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CAR T-cell therapy gets orphan designation for DLBCL
Credit: Charles Haymond
The European Commission has granted KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, orphan designation to treat patients with diffuse large B-cell lymphoma (DLBCL) in the European Union (EU).
To create KTE-C19, a patient’s T cells are genetically modified using a gammaretroviral vector to express a CAR designed to target CD19, a protein expressed on B cells.
The product received orphan designation to treat DLBCL in the US last March.
“We are pleased with the approval of orphan drug designation for KTE-C19 in the EU, another important milestone for Kite Pharma and for the progress of our lead program,” said Arie Belldegrun, MD, President and CEO of Kite Pharma, Inc., the company developing KTE-C19.
Orphan designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the EU, and where no satisfactory treatment is available.
In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, and direct access to the centralized authorization procedure.
KTE-C19 in DLBCL
In a study published in the Journal of Clinical Oncology last year, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.
The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a complete response to treatment, 2 achieved a partial response, and 1 had stable disease. Three of the complete responses were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.
In the entire patient population, KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.
Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.
For more information on KTE-C19, visit Kite Pharma’s website. 
Credit: Charles Haymond
The European Commission has granted KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, orphan designation to treat patients with diffuse large B-cell lymphoma (DLBCL) in the European Union (EU).
To create KTE-C19, a patient’s T cells are genetically modified using a gammaretroviral vector to express a CAR designed to target CD19, a protein expressed on B cells.
The product received orphan designation to treat DLBCL in the US last March.
“We are pleased with the approval of orphan drug designation for KTE-C19 in the EU, another important milestone for Kite Pharma and for the progress of our lead program,” said Arie Belldegrun, MD, President and CEO of Kite Pharma, Inc., the company developing KTE-C19.
Orphan designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the EU, and where no satisfactory treatment is available.
In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, and direct access to the centralized authorization procedure.
KTE-C19 in DLBCL
In a study published in the Journal of Clinical Oncology last year, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.
The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a complete response to treatment, 2 achieved a partial response, and 1 had stable disease. Three of the complete responses were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.
In the entire patient population, KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.
Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.
For more information on KTE-C19, visit Kite Pharma’s website.
Credit: Charles Haymond
The European Commission has granted KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, orphan designation to treat patients with diffuse large B-cell lymphoma (DLBCL) in the European Union (EU).
To create KTE-C19, a patient’s T cells are genetically modified using a gammaretroviral vector to express a CAR designed to target CD19, a protein expressed on B cells.
The product received orphan designation to treat DLBCL in the US last March.
“We are pleased with the approval of orphan drug designation for KTE-C19 in the EU, another important milestone for Kite Pharma and for the progress of our lead program,” said Arie Belldegrun, MD, President and CEO of Kite Pharma, Inc., the company developing KTE-C19.
Orphan designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the EU, and where no satisfactory treatment is available.
In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, and direct access to the centralized authorization procedure.
KTE-C19 in DLBCL
In a study published in the Journal of Clinical Oncology last year, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.
The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a complete response to treatment, 2 achieved a partial response, and 1 had stable disease. Three of the complete responses were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.
In the entire patient population, KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.
Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.
For more information on KTE-C19, visit Kite Pharma’s website.
HIV doesn’t hinder lymphoma patients’ response to ASCT
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).
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).
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).
Maintenance prolongs PFS, not OS, in relapsed CLL
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.
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.
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.
Enzyme targets the Achilles heel of sepsis
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.”
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.”
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.”
Treated RBCs prove comparable to controls
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.
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.
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.
Older patients benefit from brentuximab treatment
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.
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.
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.
CRISPR bests TALEN in 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.
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.
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.
Ibrutinib proves active in high-risk CLL
Credit: Mary Ann Thompson
Single-agent ibrutinib can elicit a high response rate in patients with high-risk chronic lymphocytic leukemia (CLL), results of a phase 2 trial suggest.
The Bruton’s tyrosine kinase inhibitor prompted a 92% objective response rate in patients who had previously untreated or relapsed/refractory CLL with either 17p deletion (del 17p) or tumor protein 53 (TP53) aberrations.
Researchers reported this and other results of the trial in The Lancet Oncology.
“Ibrutinib treatment results observed in CLL patients with del 17p or TP53 aberrations are very encouraging given that these patients have a high relapse rate after chemotherapy and are in need of tolerable, effective, and durable treatment options,” said study author Mohammed Farooqui, DO, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland.
He and his colleagues studied 51 patients in this trial, 35 with previously untreated CLL and 16 with relapsed or refractory CLL. Forty-seven of the patients (92%) had del 17p, and 4 patients carried the TP53 aberration but did not have del 17p.
The study’s primary endpoint was overall response rate after 24 weeks. Secondary endpoints included safety, overall survival, progression-free survival, best response, and nodal response.
The median follow-up for all patients was 24 months (15 months for the previously untreated cohort). At 24 weeks, 48 patients were evaluable for response, assessed according to the modified IWCLL 2008 criteria.
Response rates
At 24 weeks, 92% (n=44) of the 48 evaluable patients achieved an objective response. Fifty percent of all evaluable patients achieved a partial response (n=24)—55% of previously untreated patients (n=18) and 40% of relapsed/refractory patients (n=6).
As for best response, 10% of all patients achieved a complete response (n=5)—12% of previously untreated patients (n=4) and 7% of relapsed/refractory patients (n=1). And 67% of patients had a partial response (n=32)—70% of previously untreated patients (n=23) and 60% of relapsed/refractory patients (n=9).
After 8 weeks on therapy, ibrutinib was associated with a more than 50% mean reduction in tumor burden in the bone marrow (44%), lymph nodes (70%), and spleen (79%). After 24 weeks of therapy, the rates of tumor burden reduction (> 50%) increased to 83%, 93%, and 95%, respectively.
Survival and safety
The estimated progression-free survival at 24 months for all patients on an intention-to-treat basis was 82%. Forty-two of the 51 patients (82%) continued on ibrutinib treatment without disease progression.
The estimated overall survival at 24 months was 80% for all patients—84% for previously untreated patients and 74% for patients with relapsed or refractory disease.
At the final follow-up, 8 (16%) patients had died—5 (10%) from progressive disease, 2 (4%) from infection, and 1 (2%) patient with a sudden, unexplained death that may have been treatment-related.
The most common adverse events (occurring in more than 30% of all patients) potentially related to ibrutinib were arthralgia (59%), diarrhea (51%), rash (47%), nail ridging (43%), bruising (33%), and muscle spasms (31%).
The most frequent grade 3 or 4 hematologic adverse events were neutropenia (24%), anemia (14%), and thrombocytopenia (10%). The most common nonhematologic grade 3 adverse event was pneumonia, which occurred in 3 patients (6%).
Nine patients (18%) discontinued treatment. The reasons for discontinuation included disease progression in 5 patients (10%) and death for 3 patients (6%).
This research was sponsored by the Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute; Danish Cancer Society; Novo Nordisk Foundation; National Institutes of Health Medical Research Scholars Program; and Pharmacyclics Inc.
Ibrutinib is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.
Credit: Mary Ann Thompson
Single-agent ibrutinib can elicit a high response rate in patients with high-risk chronic lymphocytic leukemia (CLL), results of a phase 2 trial suggest.
The Bruton’s tyrosine kinase inhibitor prompted a 92% objective response rate in patients who had previously untreated or relapsed/refractory CLL with either 17p deletion (del 17p) or tumor protein 53 (TP53) aberrations.
Researchers reported this and other results of the trial in The Lancet Oncology.
“Ibrutinib treatment results observed in CLL patients with del 17p or TP53 aberrations are very encouraging given that these patients have a high relapse rate after chemotherapy and are in need of tolerable, effective, and durable treatment options,” said study author Mohammed Farooqui, DO, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland.
He and his colleagues studied 51 patients in this trial, 35 with previously untreated CLL and 16 with relapsed or refractory CLL. Forty-seven of the patients (92%) had del 17p, and 4 patients carried the TP53 aberration but did not have del 17p.
The study’s primary endpoint was overall response rate after 24 weeks. Secondary endpoints included safety, overall survival, progression-free survival, best response, and nodal response.
The median follow-up for all patients was 24 months (15 months for the previously untreated cohort). At 24 weeks, 48 patients were evaluable for response, assessed according to the modified IWCLL 2008 criteria.
Response rates
At 24 weeks, 92% (n=44) of the 48 evaluable patients achieved an objective response. Fifty percent of all evaluable patients achieved a partial response (n=24)—55% of previously untreated patients (n=18) and 40% of relapsed/refractory patients (n=6).
As for best response, 10% of all patients achieved a complete response (n=5)—12% of previously untreated patients (n=4) and 7% of relapsed/refractory patients (n=1). And 67% of patients had a partial response (n=32)—70% of previously untreated patients (n=23) and 60% of relapsed/refractory patients (n=9).
After 8 weeks on therapy, ibrutinib was associated with a more than 50% mean reduction in tumor burden in the bone marrow (44%), lymph nodes (70%), and spleen (79%). After 24 weeks of therapy, the rates of tumor burden reduction (> 50%) increased to 83%, 93%, and 95%, respectively.
Survival and safety
The estimated progression-free survival at 24 months for all patients on an intention-to-treat basis was 82%. Forty-two of the 51 patients (82%) continued on ibrutinib treatment without disease progression.
The estimated overall survival at 24 months was 80% for all patients—84% for previously untreated patients and 74% for patients with relapsed or refractory disease.
At the final follow-up, 8 (16%) patients had died—5 (10%) from progressive disease, 2 (4%) from infection, and 1 (2%) patient with a sudden, unexplained death that may have been treatment-related.
The most common adverse events (occurring in more than 30% of all patients) potentially related to ibrutinib were arthralgia (59%), diarrhea (51%), rash (47%), nail ridging (43%), bruising (33%), and muscle spasms (31%).
The most frequent grade 3 or 4 hematologic adverse events were neutropenia (24%), anemia (14%), and thrombocytopenia (10%). The most common nonhematologic grade 3 adverse event was pneumonia, which occurred in 3 patients (6%).
Nine patients (18%) discontinued treatment. The reasons for discontinuation included disease progression in 5 patients (10%) and death for 3 patients (6%).
This research was sponsored by the Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute; Danish Cancer Society; Novo Nordisk Foundation; National Institutes of Health Medical Research Scholars Program; and Pharmacyclics Inc.
Ibrutinib is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.
Credit: Mary Ann Thompson
Single-agent ibrutinib can elicit a high response rate in patients with high-risk chronic lymphocytic leukemia (CLL), results of a phase 2 trial suggest.
The Bruton’s tyrosine kinase inhibitor prompted a 92% objective response rate in patients who had previously untreated or relapsed/refractory CLL with either 17p deletion (del 17p) or tumor protein 53 (TP53) aberrations.
Researchers reported this and other results of the trial in The Lancet Oncology.
“Ibrutinib treatment results observed in CLL patients with del 17p or TP53 aberrations are very encouraging given that these patients have a high relapse rate after chemotherapy and are in need of tolerable, effective, and durable treatment options,” said study author Mohammed Farooqui, DO, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland.
He and his colleagues studied 51 patients in this trial, 35 with previously untreated CLL and 16 with relapsed or refractory CLL. Forty-seven of the patients (92%) had del 17p, and 4 patients carried the TP53 aberration but did not have del 17p.
The study’s primary endpoint was overall response rate after 24 weeks. Secondary endpoints included safety, overall survival, progression-free survival, best response, and nodal response.
The median follow-up for all patients was 24 months (15 months for the previously untreated cohort). At 24 weeks, 48 patients were evaluable for response, assessed according to the modified IWCLL 2008 criteria.
Response rates
At 24 weeks, 92% (n=44) of the 48 evaluable patients achieved an objective response. Fifty percent of all evaluable patients achieved a partial response (n=24)—55% of previously untreated patients (n=18) and 40% of relapsed/refractory patients (n=6).
As for best response, 10% of all patients achieved a complete response (n=5)—12% of previously untreated patients (n=4) and 7% of relapsed/refractory patients (n=1). And 67% of patients had a partial response (n=32)—70% of previously untreated patients (n=23) and 60% of relapsed/refractory patients (n=9).
After 8 weeks on therapy, ibrutinib was associated with a more than 50% mean reduction in tumor burden in the bone marrow (44%), lymph nodes (70%), and spleen (79%). After 24 weeks of therapy, the rates of tumor burden reduction (> 50%) increased to 83%, 93%, and 95%, respectively.
Survival and safety
The estimated progression-free survival at 24 months for all patients on an intention-to-treat basis was 82%. Forty-two of the 51 patients (82%) continued on ibrutinib treatment without disease progression.
The estimated overall survival at 24 months was 80% for all patients—84% for previously untreated patients and 74% for patients with relapsed or refractory disease.
At the final follow-up, 8 (16%) patients had died—5 (10%) from progressive disease, 2 (4%) from infection, and 1 (2%) patient with a sudden, unexplained death that may have been treatment-related.
The most common adverse events (occurring in more than 30% of all patients) potentially related to ibrutinib were arthralgia (59%), diarrhea (51%), rash (47%), nail ridging (43%), bruising (33%), and muscle spasms (31%).
The most frequent grade 3 or 4 hematologic adverse events were neutropenia (24%), anemia (14%), and thrombocytopenia (10%). The most common nonhematologic grade 3 adverse event was pneumonia, which occurred in 3 patients (6%).
Nine patients (18%) discontinued treatment. The reasons for discontinuation included disease progression in 5 patients (10%) and death for 3 patients (6%).
This research was sponsored by the Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute; Danish Cancer Society; Novo Nordisk Foundation; National Institutes of Health Medical Research Scholars Program; and Pharmacyclics Inc.
Ibrutinib is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.
Whole plant treats malaria better
artemisinin is derived
Credit: Jorge Ferreira
Preclinical research suggests that using the whole plant Artemesia annua, from which the drug artemisinin is extracted, may treat malaria more effectively than artemisinin itself.
Whole-plant treatment withstood the evolution of resistance and remained effective for up to 3 times longer than pure artemisinin.
Whole-plant therapy was also more effective in killing rodent parasites that have previously evolved resistance to pure artemisinin.
Stephen Rich, PhD, of the University of Massachusetts Amherst, and his colleagues reported these findings in PNAS.
The team previously showed that the whole-plant approach is more effective at killing rodent malaria than purified artemisinin.
In the present study, the investigators conducted a series of experiments to determine the rates at which parasites become resistant to whole-plant treatment compared to the rate with pure artemisinin, and if the whole-plant treatment can overcome resistance to pharmaceutical artemisinin.
The team chose 2 rodent malaria species for particular characteristics. They chose Plasmodium yoelii because an artemisinin-resistant strain exists and could be used to test whether the whole plant can overcome that resistance.
And they chose Plasmodium chabaudi because, among several species of rodent malaria, it most closely biologically resembles the deadliest of the 5 human malaria parasites, Plasmodium falciparum.
“Conducting these experiments in different rodent malaria species also provides a robust test of the therapy,” Dr Rich noted.
To determine the respective evolutionary rates of resistance to whole-plant therapy and artemisinin, Dr Rich and his colleagues conducted artificial evolution experiments. The goal was to compare the rates at which resistance to these two treatments arises in serial passage among wild-type parasite lines.
In this technique, parasite proliferation rates determine resistance. Resistant parasites are expected to reach a certain target level at the same time, whether treatment is present or absent. Sensitive parasite strains will grow more slowly in the presence of treatment and reach the target later than untreated strains.
The investigators found that artemisinin-treated parasites achieved stable resistance to low-dose (100 mg/kg) therapy on passage 16. Those parasites were then treated with a doubled artemisinin dose, and they became resistant to this after an additional 24 passages.
By comparison, parasites did not become resistant to even the low dose of whole-plant therapy (100 mg/kg) after 49 passages.
From this, the investigators concluded that the whole-plant therapy lasts at least 3 times longer than its artemisinin counterpart, and at least twice as long as the doubled dose of pure artemisinin.
“This is especially important given the recent reports of resistance to artemisinin in malaria-endemic regions of the world,” Dr Rich said.
He and his colleagues also tested whether dried, whole-plant therapy can overcome existing resistance to pharmaceutical artemisinin.
They fed groups of mice infected with artemisinin-resistant malaria either the whole-plant therapy or artemisinin mixed with water. Single treatments were given in low (40 mg) and high (200 mg) doses. Control groups received a mouse chow placebo.
The investigators then measured the parasite levels in the rodents’ bloodstream at 9 points after treatment began.
Mice given either the low or high dose of whole-plant therapy showed a significantly greater reduction in parasitemia than those in their respective artemisinin groups. As expected for these resistant parasites, parasitemia in mice in the low-dose artemisinin group did not differ from controls.
The investigators said consuming the whole plant may be more effective than the single purified drug because the whole plant “may constitute a naturally occurring combination therapy that augments artemisinin delivery and synergizes the drug’s activity.”
Dr Rich did note that the exact mechanisms of whole-plant therapy’s effectiveness still need to be identified. But he also said the antimalarial activity of whole-plant therapy against artemisinin-resistant parasites provides “compelling reasons to further explore the role of non-pharmaceutical forms of artemisinin to treat human malaria.”
artemisinin is derived
Credit: Jorge Ferreira
Preclinical research suggests that using the whole plant Artemesia annua, from which the drug artemisinin is extracted, may treat malaria more effectively than artemisinin itself.
Whole-plant treatment withstood the evolution of resistance and remained effective for up to 3 times longer than pure artemisinin.
Whole-plant therapy was also more effective in killing rodent parasites that have previously evolved resistance to pure artemisinin.
Stephen Rich, PhD, of the University of Massachusetts Amherst, and his colleagues reported these findings in PNAS.
The team previously showed that the whole-plant approach is more effective at killing rodent malaria than purified artemisinin.
In the present study, the investigators conducted a series of experiments to determine the rates at which parasites become resistant to whole-plant treatment compared to the rate with pure artemisinin, and if the whole-plant treatment can overcome resistance to pharmaceutical artemisinin.
The team chose 2 rodent malaria species for particular characteristics. They chose Plasmodium yoelii because an artemisinin-resistant strain exists and could be used to test whether the whole plant can overcome that resistance.
And they chose Plasmodium chabaudi because, among several species of rodent malaria, it most closely biologically resembles the deadliest of the 5 human malaria parasites, Plasmodium falciparum.
“Conducting these experiments in different rodent malaria species also provides a robust test of the therapy,” Dr Rich noted.
To determine the respective evolutionary rates of resistance to whole-plant therapy and artemisinin, Dr Rich and his colleagues conducted artificial evolution experiments. The goal was to compare the rates at which resistance to these two treatments arises in serial passage among wild-type parasite lines.
In this technique, parasite proliferation rates determine resistance. Resistant parasites are expected to reach a certain target level at the same time, whether treatment is present or absent. Sensitive parasite strains will grow more slowly in the presence of treatment and reach the target later than untreated strains.
The investigators found that artemisinin-treated parasites achieved stable resistance to low-dose (100 mg/kg) therapy on passage 16. Those parasites were then treated with a doubled artemisinin dose, and they became resistant to this after an additional 24 passages.
By comparison, parasites did not become resistant to even the low dose of whole-plant therapy (100 mg/kg) after 49 passages.
From this, the investigators concluded that the whole-plant therapy lasts at least 3 times longer than its artemisinin counterpart, and at least twice as long as the doubled dose of pure artemisinin.
“This is especially important given the recent reports of resistance to artemisinin in malaria-endemic regions of the world,” Dr Rich said.
He and his colleagues also tested whether dried, whole-plant therapy can overcome existing resistance to pharmaceutical artemisinin.
They fed groups of mice infected with artemisinin-resistant malaria either the whole-plant therapy or artemisinin mixed with water. Single treatments were given in low (40 mg) and high (200 mg) doses. Control groups received a mouse chow placebo.
The investigators then measured the parasite levels in the rodents’ bloodstream at 9 points after treatment began.
Mice given either the low or high dose of whole-plant therapy showed a significantly greater reduction in parasitemia than those in their respective artemisinin groups. As expected for these resistant parasites, parasitemia in mice in the low-dose artemisinin group did not differ from controls.
The investigators said consuming the whole plant may be more effective than the single purified drug because the whole plant “may constitute a naturally occurring combination therapy that augments artemisinin delivery and synergizes the drug’s activity.”
Dr Rich did note that the exact mechanisms of whole-plant therapy’s effectiveness still need to be identified. But he also said the antimalarial activity of whole-plant therapy against artemisinin-resistant parasites provides “compelling reasons to further explore the role of non-pharmaceutical forms of artemisinin to treat human malaria.”
artemisinin is derived
Credit: Jorge Ferreira
Preclinical research suggests that using the whole plant Artemesia annua, from which the drug artemisinin is extracted, may treat malaria more effectively than artemisinin itself.
Whole-plant treatment withstood the evolution of resistance and remained effective for up to 3 times longer than pure artemisinin.
Whole-plant therapy was also more effective in killing rodent parasites that have previously evolved resistance to pure artemisinin.
Stephen Rich, PhD, of the University of Massachusetts Amherst, and his colleagues reported these findings in PNAS.
The team previously showed that the whole-plant approach is more effective at killing rodent malaria than purified artemisinin.
In the present study, the investigators conducted a series of experiments to determine the rates at which parasites become resistant to whole-plant treatment compared to the rate with pure artemisinin, and if the whole-plant treatment can overcome resistance to pharmaceutical artemisinin.
The team chose 2 rodent malaria species for particular characteristics. They chose Plasmodium yoelii because an artemisinin-resistant strain exists and could be used to test whether the whole plant can overcome that resistance.
And they chose Plasmodium chabaudi because, among several species of rodent malaria, it most closely biologically resembles the deadliest of the 5 human malaria parasites, Plasmodium falciparum.
“Conducting these experiments in different rodent malaria species also provides a robust test of the therapy,” Dr Rich noted.
To determine the respective evolutionary rates of resistance to whole-plant therapy and artemisinin, Dr Rich and his colleagues conducted artificial evolution experiments. The goal was to compare the rates at which resistance to these two treatments arises in serial passage among wild-type parasite lines.
In this technique, parasite proliferation rates determine resistance. Resistant parasites are expected to reach a certain target level at the same time, whether treatment is present or absent. Sensitive parasite strains will grow more slowly in the presence of treatment and reach the target later than untreated strains.
The investigators found that artemisinin-treated parasites achieved stable resistance to low-dose (100 mg/kg) therapy on passage 16. Those parasites were then treated with a doubled artemisinin dose, and they became resistant to this after an additional 24 passages.
By comparison, parasites did not become resistant to even the low dose of whole-plant therapy (100 mg/kg) after 49 passages.
From this, the investigators concluded that the whole-plant therapy lasts at least 3 times longer than its artemisinin counterpart, and at least twice as long as the doubled dose of pure artemisinin.
“This is especially important given the recent reports of resistance to artemisinin in malaria-endemic regions of the world,” Dr Rich said.
He and his colleagues also tested whether dried, whole-plant therapy can overcome existing resistance to pharmaceutical artemisinin.
They fed groups of mice infected with artemisinin-resistant malaria either the whole-plant therapy or artemisinin mixed with water. Single treatments were given in low (40 mg) and high (200 mg) doses. Control groups received a mouse chow placebo.
The investigators then measured the parasite levels in the rodents’ bloodstream at 9 points after treatment began.
Mice given either the low or high dose of whole-plant therapy showed a significantly greater reduction in parasitemia than those in their respective artemisinin groups. As expected for these resistant parasites, parasitemia in mice in the low-dose artemisinin group did not differ from controls.
The investigators said consuming the whole plant may be more effective than the single purified drug because the whole plant “may constitute a naturally occurring combination therapy that augments artemisinin delivery and synergizes the drug’s activity.”
Dr Rich did note that the exact mechanisms of whole-plant therapy’s effectiveness still need to be identified. But he also said the antimalarial activity of whole-plant therapy against artemisinin-resistant parasites provides “compelling reasons to further explore the role of non-pharmaceutical forms of artemisinin to treat human malaria.”
Drug gets orphan designation for WM
The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal Toll-like receptors (TLRs) 7, 8 and 9, for the treatment of Waldenström’s macroglobulinemia (WM).
The designation provides the drug’s maker, Idera Pharmaceuticals, with certain incentives, including eligibility for federal grants, research and development tax credits, and 7 years of marketing exclusivity if the product is approved.
Preclinical studies have shown that, in WM and other B‐cell lymphomas characterized by the MYD88 L265P oncogenic mutation, TLR signaling is overactivated. And this enables tumor cell survival and proliferation.
About 90% of WM patients are reported to harbor the MYD88 L265P mutation.
In research presented at the 2014 AACR Annual Meeting, investigators showed that IMO-8400 decreased the viability of mutated WM cells and diffuse large B-cell lymphoma (DLBCL) cells in vitro. The drug also decreased tumor growth and prolonged survival in mice with MYD88 L265P-positive DLBCL.
Now, Idera is conducting a phase 1/2 trial (NCT02092909) of IMO-8400 in patients with WM who have a history of relapse or failure to respond to one or more prior therapies. The protocol includes 3 dose-escalation cohorts of IMO-8400 administered subcutaneously.
The trial’s independent data review committee has completed its review of 4-week safety data from the second dose cohort (1.2 mg/kg/week) and has determined that Idera may open enrollment in the third dose cohort (2.4 mg/kg/week).
Final 24-week safety and clinical activity data are anticipated in the second half of 2015.
Aside from WM, Idera is pursuing clinical development of IMO-8400 in DLBCL patients harboring the MYD88 L265P mutation and in rare autoimmune diseases, including dermatomyositis.
The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal Toll-like receptors (TLRs) 7, 8 and 9, for the treatment of Waldenström’s macroglobulinemia (WM).
The designation provides the drug’s maker, Idera Pharmaceuticals, with certain incentives, including eligibility for federal grants, research and development tax credits, and 7 years of marketing exclusivity if the product is approved.
Preclinical studies have shown that, in WM and other B‐cell lymphomas characterized by the MYD88 L265P oncogenic mutation, TLR signaling is overactivated. And this enables tumor cell survival and proliferation.
About 90% of WM patients are reported to harbor the MYD88 L265P mutation.
In research presented at the 2014 AACR Annual Meeting, investigators showed that IMO-8400 decreased the viability of mutated WM cells and diffuse large B-cell lymphoma (DLBCL) cells in vitro. The drug also decreased tumor growth and prolonged survival in mice with MYD88 L265P-positive DLBCL.
Now, Idera is conducting a phase 1/2 trial (NCT02092909) of IMO-8400 in patients with WM who have a history of relapse or failure to respond to one or more prior therapies. The protocol includes 3 dose-escalation cohorts of IMO-8400 administered subcutaneously.
The trial’s independent data review committee has completed its review of 4-week safety data from the second dose cohort (1.2 mg/kg/week) and has determined that Idera may open enrollment in the third dose cohort (2.4 mg/kg/week).
Final 24-week safety and clinical activity data are anticipated in the second half of 2015.
Aside from WM, Idera is pursuing clinical development of IMO-8400 in DLBCL patients harboring the MYD88 L265P mutation and in rare autoimmune diseases, including dermatomyositis.
The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal Toll-like receptors (TLRs) 7, 8 and 9, for the treatment of Waldenström’s macroglobulinemia (WM).
The designation provides the drug’s maker, Idera Pharmaceuticals, with certain incentives, including eligibility for federal grants, research and development tax credits, and 7 years of marketing exclusivity if the product is approved.
Preclinical studies have shown that, in WM and other B‐cell lymphomas characterized by the MYD88 L265P oncogenic mutation, TLR signaling is overactivated. And this enables tumor cell survival and proliferation.
About 90% of WM patients are reported to harbor the MYD88 L265P mutation.
In research presented at the 2014 AACR Annual Meeting, investigators showed that IMO-8400 decreased the viability of mutated WM cells and diffuse large B-cell lymphoma (DLBCL) cells in vitro. The drug also decreased tumor growth and prolonged survival in mice with MYD88 L265P-positive DLBCL.
Now, Idera is conducting a phase 1/2 trial (NCT02092909) of IMO-8400 in patients with WM who have a history of relapse or failure to respond to one or more prior therapies. The protocol includes 3 dose-escalation cohorts of IMO-8400 administered subcutaneously.
The trial’s independent data review committee has completed its review of 4-week safety data from the second dose cohort (1.2 mg/kg/week) and has determined that Idera may open enrollment in the third dose cohort (2.4 mg/kg/week).
Final 24-week safety and clinical activity data are anticipated in the second half of 2015.
Aside from WM, Idera is pursuing clinical development of IMO-8400 in DLBCL patients harboring the MYD88 L265P mutation and in rare autoimmune diseases, including dermatomyositis.