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Research provides new insight into CLL
New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use. 
New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use.
New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use.
CAR T-cell therapy granted orphan designation
Photo courtesy of NIAID
The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).
The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.
ICG122 is being developed by iCell Gene Therapeutics.
The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.
“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.
“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
Photo courtesy of NIAID
The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).
The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.
ICG122 is being developed by iCell Gene Therapeutics.
The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.
“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.
“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
Photo courtesy of NIAID
The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).
The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.
ICG122 is being developed by iCell Gene Therapeutics.
The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.
“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.
“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
Antibody prevents migration of lymphoma cells
Preclinical research suggests a novel antibody can inhibit the migration of lymphoma cells and stop the cells from proliferating.
“Since they cannot survive in the blood for long, [lymphoma] cells are compelled to find a more accommodating environment—such as the lymphatic system—where they can proliferate,” explained Thomas Matthes, MD, of the University of Geneva in Switzerland.
“We decided to focus on this Achilles’ heel by containing them in the blood so as to prevent any resulting harm.”
Dr Matthes and his colleagues described this approach in the Journal of Leukocyte Biology.
The team noted that the inner wall of blood vessels is formed by a layer of endothelial cells that act as a barrier, which prevents the blood cells from leaving the circulation.
Yet, some lymphoma cells are equipped with a surface marker, the JAM-C protein, that is also present on the surface of endothelial cells. JAM-C’s presence on the surface of lymphoma cells facilitates their migration through the vessel walls between adjacent endothelial cells.
To block the effect of this protein, Dr Matthes and his colleagues developed an antibody targeting JAM-C.
This antibody, H225, was designed to bind solely to JAM-C. In doing so, H225 was able to prevent lymphoma cells from migrating out of the blood vessels.
In fact, H225 decreased the transit of lymphoma cells into the organs of the lymphatic system by over 50%.
“This is not its only effect,” Dr Matthes noted. “H225 also significantly limited cell proliferation, even when tumor cells had already settled in the lymphatic system. In our mice, we observed the nearly complete disappearance of already present tumor cells in the organs.”
Specifically, H225 reduced tumor growth of JAM-C+ mantle cell lymphoma cells in the bone marrow, spleen, liver, and lymph nodes.
The researchers believe this work has laid the foundation for a new therapeutic strategy against lymphoma. The team is now focusing its efforts on the quest for an efficient treatment that could be offered to patients.
Preclinical research suggests a novel antibody can inhibit the migration of lymphoma cells and stop the cells from proliferating.
“Since they cannot survive in the blood for long, [lymphoma] cells are compelled to find a more accommodating environment—such as the lymphatic system—where they can proliferate,” explained Thomas Matthes, MD, of the University of Geneva in Switzerland.
“We decided to focus on this Achilles’ heel by containing them in the blood so as to prevent any resulting harm.”
Dr Matthes and his colleagues described this approach in the Journal of Leukocyte Biology.
The team noted that the inner wall of blood vessels is formed by a layer of endothelial cells that act as a barrier, which prevents the blood cells from leaving the circulation.
Yet, some lymphoma cells are equipped with a surface marker, the JAM-C protein, that is also present on the surface of endothelial cells. JAM-C’s presence on the surface of lymphoma cells facilitates their migration through the vessel walls between adjacent endothelial cells.
To block the effect of this protein, Dr Matthes and his colleagues developed an antibody targeting JAM-C.
This antibody, H225, was designed to bind solely to JAM-C. In doing so, H225 was able to prevent lymphoma cells from migrating out of the blood vessels.
In fact, H225 decreased the transit of lymphoma cells into the organs of the lymphatic system by over 50%.
“This is not its only effect,” Dr Matthes noted. “H225 also significantly limited cell proliferation, even when tumor cells had already settled in the lymphatic system. In our mice, we observed the nearly complete disappearance of already present tumor cells in the organs.”
Specifically, H225 reduced tumor growth of JAM-C+ mantle cell lymphoma cells in the bone marrow, spleen, liver, and lymph nodes.
The researchers believe this work has laid the foundation for a new therapeutic strategy against lymphoma. The team is now focusing its efforts on the quest for an efficient treatment that could be offered to patients.
Preclinical research suggests a novel antibody can inhibit the migration of lymphoma cells and stop the cells from proliferating.
“Since they cannot survive in the blood for long, [lymphoma] cells are compelled to find a more accommodating environment—such as the lymphatic system—where they can proliferate,” explained Thomas Matthes, MD, of the University of Geneva in Switzerland.
“We decided to focus on this Achilles’ heel by containing them in the blood so as to prevent any resulting harm.”
Dr Matthes and his colleagues described this approach in the Journal of Leukocyte Biology.
The team noted that the inner wall of blood vessels is formed by a layer of endothelial cells that act as a barrier, which prevents the blood cells from leaving the circulation.
Yet, some lymphoma cells are equipped with a surface marker, the JAM-C protein, that is also present on the surface of endothelial cells. JAM-C’s presence on the surface of lymphoma cells facilitates their migration through the vessel walls between adjacent endothelial cells.
To block the effect of this protein, Dr Matthes and his colleagues developed an antibody targeting JAM-C.
This antibody, H225, was designed to bind solely to JAM-C. In doing so, H225 was able to prevent lymphoma cells from migrating out of the blood vessels.
In fact, H225 decreased the transit of lymphoma cells into the organs of the lymphatic system by over 50%.
“This is not its only effect,” Dr Matthes noted. “H225 also significantly limited cell proliferation, even when tumor cells had already settled in the lymphatic system. In our mice, we observed the nearly complete disappearance of already present tumor cells in the organs.”
Specifically, H225 reduced tumor growth of JAM-C+ mantle cell lymphoma cells in the bone marrow, spleen, liver, and lymph nodes.
The researchers believe this work has laid the foundation for a new therapeutic strategy against lymphoma. The team is now focusing its efforts on the quest for an efficient treatment that could be offered to patients.
SB-generated CAR T cells show promise
Image by NIAID
Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.
These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).
In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.
The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.
The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).
The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.
The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.
Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.
Safety
The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.
Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.
The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.
There were 5 other deaths, all of them due to disease relapse.
Efficacy: Autologous HSCT
Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.
Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).
The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.
Efficacy: Allogeneic HSCT
Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.
Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.
The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.
“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.
“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”
Image by NIAID
Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.
These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).
In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.
The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.
The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).
The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.
The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.
Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.
Safety
The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.
Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.
The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.
There were 5 other deaths, all of them due to disease relapse.
Efficacy: Autologous HSCT
Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.
Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).
The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.
Efficacy: Allogeneic HSCT
Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.
Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.
The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.
“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.
“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”
Image by NIAID
Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.
These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).
In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.
The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.
The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).
The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.
The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.
Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.
Safety
The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.
Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.
The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.
There were 5 other deaths, all of them due to disease relapse.
Efficacy: Autologous HSCT
Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.
Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).
The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.
Efficacy: Allogeneic HSCT
Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.
Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.
The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.
“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.
“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”
Compounds can fight lymphoma, other cancers
Image by Ed Uthman
Preclinical research suggests a novel class of compounds are effective against pediatric and adult cancers, including lymphoma.
The compounds are amphiphilic amines (RCn) based on a tricyclic amine hydrophilic head and a hydrophobic linear alkyl tail of variable length.
The RCn compounds proved cytotoxic in a range of cancer cell lines, including the Burkitt lymphoma cell line Ramos.
The lead compound, RC16, exhibited antitumor effects in vivo and enhanced the in vitro activity of 3 other anticancer agents.
Timothy Cripe, MD, PhD, of Nationwide Children’s Hospital in Columbus, Ohio, and his colleagues reported these results in Pharmaceutical Research.
The investigators first evaluated the RCn compounds for cytotoxicity and mechanism of cell death in several adult and pediatric cancer cell lines.
“We tested RCn’s tumor killing efficacy in cell lines of numerous cancers, including sarcomas, lymphoma, and neuroblastoma,” Dr Cripe said. “We observed anticancer activity of the RCn amines in all the cancer cell lines analyzed.”
The investigators also found that RC16 was 10 times more effective in harming tumor cells than normal cells, including keratinocytes, fibroblasts, and umbilical vein endothelial cells.
In addition, RC16 demonstrated “significant antitumor effects” in several mouse models of malignancy, both when given intravenously and orally.
Because of the amphiphilic molecular structure of RC16, it self-assembled into micelles in water. This chemical structure allowed complexation of the anticancer drugs doxorubicin, etoposide, and paclitaxel.
The micelles significantly improved the in vitro antitumor activity of these drugs by enhancing their solubility in water.
“The antitumor activity of lipophilic amines was interesting because of its action on the mitochondria and lysosomes of cells,” said study author Isabella Orienti, PhD, of the University of Bologna in Italy.
“Moreover, their amphiphilic character improves their bioavailability. We correctly hypothesized these amphiphilic amines would have high antitumor activity and high bioavailability.”
“We are in the process of determining our next steps with testing this new drug,” Dr Cripe added. “This is a promising new therapy for adult and pediatric cancers, and we look forward to further testing its merits.”
Image by Ed Uthman
Preclinical research suggests a novel class of compounds are effective against pediatric and adult cancers, including lymphoma.
The compounds are amphiphilic amines (RCn) based on a tricyclic amine hydrophilic head and a hydrophobic linear alkyl tail of variable length.
The RCn compounds proved cytotoxic in a range of cancer cell lines, including the Burkitt lymphoma cell line Ramos.
The lead compound, RC16, exhibited antitumor effects in vivo and enhanced the in vitro activity of 3 other anticancer agents.
Timothy Cripe, MD, PhD, of Nationwide Children’s Hospital in Columbus, Ohio, and his colleagues reported these results in Pharmaceutical Research.
The investigators first evaluated the RCn compounds for cytotoxicity and mechanism of cell death in several adult and pediatric cancer cell lines.
“We tested RCn’s tumor killing efficacy in cell lines of numerous cancers, including sarcomas, lymphoma, and neuroblastoma,” Dr Cripe said. “We observed anticancer activity of the RCn amines in all the cancer cell lines analyzed.”
The investigators also found that RC16 was 10 times more effective in harming tumor cells than normal cells, including keratinocytes, fibroblasts, and umbilical vein endothelial cells.
In addition, RC16 demonstrated “significant antitumor effects” in several mouse models of malignancy, both when given intravenously and orally.
Because of the amphiphilic molecular structure of RC16, it self-assembled into micelles in water. This chemical structure allowed complexation of the anticancer drugs doxorubicin, etoposide, and paclitaxel.
The micelles significantly improved the in vitro antitumor activity of these drugs by enhancing their solubility in water.
“The antitumor activity of lipophilic amines was interesting because of its action on the mitochondria and lysosomes of cells,” said study author Isabella Orienti, PhD, of the University of Bologna in Italy.
“Moreover, their amphiphilic character improves their bioavailability. We correctly hypothesized these amphiphilic amines would have high antitumor activity and high bioavailability.”
“We are in the process of determining our next steps with testing this new drug,” Dr Cripe added. “This is a promising new therapy for adult and pediatric cancers, and we look forward to further testing its merits.”
Image by Ed Uthman
Preclinical research suggests a novel class of compounds are effective against pediatric and adult cancers, including lymphoma.
The compounds are amphiphilic amines (RCn) based on a tricyclic amine hydrophilic head and a hydrophobic linear alkyl tail of variable length.
The RCn compounds proved cytotoxic in a range of cancer cell lines, including the Burkitt lymphoma cell line Ramos.
The lead compound, RC16, exhibited antitumor effects in vivo and enhanced the in vitro activity of 3 other anticancer agents.
Timothy Cripe, MD, PhD, of Nationwide Children’s Hospital in Columbus, Ohio, and his colleagues reported these results in Pharmaceutical Research.
The investigators first evaluated the RCn compounds for cytotoxicity and mechanism of cell death in several adult and pediatric cancer cell lines.
“We tested RCn’s tumor killing efficacy in cell lines of numerous cancers, including sarcomas, lymphoma, and neuroblastoma,” Dr Cripe said. “We observed anticancer activity of the RCn amines in all the cancer cell lines analyzed.”
The investigators also found that RC16 was 10 times more effective in harming tumor cells than normal cells, including keratinocytes, fibroblasts, and umbilical vein endothelial cells.
In addition, RC16 demonstrated “significant antitumor effects” in several mouse models of malignancy, both when given intravenously and orally.
Because of the amphiphilic molecular structure of RC16, it self-assembled into micelles in water. This chemical structure allowed complexation of the anticancer drugs doxorubicin, etoposide, and paclitaxel.
The micelles significantly improved the in vitro antitumor activity of these drugs by enhancing their solubility in water.
“The antitumor activity of lipophilic amines was interesting because of its action on the mitochondria and lysosomes of cells,” said study author Isabella Orienti, PhD, of the University of Bologna in Italy.
“Moreover, their amphiphilic character improves their bioavailability. We correctly hypothesized these amphiphilic amines would have high antitumor activity and high bioavailability.”
“We are in the process of determining our next steps with testing this new drug,” Dr Cripe added. “This is a promising new therapy for adult and pediatric cancers, and we look forward to further testing its merits.”
Lenalidomide maintenance doesn’t improve OS in DLBCL
Photo courtesy of Celgene
Initial results from the phase 3 REMARC study suggest that lenalidomide (Revlimid) maintenance does not prolong overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who have responded to first-line treatment with R-CHOP.
Based on these results, Celgene Corporation, the company developing lenalidomide, said it does not plan to seek approval for the drug for this indication.
REMARC is a randomized, double-blind study designed to compare lenalidomide maintenance to placebo in 650 patients responding to induction therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients in REMARC had received 6 to 8 cycles of the R-CHOP-14 regimen, 6 to 8 cycles of the R-CHOP-21 regimen, or 6 cycles of R-CHOP-14/R-CHOP-21 completed by 2 cycles of rituximab alone.
The primary endpoint of the study—a significant improvement in progression-free survival for patients receiving lenalidomide—was met.
However, the interim analysis of OS showed no benefit for patients in the lenalidomide arm.
Celgene said that, based on these results, the company is not planning to seek approval for lenalidomide as maintenance in this patient population.
“We are continuing to partner with LYSA [Lymphoma Study Association] to complete the analyses of the REMARC study,” said Michael Pehl, of Celgene.
“We remain committed to finishing the 4 ongoing phase 3 trials evaluating Revlimid and are confident about its potential as a treatment option across different settings in lymphoma.”
The REMARC study is part of a research program focused on non-Hodgkin lymphoma. In addition to the REMARC study, lenalidomide is also being evaluated in:
- The RELEVANCE study—in combination with rituximab in previously untreated follicular lymphoma (FL)
- The AUGMENT study—in combination with rituximab in relapsed/refractory FL and marginal zone lymphoma
- The MAGNIFY study—in combination with rituximab in relapsed/refractory FL, marginal zone lymphoma, and mantle cell lymphoma
- The ROBUST study—in combination with R-CHOP in previously untreated ABC-subtype DLBCL.
Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively.
Photo courtesy of Celgene
Initial results from the phase 3 REMARC study suggest that lenalidomide (Revlimid) maintenance does not prolong overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who have responded to first-line treatment with R-CHOP.
Based on these results, Celgene Corporation, the company developing lenalidomide, said it does not plan to seek approval for the drug for this indication.
REMARC is a randomized, double-blind study designed to compare lenalidomide maintenance to placebo in 650 patients responding to induction therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients in REMARC had received 6 to 8 cycles of the R-CHOP-14 regimen, 6 to 8 cycles of the R-CHOP-21 regimen, or 6 cycles of R-CHOP-14/R-CHOP-21 completed by 2 cycles of rituximab alone.
The primary endpoint of the study—a significant improvement in progression-free survival for patients receiving lenalidomide—was met.
However, the interim analysis of OS showed no benefit for patients in the lenalidomide arm.
Celgene said that, based on these results, the company is not planning to seek approval for lenalidomide as maintenance in this patient population.
“We are continuing to partner with LYSA [Lymphoma Study Association] to complete the analyses of the REMARC study,” said Michael Pehl, of Celgene.
“We remain committed to finishing the 4 ongoing phase 3 trials evaluating Revlimid and are confident about its potential as a treatment option across different settings in lymphoma.”
The REMARC study is part of a research program focused on non-Hodgkin lymphoma. In addition to the REMARC study, lenalidomide is also being evaluated in:
- The RELEVANCE study—in combination with rituximab in previously untreated follicular lymphoma (FL)
- The AUGMENT study—in combination with rituximab in relapsed/refractory FL and marginal zone lymphoma
- The MAGNIFY study—in combination with rituximab in relapsed/refractory FL, marginal zone lymphoma, and mantle cell lymphoma
- The ROBUST study—in combination with R-CHOP in previously untreated ABC-subtype DLBCL.
Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively.
Photo courtesy of Celgene
Initial results from the phase 3 REMARC study suggest that lenalidomide (Revlimid) maintenance does not prolong overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who have responded to first-line treatment with R-CHOP.
Based on these results, Celgene Corporation, the company developing lenalidomide, said it does not plan to seek approval for the drug for this indication.
REMARC is a randomized, double-blind study designed to compare lenalidomide maintenance to placebo in 650 patients responding to induction therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients in REMARC had received 6 to 8 cycles of the R-CHOP-14 regimen, 6 to 8 cycles of the R-CHOP-21 regimen, or 6 cycles of R-CHOP-14/R-CHOP-21 completed by 2 cycles of rituximab alone.
The primary endpoint of the study—a significant improvement in progression-free survival for patients receiving lenalidomide—was met.
However, the interim analysis of OS showed no benefit for patients in the lenalidomide arm.
Celgene said that, based on these results, the company is not planning to seek approval for lenalidomide as maintenance in this patient population.
“We are continuing to partner with LYSA [Lymphoma Study Association] to complete the analyses of the REMARC study,” said Michael Pehl, of Celgene.
“We remain committed to finishing the 4 ongoing phase 3 trials evaluating Revlimid and are confident about its potential as a treatment option across different settings in lymphoma.”
The REMARC study is part of a research program focused on non-Hodgkin lymphoma. In addition to the REMARC study, lenalidomide is also being evaluated in:
- The RELEVANCE study—in combination with rituximab in previously untreated follicular lymphoma (FL)
- The AUGMENT study—in combination with rituximab in relapsed/refractory FL and marginal zone lymphoma
- The MAGNIFY study—in combination with rituximab in relapsed/refractory FL, marginal zone lymphoma, and mantle cell lymphoma
- The ROBUST study—in combination with R-CHOP in previously untreated ABC-subtype DLBCL.
Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively.
EC grants immunotherapy orphan designation
among uninfected cells (blue)
Image courtesy of
Benjamin Chaigne-Delalande
The European Commission (EC) has granted orphan drug designation for CMD-003 (baltaleucel-T) as a treatment for nasal type extranodal NK/T-cell lymphoma and post-transplant lymphoproliferative disorder.
CMD-003 consists of patient-derived T cells that have been activated to kill malignant cells expressing antigens associated with Epstein-Barr virus (EBV).
The T cells specifically target 4 EBV epitopes—LMP1, LMP2, EBNA, and BARF1.
CMD-003 is being developed by Cell Medica and the Baylor College of Medicine, with funding provided, in part, by the Cancer Prevention and Research Institute of Texas.
About orphan designation
Orphan designation from the EC 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 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval. The designation also 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.
CMD-003 also has orphan designation from the US Food and Drug Administration to treat all EBV-associated non-Hodgkin lymphomas.
CMD-003-related research
CMD-003 is currently under investigation in a phase 2 trial, CITADEL, for the treatment of advanced NK/T-cell lymphoma.
Researchers have not published results from any trials of CMD-003, but they have published results with EBV-specific T-cell products related to CMD-003.
In one study, published in the Journal of Clinical Oncology, researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.
Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.
Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of the patients died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.
Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.
The researchers said there were no toxicities that were definitively related to CTL infusion.
One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.
Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.
among uninfected cells (blue)
Image courtesy of
Benjamin Chaigne-Delalande
The European Commission (EC) has granted orphan drug designation for CMD-003 (baltaleucel-T) as a treatment for nasal type extranodal NK/T-cell lymphoma and post-transplant lymphoproliferative disorder.
CMD-003 consists of patient-derived T cells that have been activated to kill malignant cells expressing antigens associated with Epstein-Barr virus (EBV).
The T cells specifically target 4 EBV epitopes—LMP1, LMP2, EBNA, and BARF1.
CMD-003 is being developed by Cell Medica and the Baylor College of Medicine, with funding provided, in part, by the Cancer Prevention and Research Institute of Texas.
About orphan designation
Orphan designation from the EC 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 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval. The designation also 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.
CMD-003 also has orphan designation from the US Food and Drug Administration to treat all EBV-associated non-Hodgkin lymphomas.
CMD-003-related research
CMD-003 is currently under investigation in a phase 2 trial, CITADEL, for the treatment of advanced NK/T-cell lymphoma.
Researchers have not published results from any trials of CMD-003, but they have published results with EBV-specific T-cell products related to CMD-003.
In one study, published in the Journal of Clinical Oncology, researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.
Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.
Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of the patients died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.
Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.
The researchers said there were no toxicities that were definitively related to CTL infusion.
One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.
Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.
among uninfected cells (blue)
Image courtesy of
Benjamin Chaigne-Delalande
The European Commission (EC) has granted orphan drug designation for CMD-003 (baltaleucel-T) as a treatment for nasal type extranodal NK/T-cell lymphoma and post-transplant lymphoproliferative disorder.
CMD-003 consists of patient-derived T cells that have been activated to kill malignant cells expressing antigens associated with Epstein-Barr virus (EBV).
The T cells specifically target 4 EBV epitopes—LMP1, LMP2, EBNA, and BARF1.
CMD-003 is being developed by Cell Medica and the Baylor College of Medicine, with funding provided, in part, by the Cancer Prevention and Research Institute of Texas.
About orphan designation
Orphan designation from the EC 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 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval. The designation also 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.
CMD-003 also has orphan designation from the US Food and Drug Administration to treat all EBV-associated non-Hodgkin lymphomas.
CMD-003-related research
CMD-003 is currently under investigation in a phase 2 trial, CITADEL, for the treatment of advanced NK/T-cell lymphoma.
Researchers have not published results from any trials of CMD-003, but they have published results with EBV-specific T-cell products related to CMD-003.
In one study, published in the Journal of Clinical Oncology, researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.
Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.
Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of the patients died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.
Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.
The researchers said there were no toxicities that were definitively related to CTL infusion.
One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.
Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.
Ibrutinib approved for first-line treatment of CLL
Photo courtesy of Janssen
Health Canada has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) as a first-line treatment for patients with active chronic lymphocytic leukemia (CLL).
This is the fourth approval for ibrutinib in Canada. The drug is now approved for use in all CLL patients, patients with Waldenström’s macroglobulinemia, and patients with relapsed or refractory mantle cell lymphoma (conditional approval).
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
The latest approval of ibrutinib is based on results from the phase 3 RESONATE-2 trial
(PCYC-1115), which were presented at the 2015 ASH Annual Meeting and
simultaneously published in NEJM.
RESONATE-2 enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma who were 65 or older.
Patients were randomized to receive ibrutinib (n=136) at 420 mg once a day until progression or unacceptable toxicity, or chlorambucil (n=133) on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis.
Key secondary endpoints included overall response rate (based on the same iWCLL criteria), overall survival (OS), and safety.
Ibrutinib significantly prolonged PFS, as determined by the IRC, reducing the risk of progression or death by 84% compared to chlorambucil. The hazard ratio was 0.16 (P<0.001). The median PFS was not reached in the ibrutinib arm but was 18.9 months for the chlorambucil arm.
Ibrutinib significantly prolonged OS as well, although the median OS was not reached in either treatment arm. The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil. The relative risk of death with ibrutinib was 84% lower than that with chlorambucil. The hazard ratio was 0.16 (P=0.001).
Ibrutinib was associated with a significantly higher IRC-assessed overall response rate compared to chlorambucil—82% and 35%, respectively (P<0.0001). Five
patients (4%) in the ibrutinib arm achieved a complete response, as did 2 patients (2%) in the chlorambucil arm.
The median duration of treatment was 17.4 months in the ibrutinib arm and 7.1 months in the chlorambucil arm.
The most common adverse events of any grade—in the ibrutinib and chlorambucil arms, respectively—were diarrhea (42% and 17%), fatigue (30% and 38%), cough (22% and 15%), nausea (22% and 39%), peripheral edema (19% and 9%), dry eye (17% and 5%), arthralgia (16% and 7%), neutropenia (16% and 23%), and vomiting (13% and 20%).
Adverse events of grade 3 or higher—in the ibrutinib and chlorambucil arms, respectively—were neutropenia (10% and 18%), anemia (6% and 8%), hypertension (4% and 0%), pneumonia (4% and 2%), diarrhea (4% and 0%), maculopapular rash (3% and 2%), decreased platelet count (3% and 1%), abdominal pain (3% and 1%), hyponatremia (3% and 0%), thrombocytopenia (2% and 6%), febrile neutropenia (2% and 2%), upper respiratory tract infection (2% and 2%), pleural effusion (2% and 1%), cellulitis (2% and 0%), fatigue (1% and 5%), syncope (1% and 2%), and hemolytic anemia (0% and 2%).
Photo courtesy of Janssen
Health Canada has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) as a first-line treatment for patients with active chronic lymphocytic leukemia (CLL).
This is the fourth approval for ibrutinib in Canada. The drug is now approved for use in all CLL patients, patients with Waldenström’s macroglobulinemia, and patients with relapsed or refractory mantle cell lymphoma (conditional approval).
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
The latest approval of ibrutinib is based on results from the phase 3 RESONATE-2 trial
(PCYC-1115), which were presented at the 2015 ASH Annual Meeting and
simultaneously published in NEJM.
RESONATE-2 enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma who were 65 or older.
Patients were randomized to receive ibrutinib (n=136) at 420 mg once a day until progression or unacceptable toxicity, or chlorambucil (n=133) on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis.
Key secondary endpoints included overall response rate (based on the same iWCLL criteria), overall survival (OS), and safety.
Ibrutinib significantly prolonged PFS, as determined by the IRC, reducing the risk of progression or death by 84% compared to chlorambucil. The hazard ratio was 0.16 (P<0.001). The median PFS was not reached in the ibrutinib arm but was 18.9 months for the chlorambucil arm.
Ibrutinib significantly prolonged OS as well, although the median OS was not reached in either treatment arm. The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil. The relative risk of death with ibrutinib was 84% lower than that with chlorambucil. The hazard ratio was 0.16 (P=0.001).
Ibrutinib was associated with a significantly higher IRC-assessed overall response rate compared to chlorambucil—82% and 35%, respectively (P<0.0001). Five
patients (4%) in the ibrutinib arm achieved a complete response, as did 2 patients (2%) in the chlorambucil arm.
The median duration of treatment was 17.4 months in the ibrutinib arm and 7.1 months in the chlorambucil arm.
The most common adverse events of any grade—in the ibrutinib and chlorambucil arms, respectively—were diarrhea (42% and 17%), fatigue (30% and 38%), cough (22% and 15%), nausea (22% and 39%), peripheral edema (19% and 9%), dry eye (17% and 5%), arthralgia (16% and 7%), neutropenia (16% and 23%), and vomiting (13% and 20%).
Adverse events of grade 3 or higher—in the ibrutinib and chlorambucil arms, respectively—were neutropenia (10% and 18%), anemia (6% and 8%), hypertension (4% and 0%), pneumonia (4% and 2%), diarrhea (4% and 0%), maculopapular rash (3% and 2%), decreased platelet count (3% and 1%), abdominal pain (3% and 1%), hyponatremia (3% and 0%), thrombocytopenia (2% and 6%), febrile neutropenia (2% and 2%), upper respiratory tract infection (2% and 2%), pleural effusion (2% and 1%), cellulitis (2% and 0%), fatigue (1% and 5%), syncope (1% and 2%), and hemolytic anemia (0% and 2%).
Photo courtesy of Janssen
Health Canada has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) as a first-line treatment for patients with active chronic lymphocytic leukemia (CLL).
This is the fourth approval for ibrutinib in Canada. The drug is now approved for use in all CLL patients, patients with Waldenström’s macroglobulinemia, and patients with relapsed or refractory mantle cell lymphoma (conditional approval).
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
The latest approval of ibrutinib is based on results from the phase 3 RESONATE-2 trial
(PCYC-1115), which were presented at the 2015 ASH Annual Meeting and
simultaneously published in NEJM.
RESONATE-2 enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma who were 65 or older.
Patients were randomized to receive ibrutinib (n=136) at 420 mg once a day until progression or unacceptable toxicity, or chlorambucil (n=133) on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis.
Key secondary endpoints included overall response rate (based on the same iWCLL criteria), overall survival (OS), and safety.
Ibrutinib significantly prolonged PFS, as determined by the IRC, reducing the risk of progression or death by 84% compared to chlorambucil. The hazard ratio was 0.16 (P<0.001). The median PFS was not reached in the ibrutinib arm but was 18.9 months for the chlorambucil arm.
Ibrutinib significantly prolonged OS as well, although the median OS was not reached in either treatment arm. The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil. The relative risk of death with ibrutinib was 84% lower than that with chlorambucil. The hazard ratio was 0.16 (P=0.001).
Ibrutinib was associated with a significantly higher IRC-assessed overall response rate compared to chlorambucil—82% and 35%, respectively (P<0.0001). Five
patients (4%) in the ibrutinib arm achieved a complete response, as did 2 patients (2%) in the chlorambucil arm.
The median duration of treatment was 17.4 months in the ibrutinib arm and 7.1 months in the chlorambucil arm.
The most common adverse events of any grade—in the ibrutinib and chlorambucil arms, respectively—were diarrhea (42% and 17%), fatigue (30% and 38%), cough (22% and 15%), nausea (22% and 39%), peripheral edema (19% and 9%), dry eye (17% and 5%), arthralgia (16% and 7%), neutropenia (16% and 23%), and vomiting (13% and 20%).
Adverse events of grade 3 or higher—in the ibrutinib and chlorambucil arms, respectively—were neutropenia (10% and 18%), anemia (6% and 8%), hypertension (4% and 0%), pneumonia (4% and 2%), diarrhea (4% and 0%), maculopapular rash (3% and 2%), decreased platelet count (3% and 1%), abdominal pain (3% and 1%), hyponatremia (3% and 0%), thrombocytopenia (2% and 6%), febrile neutropenia (2% and 2%), upper respiratory tract infection (2% and 2%), pleural effusion (2% and 1%), cellulitis (2% and 0%), fatigue (1% and 5%), syncope (1% and 2%), and hemolytic anemia (0% and 2%).
Combo doesn’t improve PFS in DLBCL
Results of a phase 3 study suggest that obinutuzumab may not confer a benefit over standard therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).
The data showed that obinutuzumab plus CHOP chemotherapy does not improve progression-free survival (PFS) in DLBCL patients, when compared to rituximab plus CHOP.
Adverse events with both treatment regimens were consistent with those seen in previous clinical trials, according to Genentech and Biogen, the companies developing obinutuzumab.
The companies have not released any data from this trial, known as GOYA, but they said results will be presented at an upcoming medical meeting.
“Two previous studies showed [obinutuzumab] helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to [rituximab], when each was combined with chemotherapy,” said Sandra Horning, MD, chief medical officer and head of global product development at Genentech.
“We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care. We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”
The GOYA trial enrolled 1418 previously untreated patients with CD20-positive DLBCL. The patients were randomized to receive obinutuzumab at 1000 mg every 21 days or rituximab at 375 mg/m2 every 21 days for 8 cycles, in addition to 6 to 8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 21 days.
The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by an independent review committee, response rate, overall survival, disease-free survival, and safety profile.
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain B cells. The drug is thought to work by attacking targeted cells both directly and together with the immune system.
In the US and the European Union (EU), obinutuzumab is approved for use in combination with chlorambucil to treat adults with previously untreated chronic lymphocytic leukemia.
Obinutuzumab is also approved in the US and the EU to treat patients with follicular lymphoma. The drug can be given, first in combination with bendamustine and then alone as maintenance therapy, to adults with follicular lymphoma who did not respond to a rituximab-containing regimen or whose disease returned after such treatment.
Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland and Gazyva in the rest of the world.
Results of a phase 3 study suggest that obinutuzumab may not confer a benefit over standard therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).
The data showed that obinutuzumab plus CHOP chemotherapy does not improve progression-free survival (PFS) in DLBCL patients, when compared to rituximab plus CHOP.
Adverse events with both treatment regimens were consistent with those seen in previous clinical trials, according to Genentech and Biogen, the companies developing obinutuzumab.
The companies have not released any data from this trial, known as GOYA, but they said results will be presented at an upcoming medical meeting.
“Two previous studies showed [obinutuzumab] helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to [rituximab], when each was combined with chemotherapy,” said Sandra Horning, MD, chief medical officer and head of global product development at Genentech.
“We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care. We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”
The GOYA trial enrolled 1418 previously untreated patients with CD20-positive DLBCL. The patients were randomized to receive obinutuzumab at 1000 mg every 21 days or rituximab at 375 mg/m2 every 21 days for 8 cycles, in addition to 6 to 8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 21 days.
The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by an independent review committee, response rate, overall survival, disease-free survival, and safety profile.
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain B cells. The drug is thought to work by attacking targeted cells both directly and together with the immune system.
In the US and the European Union (EU), obinutuzumab is approved for use in combination with chlorambucil to treat adults with previously untreated chronic lymphocytic leukemia.
Obinutuzumab is also approved in the US and the EU to treat patients with follicular lymphoma. The drug can be given, first in combination with bendamustine and then alone as maintenance therapy, to adults with follicular lymphoma who did not respond to a rituximab-containing regimen or whose disease returned after such treatment.
Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland and Gazyva in the rest of the world.
Results of a phase 3 study suggest that obinutuzumab may not confer a benefit over standard therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).
The data showed that obinutuzumab plus CHOP chemotherapy does not improve progression-free survival (PFS) in DLBCL patients, when compared to rituximab plus CHOP.
Adverse events with both treatment regimens were consistent with those seen in previous clinical trials, according to Genentech and Biogen, the companies developing obinutuzumab.
The companies have not released any data from this trial, known as GOYA, but they said results will be presented at an upcoming medical meeting.
“Two previous studies showed [obinutuzumab] helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to [rituximab], when each was combined with chemotherapy,” said Sandra Horning, MD, chief medical officer and head of global product development at Genentech.
“We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care. We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”
The GOYA trial enrolled 1418 previously untreated patients with CD20-positive DLBCL. The patients were randomized to receive obinutuzumab at 1000 mg every 21 days or rituximab at 375 mg/m2 every 21 days for 8 cycles, in addition to 6 to 8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 21 days.
The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by an independent review committee, response rate, overall survival, disease-free survival, and safety profile.
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain B cells. The drug is thought to work by attacking targeted cells both directly and together with the immune system.
In the US and the European Union (EU), obinutuzumab is approved for use in combination with chlorambucil to treat adults with previously untreated chronic lymphocytic leukemia.
Obinutuzumab is also approved in the US and the EU to treat patients with follicular lymphoma. The drug can be given, first in combination with bendamustine and then alone as maintenance therapy, to adults with follicular lymphoma who did not respond to a rituximab-containing regimen or whose disease returned after such treatment.
Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland and Gazyva in the rest of the world.
EC approves lenalidomide for rel/ref MCL
Photo courtesy of Celgene
The European Commission (EC) has approved lenalidomide (Revlimid®) for the treatment of adults with relapsed or refractory mantle cell lymphoma (MCL).
The EC previously approved lenalidomide as a single agent to treat adults with newly diagnosed multiple myeloma who are not eligible for transplant and in combination with dexamethasone to treat adults with multiple myeloma who have received at least 1 prior therapy.
The EC also approved lenalidomide for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
Lenalidomide is a product of Celgene Corporation.
The EC’s decision to approve lenalidomide for MCL was based on data from a phase 2 trial known as SPRINT or MCL-002. The study included 254 MCL patients who were refractory to their last treatment or had relapsed 1 to 3 times.
The patients were randomized (2:1) to receive lenalidomide (n=170) or a single-agent therapy of the investigator’s choice (n=84), which included rituximab, gemcitabine, fludarabine, chlorambucil, and cytarabine. Patients who progressed on investigator’s choice could cross over to the lenalidomide arm.
At a median follow-up of 15.9 months, the overall response rate was 40% in the lenalidomide arm and 11% in the investigator’s choice arm (P<0.001).
The complete response rates were 5% and 0%, respectively (P=0.04). The median duration of response was 16 months and 10.4 months, respectively.
Lenalidomide significantly prolonged progression-free survival. The median was 8.7 months in the lenalidomide arm and 5.2 months in the investigator’s choice arm (P=0.004).
However, there was no significant difference in overall survival between the treatment arms. The median was 27.8 months in the lenalidomide arm and 21.2 months in the investigator’s choice arm (P=0.45).
The incidence of treatment-related adverse events was 84% in the lenalidomide arm and 60% in the investigator’s choice arm.
Common adverse events that occurred more frequently in the lenalidomide arm than the investigator’s choice arm were neutropenia (51%), anemia (29%), diarrhea (23%), fatigue (21%), constipation (17%), pyrexia (17%), and rash (16%).
Photo courtesy of Celgene
The European Commission (EC) has approved lenalidomide (Revlimid®) for the treatment of adults with relapsed or refractory mantle cell lymphoma (MCL).
The EC previously approved lenalidomide as a single agent to treat adults with newly diagnosed multiple myeloma who are not eligible for transplant and in combination with dexamethasone to treat adults with multiple myeloma who have received at least 1 prior therapy.
The EC also approved lenalidomide for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
Lenalidomide is a product of Celgene Corporation.
The EC’s decision to approve lenalidomide for MCL was based on data from a phase 2 trial known as SPRINT or MCL-002. The study included 254 MCL patients who were refractory to their last treatment or had relapsed 1 to 3 times.
The patients were randomized (2:1) to receive lenalidomide (n=170) or a single-agent therapy of the investigator’s choice (n=84), which included rituximab, gemcitabine, fludarabine, chlorambucil, and cytarabine. Patients who progressed on investigator’s choice could cross over to the lenalidomide arm.
At a median follow-up of 15.9 months, the overall response rate was 40% in the lenalidomide arm and 11% in the investigator’s choice arm (P<0.001).
The complete response rates were 5% and 0%, respectively (P=0.04). The median duration of response was 16 months and 10.4 months, respectively.
Lenalidomide significantly prolonged progression-free survival. The median was 8.7 months in the lenalidomide arm and 5.2 months in the investigator’s choice arm (P=0.004).
However, there was no significant difference in overall survival between the treatment arms. The median was 27.8 months in the lenalidomide arm and 21.2 months in the investigator’s choice arm (P=0.45).
The incidence of treatment-related adverse events was 84% in the lenalidomide arm and 60% in the investigator’s choice arm.
Common adverse events that occurred more frequently in the lenalidomide arm than the investigator’s choice arm were neutropenia (51%), anemia (29%), diarrhea (23%), fatigue (21%), constipation (17%), pyrexia (17%), and rash (16%).
Photo courtesy of Celgene
The European Commission (EC) has approved lenalidomide (Revlimid®) for the treatment of adults with relapsed or refractory mantle cell lymphoma (MCL).
The EC previously approved lenalidomide as a single agent to treat adults with newly diagnosed multiple myeloma who are not eligible for transplant and in combination with dexamethasone to treat adults with multiple myeloma who have received at least 1 prior therapy.
The EC also approved lenalidomide for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
Lenalidomide is a product of Celgene Corporation.
The EC’s decision to approve lenalidomide for MCL was based on data from a phase 2 trial known as SPRINT or MCL-002. The study included 254 MCL patients who were refractory to their last treatment or had relapsed 1 to 3 times.
The patients were randomized (2:1) to receive lenalidomide (n=170) or a single-agent therapy of the investigator’s choice (n=84), which included rituximab, gemcitabine, fludarabine, chlorambucil, and cytarabine. Patients who progressed on investigator’s choice could cross over to the lenalidomide arm.
At a median follow-up of 15.9 months, the overall response rate was 40% in the lenalidomide arm and 11% in the investigator’s choice arm (P<0.001).
The complete response rates were 5% and 0%, respectively (P=0.04). The median duration of response was 16 months and 10.4 months, respectively.
Lenalidomide significantly prolonged progression-free survival. The median was 8.7 months in the lenalidomide arm and 5.2 months in the investigator’s choice arm (P=0.004).
However, there was no significant difference in overall survival between the treatment arms. The median was 27.8 months in the lenalidomide arm and 21.2 months in the investigator’s choice arm (P=0.45).
The incidence of treatment-related adverse events was 84% in the lenalidomide arm and 60% in the investigator’s choice arm.
Common adverse events that occurred more frequently in the lenalidomide arm than the investigator’s choice arm were neutropenia (51%), anemia (29%), diarrhea (23%), fatigue (21%), constipation (17%), pyrexia (17%), and rash (16%).