, this is a major discovery.”

Blood for transfusion

Credit: UAB Hospital

The process of pathogen inactivation does not compromise the quality of red blood cells (RBCs), results of a phase 3 study suggest.

Researchers compared untreated RBCs and RBCs treated with the INTERCEPT Blood System, a pathogen inactivation system.

The two sets of RBCs, which were given to cardiovascular surgery patients with acute anemia, had comparable hemoglobin content and in vitro quality, according to Cerus Corporation, makers of the INTERCEPT system.

Cerus recently announced these results, and the researchers plan to submit data from this study for presentation at upcoming scientific congresses.

“In our prior US phase 3 study in a similar patient population, INTERCEPT red cells were shown to be noninferior to control red cells in 148 patients based on a composite endpoint of myocardial infarction, renal failure, and death,” said Laurence Corash, MD, Cerus’s chief medical officer.

“The data from the recent phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. We believe that the successful results from this study, combined with data from the prior phase 3 study, support the safety and efficacy of the INTERCEPT RBC system for CE Mark registration.”

In the current trial, researchers evaluated the efficacy of the INTERCEPT system to process RBCs with quality and mean hemoglobin content (> 40 g) suitable to support transfusion according to the European Directorate for the Quality of Medicines.

The blood components were transfused in 51 cardiovascular surgery patients at 2 German trial sites. Patients undergoing procedures for coronary artery bypass grafting, valve repair, or combined procedures received transfusions during a 7-day treatment period that included the day of surgery and 6 days post-operatively.

The patients received either INTERCEPT-treated RBCs or control RBCs not treated for pathogen inactivation. RBC components for both clinical sites were manufactured at the German Red Cross blood center in Frankfurt, and the RBCs were stored for up to 35 days prior to transfusion.

The primary endpoint was the equivalence of mean hemoglobin content between INTERCEPT-treated RBCs and conventional RBCs. The mean hemoglobin content of INTERCEPT-treated RBCs on day 35 of storage (53.1 g) fell within the protocol-specified 5g equivalence margin, when compared to control RBCs (55.8 g).

The secondary efficacy endpoints also suggested INTERCEPT-treated RBCs were suitable for transfusion based on mean hematocrit of 60.4% (acceptance range: 55%-70%) and mean end-of-storage hemolysis rate of 0.28% (acceptance range < 0.8%).

There were no statistical differences in the adverse event rates between recipients of INTERCEPT-treated RBCs and control RBCs. There were no clinically relevant trends in severe or serious treatment-related adverse events by system organ class.

The observed adverse events were within the expected spectrum of comorbidity and mortality for patients of similar age and with advanced cardiovascular diseases undergoing cardiovascular surgery requiring RBC transfusion. And none of the patients exhibited an immune response to INTERCEPT-treated RBCs.

Blood for transfusion

Credit: UAB Hospital

The process of pathogen inactivation does not compromise the quality of red blood cells (RBCs), results of a phase 3 study suggest.

Researchers compared untreated RBCs and RBCs treated with the INTERCEPT Blood System, a pathogen inactivation system.

The two sets of RBCs, which were given to cardiovascular surgery patients with acute anemia, had comparable hemoglobin content and in vitro quality, according to Cerus Corporation, makers of the INTERCEPT system.

Cerus recently announced these results, and the researchers plan to submit data from this study for presentation at upcoming scientific congresses.

“In our prior US phase 3 study in a similar patient population, INTERCEPT red cells were shown to be noninferior to control red cells in 148 patients based on a composite endpoint of myocardial infarction, renal failure, and death,” said Laurence Corash, MD, Cerus’s chief medical officer.

“The data from the recent phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. We believe that the successful results from this study, combined with data from the prior phase 3 study, support the safety and efficacy of the INTERCEPT RBC system for CE Mark registration.”

In the current trial, researchers evaluated the efficacy of the INTERCEPT system to process RBCs with quality and mean hemoglobin content (> 40 g) suitable to support transfusion according to the European Directorate for the Quality of Medicines.

The blood components were transfused in 51 cardiovascular surgery patients at 2 German trial sites. Patients undergoing procedures for coronary artery bypass grafting, valve repair, or combined procedures received transfusions during a 7-day treatment period that included the day of surgery and 6 days post-operatively.

The patients received either INTERCEPT-treated RBCs or control RBCs not treated for pathogen inactivation. RBC components for both clinical sites were manufactured at the German Red Cross blood center in Frankfurt, and the RBCs were stored for up to 35 days prior to transfusion.

The primary endpoint was the equivalence of mean hemoglobin content between INTERCEPT-treated RBCs and conventional RBCs. The mean hemoglobin content of INTERCEPT-treated RBCs on day 35 of storage (53.1 g) fell within the protocol-specified 5g equivalence margin, when compared to control RBCs (55.8 g).

The secondary efficacy endpoints also suggested INTERCEPT-treated RBCs were suitable for transfusion based on mean hematocrit of 60.4% (acceptance range: 55%-70%) and mean end-of-storage hemolysis rate of 0.28% (acceptance range < 0.8%).

There were no statistical differences in the adverse event rates between recipients of INTERCEPT-treated RBCs and control RBCs. There were no clinically relevant trends in severe or serious treatment-related adverse events by system organ class.

The observed adverse events were within the expected spectrum of comorbidity and mortality for patients of similar age and with advanced cardiovascular diseases undergoing cardiovascular surgery requiring RBC transfusion. And none of the patients exhibited an immune response to INTERCEPT-treated RBCs.

Blood for transfusion

Credit: UAB Hospital

The process of pathogen inactivation does not compromise the quality of red blood cells (RBCs), results of a phase 3 study suggest.

Researchers compared untreated RBCs and RBCs treated with the INTERCEPT Blood System, a pathogen inactivation system.

The two sets of RBCs, which were given to cardiovascular surgery patients with acute anemia, had comparable hemoglobin content and in vitro quality, according to Cerus Corporation, makers of the INTERCEPT system.

Cerus recently announced these results, and the researchers plan to submit data from this study for presentation at upcoming scientific congresses.

“In our prior US phase 3 study in a similar patient population, INTERCEPT red cells were shown to be noninferior to control red cells in 148 patients based on a composite endpoint of myocardial infarction, renal failure, and death,” said Laurence Corash, MD, Cerus’s chief medical officer.

“The data from the recent phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. We believe that the successful results from this study, combined with data from the prior phase 3 study, support the safety and efficacy of the INTERCEPT RBC system for CE Mark registration.”

In the current trial, researchers evaluated the efficacy of the INTERCEPT system to process RBCs with quality and mean hemoglobin content (> 40 g) suitable to support transfusion according to the European Directorate for the Quality of Medicines.

The blood components were transfused in 51 cardiovascular surgery patients at 2 German trial sites. Patients undergoing procedures for coronary artery bypass grafting, valve repair, or combined procedures received transfusions during a 7-day treatment period that included the day of surgery and 6 days post-operatively.

The patients received either INTERCEPT-treated RBCs or control RBCs not treated for pathogen inactivation. RBC components for both clinical sites were manufactured at the German Red Cross blood center in Frankfurt, and the RBCs were stored for up to 35 days prior to transfusion.

The primary endpoint was the equivalence of mean hemoglobin content between INTERCEPT-treated RBCs and conventional RBCs. The mean hemoglobin content of INTERCEPT-treated RBCs on day 35 of storage (53.1 g) fell within the protocol-specified 5g equivalence margin, when compared to control RBCs (55.8 g).

The secondary efficacy endpoints also suggested INTERCEPT-treated RBCs were suitable for transfusion based on mean hematocrit of 60.4% (acceptance range: 55%-70%) and mean end-of-storage hemolysis rate of 0.28% (acceptance range < 0.8%).

There were no statistical differences in the adverse event rates between recipients of INTERCEPT-treated RBCs and control RBCs. There were no clinically relevant trends in severe or serious treatment-related adverse events by system organ class.

The observed adverse events were within the expected spectrum of comorbidity and mortality for patients of similar age and with advanced cardiovascular diseases undergoing cardiovascular surgery requiring RBC transfusion. And none of the patients exhibited an immune response to INTERCEPT-treated RBCs.

CHICAGO – Patients with atrial fibrillation who frequently have a supratherapeutic international normalized ratio are at sharply increased risk for developing dementia, according to a large observational study.

“We postulate that the mechanism is an accumulation of microbleeds in the brain,” Dr. T. Jared Bunch said at the American Heart Association Scientific Sessions.

“In patients with hypertension, a condition that’s extremely common with atrial fibrillation, these repetitive small bleeds are preferentially in the hippocampus, where memory is stored,” added Dr. Bunch, who is medical director for heart rhythm services at the Intermountain Medical Center Heart Institute in Salt Lake City.

He presented a study of 1,031 patients with atrial fibrillation (AF) in Intermountain’s centralized anticoagulation service. All were on dual therapy with warfarin plus aspirin or, much less commonly, another antiplatelet agent. At baseline, their average age was in the early- to mid-70s, and none of the subjects had a history of stroke or any notes in their medical record suggestive of early cognitive decline. At this dedicated anticoagulation center, their INR was measured on a weekly or biweekly basis, as a result of which their average time spent in the therapeutic range of 2.0-3.0 was relatively high at nearly 70%.

The increased risk of dementia in patients with AF has previously been recognized. The association is stronger in patients under age 75 than in those who are older. But the mechanism has been unknown. Dr. Bunch and coinvestigators decided to test their hypothesis that the mechanism involves microbleeds secondary to long-term overanticoagulation by dividing the patients into three groups based upon their percentage of INR measurements above 3.0 during a mean follow-up of more than 4 and up to a maximum of 10 years: 240 patients had a supratherapeutic INR 25% of the time or more; 374 did so less than 10% of the time; and 417 had an elevated INR 10%-24% of the time.

The incidence of dementia diagnosed by a consultant neurologist during follow-up was 5.8% in the group with an INR above 3.0 at least 25% of the time, more than twice the 2.7% rate in patients with a high INR less than 10% of the time. In the middle group, the incidence of dementia was 4.1%. In a multivariate Cox regression analysis, having an INR above 3.0 on at least 25% of occasions was independently associated with a 2.59-fold increased risk of developing dementia, making it by far the most potent risk factor in their analysis.

The next step in their research will be to perform serial brain imaging and volumetric scans, Dr. Bunch said. Also, he and his coworkers are 3 years into an ongoing study looking at the incidence of dementia in AF patients on the various novel oral anticoagulants, where INR is a nonissue. Their hypothesis is the dementia risk will be lower than in patients on warfarin. Dr. Bunch has particularly high hopes for AF patients on apixaban (Eliquis) because it’s known to have a reduced risk of large bleeds, stroke, and GI bleeding; the hope is it will cause fewer cerebral microbleeds as well.

In an interview, the cardiologist said he believes his study showing an increased risk of dementia in AF patients with supratherapeutic INRs on warfarin plus antiplatelet therapy holds several important lessons for AF patients and physicians alike.

For patients, the message is don’t just start taking aspirin on your own because you’ve read it’s good for your heart or may reduce cancer risk; consult your physician.

And for physicians, it’s important to ask all patients on warfarin if they’re using aspirin; many don’t ask. Also, periodically reconsider the need for dual therapy with warfarin and aspirin.

“We find the risks of stroke and bleeding change dynamically over time, so the initial therapy for stroke prevention may not be the ideal therapy after 5-10 years,” Dr. Bunch said.

Lastly, for patients who are overanticoagulated on a substantial percentage of their INR measurements, it’s essential to consider a change in strategy. Either follow their INRs more closely and adjust warfarin dosing accordingly, or switch to one of the novel, more predictable oral anticoagulants, he concluded.

This study was funded internally by Intermountain Healthcare. Dr. Bunch reported having no financial conflicts.

[email protected]

CHICAGO – Patients with atrial fibrillation who frequently have a supratherapeutic international normalized ratio are at sharply increased risk for developing dementia, according to a large observational study.

“We postulate that the mechanism is an accumulation of microbleeds in the brain,” Dr. T. Jared Bunch said at the American Heart Association Scientific Sessions.

“In patients with hypertension, a condition that’s extremely common with atrial fibrillation, these repetitive small bleeds are preferentially in the hippocampus, where memory is stored,” added Dr. Bunch, who is medical director for heart rhythm services at the Intermountain Medical Center Heart Institute in Salt Lake City.

He presented a study of 1,031 patients with atrial fibrillation (AF) in Intermountain’s centralized anticoagulation service. All were on dual therapy with warfarin plus aspirin or, much less commonly, another antiplatelet agent. At baseline, their average age was in the early- to mid-70s, and none of the subjects had a history of stroke or any notes in their medical record suggestive of early cognitive decline. At this dedicated anticoagulation center, their INR was measured on a weekly or biweekly basis, as a result of which their average time spent in the therapeutic range of 2.0-3.0 was relatively high at nearly 70%.

The increased risk of dementia in patients with AF has previously been recognized. The association is stronger in patients under age 75 than in those who are older. But the mechanism has been unknown. Dr. Bunch and coinvestigators decided to test their hypothesis that the mechanism involves microbleeds secondary to long-term overanticoagulation by dividing the patients into three groups based upon their percentage of INR measurements above 3.0 during a mean follow-up of more than 4 and up to a maximum of 10 years: 240 patients had a supratherapeutic INR 25% of the time or more; 374 did so less than 10% of the time; and 417 had an elevated INR 10%-24% of the time.

The incidence of dementia diagnosed by a consultant neurologist during follow-up was 5.8% in the group with an INR above 3.0 at least 25% of the time, more than twice the 2.7% rate in patients with a high INR less than 10% of the time. In the middle group, the incidence of dementia was 4.1%. In a multivariate Cox regression analysis, having an INR above 3.0 on at least 25% of occasions was independently associated with a 2.59-fold increased risk of developing dementia, making it by far the most potent risk factor in their analysis.

The next step in their research will be to perform serial brain imaging and volumetric scans, Dr. Bunch said. Also, he and his coworkers are 3 years into an ongoing study looking at the incidence of dementia in AF patients on the various novel oral anticoagulants, where INR is a nonissue. Their hypothesis is the dementia risk will be lower than in patients on warfarin. Dr. Bunch has particularly high hopes for AF patients on apixaban (Eliquis) because it’s known to have a reduced risk of large bleeds, stroke, and GI bleeding; the hope is it will cause fewer cerebral microbleeds as well.

In an interview, the cardiologist said he believes his study showing an increased risk of dementia in AF patients with supratherapeutic INRs on warfarin plus antiplatelet therapy holds several important lessons for AF patients and physicians alike.

For patients, the message is don’t just start taking aspirin on your own because you’ve read it’s good for your heart or may reduce cancer risk; consult your physician.

And for physicians, it’s important to ask all patients on warfarin if they’re using aspirin; many don’t ask. Also, periodically reconsider the need for dual therapy with warfarin and aspirin.

“We find the risks of stroke and bleeding change dynamically over time, so the initial therapy for stroke prevention may not be the ideal therapy after 5-10 years,” Dr. Bunch said.

Lastly, for patients who are overanticoagulated on a substantial percentage of their INR measurements, it’s essential to consider a change in strategy. Either follow their INRs more closely and adjust warfarin dosing accordingly, or switch to one of the novel, more predictable oral anticoagulants, he concluded.

This study was funded internally by Intermountain Healthcare. Dr. Bunch reported having no financial conflicts.

[email protected]

CHICAGO – Patients with atrial fibrillation who frequently have a supratherapeutic international normalized ratio are at sharply increased risk for developing dementia, according to a large observational study.

“We postulate that the mechanism is an accumulation of microbleeds in the brain,” Dr. T. Jared Bunch said at the American Heart Association Scientific Sessions.

“In patients with hypertension, a condition that’s extremely common with atrial fibrillation, these repetitive small bleeds are preferentially in the hippocampus, where memory is stored,” added Dr. Bunch, who is medical director for heart rhythm services at the Intermountain Medical Center Heart Institute in Salt Lake City.

He presented a study of 1,031 patients with atrial fibrillation (AF) in Intermountain’s centralized anticoagulation service. All were on dual therapy with warfarin plus aspirin or, much less commonly, another antiplatelet agent. At baseline, their average age was in the early- to mid-70s, and none of the subjects had a history of stroke or any notes in their medical record suggestive of early cognitive decline. At this dedicated anticoagulation center, their INR was measured on a weekly or biweekly basis, as a result of which their average time spent in the therapeutic range of 2.0-3.0 was relatively high at nearly 70%.

The increased risk of dementia in patients with AF has previously been recognized. The association is stronger in patients under age 75 than in those who are older. But the mechanism has been unknown. Dr. Bunch and coinvestigators decided to test their hypothesis that the mechanism involves microbleeds secondary to long-term overanticoagulation by dividing the patients into three groups based upon their percentage of INR measurements above 3.0 during a mean follow-up of more than 4 and up to a maximum of 10 years: 240 patients had a supratherapeutic INR 25% of the time or more; 374 did so less than 10% of the time; and 417 had an elevated INR 10%-24% of the time.

The incidence of dementia diagnosed by a consultant neurologist during follow-up was 5.8% in the group with an INR above 3.0 at least 25% of the time, more than twice the 2.7% rate in patients with a high INR less than 10% of the time. In the middle group, the incidence of dementia was 4.1%. In a multivariate Cox regression analysis, having an INR above 3.0 on at least 25% of occasions was independently associated with a 2.59-fold increased risk of developing dementia, making it by far the most potent risk factor in their analysis.

The next step in their research will be to perform serial brain imaging and volumetric scans, Dr. Bunch said. Also, he and his coworkers are 3 years into an ongoing study looking at the incidence of dementia in AF patients on the various novel oral anticoagulants, where INR is a nonissue. Their hypothesis is the dementia risk will be lower than in patients on warfarin. Dr. Bunch has particularly high hopes for AF patients on apixaban (Eliquis) because it’s known to have a reduced risk of large bleeds, stroke, and GI bleeding; the hope is it will cause fewer cerebral microbleeds as well.

In an interview, the cardiologist said he believes his study showing an increased risk of dementia in AF patients with supratherapeutic INRs on warfarin plus antiplatelet therapy holds several important lessons for AF patients and physicians alike.

For patients, the message is don’t just start taking aspirin on your own because you’ve read it’s good for your heart or may reduce cancer risk; consult your physician.

And for physicians, it’s important to ask all patients on warfarin if they’re using aspirin; many don’t ask. Also, periodically reconsider the need for dual therapy with warfarin and aspirin.

“We find the risks of stroke and bleeding change dynamically over time, so the initial therapy for stroke prevention may not be the ideal therapy after 5-10 years,” Dr. Bunch said.

Lastly, for patients who are overanticoagulated on a substantial percentage of their INR measurements, it’s essential to consider a change in strategy. Either follow their INRs more closely and adjust warfarin dosing accordingly, or switch to one of the novel, more predictable oral anticoagulants, he concluded.

This study was funded internally by Intermountain Healthcare. Dr. Bunch reported having no financial conflicts.

[email protected]

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Doctor and patient

Credit: NIH

SAN FRANCISCO—Younger patients with Hodgkin lymphoma fare well on brentuximab vedotin, experiencing an overall objective response rate (ORR) of 75% and a complete response (CR) rate of 34% in the pivotal phase 2 study of patients with relapsed/refractory disease.

And a retrospective study of patients older than 60 years showed that single-agent therapy was well tolerated, prompting an ORR of 53% and a CR rate of 40% in a relapsed or refractory population.

So investigators decided to explore in a prospective study whether patients 60 years or older could benefit from up-front treatment with brentuximab as a single agent or in combination.

Andres Forero-Torres, MD, of the University of Alabama in Birmingham, presented the results of this trial at the 2014 ASH Annual Meeting (abstract 294).*

Enrolled patients had classic Hodgkin lymphoma, were treatment-naïve, and were ineligible for or declined conventional front-line treatment. The primary endpoint was ORR.

The study is being conducted in 3 parts—brentuximab as a single agent, brentuximab plus dacarbazine, and brentuximab plus bendamustine. At the time of the ASH presentation, data for the brentuximab-bendamustine combination were not available.

Single-agent brentuximab

Twenty-seven patients on the single-agent arm were evaluable for efficacy and safety. They were a median age of 78 (range, 64 to 92). About half (52%) were male, and 78% had an ECOG performance status of grade 0 or 1.

Forty-four percent had moderate renal function impairment with a creatinine clearance between 30 and 60 mL/min. Thirty percent had B symptoms, 22% had bulky disease, and 52% had extra-nodal involvement.

Patients received 1.8 mg/kg of brentuximab intravenously on day 1 of a 21-day cycle. Response was assessed by CT scan during cycles 2, 4, 8, and 16, and by CT plus PET scan during cycles 2 and 8.

The median follow-up was 8.7 months. Dr Forero-Torres pointed out that, initially, “there were no progressions,” and all patients achieved tumor reduction.

The ORR was 93%, the CR rate was 70%, the partial response rate was 22%, and the rate of stable disease was 7%.

The median duration of response was 9.1 months (range, 0.03 to 13.14), and the median progression-free survival was 10.5 months (range, 2.6 to 14.3). For patients who had a CR, the median progression-free survival was about 12 months, Dr Forero-Torres said.

The median number of treatment cycles administered per patient was 8 (range, 3 to 23). Patients discontinued treatment primarily because of progressive disease (41%) or adverse events (AEs, 37%).

AEs occurring in 20% or more of patients were constipation, decreased appetite, diarrhea, peripheral edema, nausea, fatigue, and peripheral sensory neuropathy. All were grade 1 or 2, except for peripheral sensory neuropathy, which also had about 20% grade 3 events.

Grade 3 or higher treatment-related AEs included peripheral sensory neuropathy (n=7), peripheral motor neuropathy (n=2), rash (n=2), and 1 patient each with anemia, increased aspartate aminotransferase, asthenia, neutropenia, orthostatic hypotension, generalized rash, and maculopapular rash.

Serious AEs (SAEs) were minimal, Dr Forero-Torres said, and included 1 patient each with pyrexia, orthostatic hypotension, asthenia and rash, and deep vein thrombosis.

Seven patients discontinued treatment due to peripheral sensory neuropathy, 2 due to peripheral motor neuropathy, and 1 due to orthostatic hypotension.

Dr Forero-Torres emphasized that there were no grade 4 AEs, no AE-related deaths, and no deaths within 30 days of the last dose of medication.

Brentuximab plus dacarbazine

Fourteen of 18 patients in the combination arm were evaluable for efficacy and safety. Their median age was 72.5 (range, 62 to 87), 72% were male, 67% had an ECOG status of grade 0 or 1, and 56% had normal renal function with a creatinine clearance greater than 80 mL/min.

Forty-four percent exhibited B symptoms, 11% had bulky disease, and 50% had extra-nodal involvement.

They received brentuximab at 1.8 mg/kg plus dacarbazine at 375 mg/m² for cycles 1-12, followed by monotherapy for cycles 13-16.

At the time of the interim analysis, 83% of patients were still on treatment, “so this is very early preliminary data,” Dr Forero-Torres noted.

All of the patients achieved tumor reduction, and 4 patients achieved a CR.

They had a median treatment duration of 16.7 weeks (range, 3 to 36), received a median of 5.5 cycles (range, 1 to 12), and had a median follow-up time of 19.1 weeks (range, 6.1 to 36.1).

The most common grade 1 or 2 AEs were peripheral sensory neuropathy (33%), nausea (33%), diarrhea (28%), constipation (28%), fatigue (22%), alopecia (22%), arthralgia (22%), and headache (22%).

Grade 3 AEs or SAEs, with 1 patient each, were C difficile colitis (SAE), hypotension (SAE), and hyperglycemia.

Dr Forero-Torres noted that investigators observed “robust antitumor activity” among these older patients receiving front-line brentuximab.

The cohort combining brentuximab with bendamustine is currently enrolling patients.

The study is sponsored by Seattle Genetics, Inc., developer of brentuximab vedotin (Adcetris).

*Information in the abstract differs from that presented at the meeting.

Doctor and patient

Credit: NIH

SAN FRANCISCO—Younger patients with Hodgkin lymphoma fare well on brentuximab vedotin, experiencing an overall objective response rate (ORR) of 75% and a complete response (CR) rate of 34% in the pivotal phase 2 study of patients with relapsed/refractory disease.

And a retrospective study of patients older than 60 years showed that single-agent therapy was well tolerated, prompting an ORR of 53% and a CR rate of 40% in a relapsed or refractory population.

So investigators decided to explore in a prospective study whether patients 60 years or older could benefit from up-front treatment with brentuximab as a single agent or in combination.

Andres Forero-Torres, MD, of the University of Alabama in Birmingham, presented the results of this trial at the 2014 ASH Annual Meeting (abstract 294).*

Enrolled patients had classic Hodgkin lymphoma, were treatment-naïve, and were ineligible for or declined conventional front-line treatment. The primary endpoint was ORR.

The study is being conducted in 3 parts—brentuximab as a single agent, brentuximab plus dacarbazine, and brentuximab plus bendamustine. At the time of the ASH presentation, data for the brentuximab-bendamustine combination were not available.

Single-agent brentuximab

Twenty-seven patients on the single-agent arm were evaluable for efficacy and safety. They were a median age of 78 (range, 64 to 92). About half (52%) were male, and 78% had an ECOG performance status of grade 0 or 1.

Forty-four percent had moderate renal function impairment with a creatinine clearance between 30 and 60 mL/min. Thirty percent had B symptoms, 22% had bulky disease, and 52% had extra-nodal involvement.

Patients received 1.8 mg/kg of brentuximab intravenously on day 1 of a 21-day cycle. Response was assessed by CT scan during cycles 2, 4, 8, and 16, and by CT plus PET scan during cycles 2 and 8.

The median follow-up was 8.7 months. Dr Forero-Torres pointed out that, initially, “there were no progressions,” and all patients achieved tumor reduction.

The ORR was 93%, the CR rate was 70%, the partial response rate was 22%, and the rate of stable disease was 7%.

The median duration of response was 9.1 months (range, 0.03 to 13.14), and the median progression-free survival was 10.5 months (range, 2.6 to 14.3). For patients who had a CR, the median progression-free survival was about 12 months, Dr Forero-Torres said.

The median number of treatment cycles administered per patient was 8 (range, 3 to 23). Patients discontinued treatment primarily because of progressive disease (41%) or adverse events (AEs, 37%).

AEs occurring in 20% or more of patients were constipation, decreased appetite, diarrhea, peripheral edema, nausea, fatigue, and peripheral sensory neuropathy. All were grade 1 or 2, except for peripheral sensory neuropathy, which also had about 20% grade 3 events.

Grade 3 or higher treatment-related AEs included peripheral sensory neuropathy (n=7), peripheral motor neuropathy (n=2), rash (n=2), and 1 patient each with anemia, increased aspartate aminotransferase, asthenia, neutropenia, orthostatic hypotension, generalized rash, and maculopapular rash.

Serious AEs (SAEs) were minimal, Dr Forero-Torres said, and included 1 patient each with pyrexia, orthostatic hypotension, asthenia and rash, and deep vein thrombosis.

Seven patients discontinued treatment due to peripheral sensory neuropathy, 2 due to peripheral motor neuropathy, and 1 due to orthostatic hypotension.

Dr Forero-Torres emphasized that there were no grade 4 AEs, no AE-related deaths, and no deaths within 30 days of the last dose of medication.

Brentuximab plus dacarbazine

Fourteen of 18 patients in the combination arm were evaluable for efficacy and safety. Their median age was 72.5 (range, 62 to 87), 72% were male, 67% had an ECOG status of grade 0 or 1, and 56% had normal renal function with a creatinine clearance greater than 80 mL/min.

Forty-four percent exhibited B symptoms, 11% had bulky disease, and 50% had extra-nodal involvement.

They received brentuximab at 1.8 mg/kg plus dacarbazine at 375 mg/m² for cycles 1-12, followed by monotherapy for cycles 13-16.

At the time of the interim analysis, 83% of patients were still on treatment, “so this is very early preliminary data,” Dr Forero-Torres noted.

All of the patients achieved tumor reduction, and 4 patients achieved a CR.

They had a median treatment duration of 16.7 weeks (range, 3 to 36), received a median of 5.5 cycles (range, 1 to 12), and had a median follow-up time of 19.1 weeks (range, 6.1 to 36.1).

The most common grade 1 or 2 AEs were peripheral sensory neuropathy (33%), nausea (33%), diarrhea (28%), constipation (28%), fatigue (22%), alopecia (22%), arthralgia (22%), and headache (22%).

Grade 3 AEs or SAEs, with 1 patient each, were C difficile colitis (SAE), hypotension (SAE), and hyperglycemia.

Dr Forero-Torres noted that investigators observed “robust antitumor activity” among these older patients receiving front-line brentuximab.

The cohort combining brentuximab with bendamustine is currently enrolling patients.

The study is sponsored by Seattle Genetics, Inc., developer of brentuximab vedotin (Adcetris).

*Information in the abstract differs from that presented at the meeting.

Doctor and patient

Credit: NIH

SAN FRANCISCO—Younger patients with Hodgkin lymphoma fare well on brentuximab vedotin, experiencing an overall objective response rate (ORR) of 75% and a complete response (CR) rate of 34% in the pivotal phase 2 study of patients with relapsed/refractory disease.

And a retrospective study of patients older than 60 years showed that single-agent therapy was well tolerated, prompting an ORR of 53% and a CR rate of 40% in a relapsed or refractory population.

So investigators decided to explore in a prospective study whether patients 60 years or older could benefit from up-front treatment with brentuximab as a single agent or in combination.

Andres Forero-Torres, MD, of the University of Alabama in Birmingham, presented the results of this trial at the 2014 ASH Annual Meeting (abstract 294).*

Enrolled patients had classic Hodgkin lymphoma, were treatment-naïve, and were ineligible for or declined conventional front-line treatment. The primary endpoint was ORR.

The study is being conducted in 3 parts—brentuximab as a single agent, brentuximab plus dacarbazine, and brentuximab plus bendamustine. At the time of the ASH presentation, data for the brentuximab-bendamustine combination were not available.

Single-agent brentuximab

Twenty-seven patients on the single-agent arm were evaluable for efficacy and safety. They were a median age of 78 (range, 64 to 92). About half (52%) were male, and 78% had an ECOG performance status of grade 0 or 1.

Forty-four percent had moderate renal function impairment with a creatinine clearance between 30 and 60 mL/min. Thirty percent had B symptoms, 22% had bulky disease, and 52% had extra-nodal involvement.

Patients received 1.8 mg/kg of brentuximab intravenously on day 1 of a 21-day cycle. Response was assessed by CT scan during cycles 2, 4, 8, and 16, and by CT plus PET scan during cycles 2 and 8.

The median follow-up was 8.7 months. Dr Forero-Torres pointed out that, initially, “there were no progressions,” and all patients achieved tumor reduction.

The ORR was 93%, the CR rate was 70%, the partial response rate was 22%, and the rate of stable disease was 7%.

The median duration of response was 9.1 months (range, 0.03 to 13.14), and the median progression-free survival was 10.5 months (range, 2.6 to 14.3). For patients who had a CR, the median progression-free survival was about 12 months, Dr Forero-Torres said.

The median number of treatment cycles administered per patient was 8 (range, 3 to 23). Patients discontinued treatment primarily because of progressive disease (41%) or adverse events (AEs, 37%).

AEs occurring in 20% or more of patients were constipation, decreased appetite, diarrhea, peripheral edema, nausea, fatigue, and peripheral sensory neuropathy. All were grade 1 or 2, except for peripheral sensory neuropathy, which also had about 20% grade 3 events.

Grade 3 or higher treatment-related AEs included peripheral sensory neuropathy (n=7), peripheral motor neuropathy (n=2), rash (n=2), and 1 patient each with anemia, increased aspartate aminotransferase, asthenia, neutropenia, orthostatic hypotension, generalized rash, and maculopapular rash.

Serious AEs (SAEs) were minimal, Dr Forero-Torres said, and included 1 patient each with pyrexia, orthostatic hypotension, asthenia and rash, and deep vein thrombosis.

Seven patients discontinued treatment due to peripheral sensory neuropathy, 2 due to peripheral motor neuropathy, and 1 due to orthostatic hypotension.

Dr Forero-Torres emphasized that there were no grade 4 AEs, no AE-related deaths, and no deaths within 30 days of the last dose of medication.

Brentuximab plus dacarbazine

Fourteen of 18 patients in the combination arm were evaluable for efficacy and safety. Their median age was 72.5 (range, 62 to 87), 72% were male, 67% had an ECOG status of grade 0 or 1, and 56% had normal renal function with a creatinine clearance greater than 80 mL/min.

Forty-four percent exhibited B symptoms, 11% had bulky disease, and 50% had extra-nodal involvement.

They received brentuximab at 1.8 mg/kg plus dacarbazine at 375 mg/m² for cycles 1-12, followed by monotherapy for cycles 13-16.

At the time of the interim analysis, 83% of patients were still on treatment, “so this is very early preliminary data,” Dr Forero-Torres noted.

All of the patients achieved tumor reduction, and 4 patients achieved a CR.

They had a median treatment duration of 16.7 weeks (range, 3 to 36), received a median of 5.5 cycles (range, 1 to 12), and had a median follow-up time of 19.1 weeks (range, 6.1 to 36.1).

The most common grade 1 or 2 AEs were peripheral sensory neuropathy (33%), nausea (33%), diarrhea (28%), constipation (28%), fatigue (22%), alopecia (22%), arthralgia (22%), and headache (22%).

Grade 3 AEs or SAEs, with 1 patient each, were C difficile colitis (SAE), hypotension (SAE), and hyperglycemia.

Dr Forero-Torres noted that investigators observed “robust antitumor activity” among these older patients receiving front-line brentuximab.

The cohort combining brentuximab with bendamustine is currently enrolling patients.

The study is sponsored by Seattle Genetics, Inc., developer of brentuximab vedotin (Adcetris).

*Information in the abstract differs from that presented at the meeting.

Colony of iPSCs

Credit: Salk Institute

The gene-editing technology CRISPR can precisely and efficiently alter human stem cells, according to research published in Molecular Therapy.

Using JAK2 and other genes as models, researchers showed that CRISPR offers advantages over TALEN, another gene-editing technique, for manipulating induced pluripotent stem cells (iPSCs).

And, unlike in a previous study, CRISPR did not produce any off-target effects.

The team believes their findings could streamline and speed up efforts to modify human iPSCs for use as treatments or in the development of model systems to study diseases and test drugs.

“Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs for human therapy aren’t that far away,” said study author Zhaohui Ye, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells.”

CRISPR originated from a microbial immune system that contains DNA segments known as “clustered regularly interspaced short palindromic repeats.” The system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions more efficiently than other gene-editing techniques, such as TALEN, which is short for “transcription activator-like effector nuclease.”

Despite CRISPR’s advantages, a recent study suggested it might also produce a large number of off-target effects in human cancer cell lines; specifically, modification of genes that researchers didn’t mean to change.

To see if this unwanted effect occurred in other human cell types, Dr Ye and his colleagues pitted CRISPR against TALEN in human iPSCs. The researchers compared the ability of both techniques to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another.

As model genes, the researchers used JAK2, a gene that, when mutated, causes myeloproliferative neoplasms; SERPINA1, a gene that, when mutated, causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that’s been recently discovered to be a “safe harbor” in the human genome for inserting foreign genes.

The comparison showed that, when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all 3 gene systems, inducing up to 100 times more cuts.

However, when using these genome-editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs.

Contrary to results of the human cancer cell line study, both CRISPR and TALEN had the same targeting specificity in human iPSCs, hitting only the genes they were designed to affect.

The researchers also found that the CRISPR system has a second advantage over TALEN. It can be designed to target only the mutation-containing gene without affecting the healthy gene in patients where only one copy of a gene is affected.

These findings, according to the researchers, offer reassurance that CRISPR will be a useful tool for editing the genes of human iPSCs with little risk of off-target effects.

Colony of iPSCs

Credit: Salk Institute

The gene-editing technology CRISPR can precisely and efficiently alter human stem cells, according to research published in Molecular Therapy.

Using JAK2 and other genes as models, researchers showed that CRISPR offers advantages over TALEN, another gene-editing technique, for manipulating induced pluripotent stem cells (iPSCs).

And, unlike in a previous study, CRISPR did not produce any off-target effects.

The team believes their findings could streamline and speed up efforts to modify human iPSCs for use as treatments or in the development of model systems to study diseases and test drugs.

“Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs for human therapy aren’t that far away,” said study author Zhaohui Ye, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells.”

CRISPR originated from a microbial immune system that contains DNA segments known as “clustered regularly interspaced short palindromic repeats.” The system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions more efficiently than other gene-editing techniques, such as TALEN, which is short for “transcription activator-like effector nuclease.”

Despite CRISPR’s advantages, a recent study suggested it might also produce a large number of off-target effects in human cancer cell lines; specifically, modification of genes that researchers didn’t mean to change.

To see if this unwanted effect occurred in other human cell types, Dr Ye and his colleagues pitted CRISPR against TALEN in human iPSCs. The researchers compared the ability of both techniques to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another.

As model genes, the researchers used JAK2, a gene that, when mutated, causes myeloproliferative neoplasms; SERPINA1, a gene that, when mutated, causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that’s been recently discovered to be a “safe harbor” in the human genome for inserting foreign genes.

The comparison showed that, when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all 3 gene systems, inducing up to 100 times more cuts.

However, when using these genome-editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs.

Contrary to results of the human cancer cell line study, both CRISPR and TALEN had the same targeting specificity in human iPSCs, hitting only the genes they were designed to affect.

The researchers also found that the CRISPR system has a second advantage over TALEN. It can be designed to target only the mutation-containing gene without affecting the healthy gene in patients where only one copy of a gene is affected.

These findings, according to the researchers, offer reassurance that CRISPR will be a useful tool for editing the genes of human iPSCs with little risk of off-target effects.

Colony of iPSCs

Credit: Salk Institute

The gene-editing technology CRISPR can precisely and efficiently alter human stem cells, according to research published in Molecular Therapy.

Using JAK2 and other genes as models, researchers showed that CRISPR offers advantages over TALEN, another gene-editing technique, for manipulating induced pluripotent stem cells (iPSCs).

And, unlike in a previous study, CRISPR did not produce any off-target effects.

The team believes their findings could streamline and speed up efforts to modify human iPSCs for use as treatments or in the development of model systems to study diseases and test drugs.

“Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs for human therapy aren’t that far away,” said study author Zhaohui Ye, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells.”

CRISPR originated from a microbial immune system that contains DNA segments known as “clustered regularly interspaced short palindromic repeats.” The system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions more efficiently than other gene-editing techniques, such as TALEN, which is short for “transcription activator-like effector nuclease.”

Despite CRISPR’s advantages, a recent study suggested it might also produce a large number of off-target effects in human cancer cell lines; specifically, modification of genes that researchers didn’t mean to change.

To see if this unwanted effect occurred in other human cell types, Dr Ye and his colleagues pitted CRISPR against TALEN in human iPSCs. The researchers compared the ability of both techniques to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another.

As model genes, the researchers used JAK2, a gene that, when mutated, causes myeloproliferative neoplasms; SERPINA1, a gene that, when mutated, causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that’s been recently discovered to be a “safe harbor” in the human genome for inserting foreign genes.

The comparison showed that, when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all 3 gene systems, inducing up to 100 times more cuts.

However, when using these genome-editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs.

Contrary to results of the human cancer cell line study, both CRISPR and TALEN had the same targeting specificity in human iPSCs, hitting only the genes they were designed to affect.

The researchers also found that the CRISPR system has a second advantage over TALEN. It can be designed to target only the mutation-containing gene without affecting the healthy gene in patients where only one copy of a gene is affected.

These findings, according to the researchers, offer reassurance that CRISPR will be a useful tool for editing the genes of human iPSCs with little risk of off-target effects.