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Immunotherapy gets orphan designation
Photo by Graham Colm
The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.
CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.
Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.
CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.
Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.
CMD-003 prototype
Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.
In their most recent study, published in the Journal of Clinical Oncology, the 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 from their disease at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of them 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. 
Photo by Graham Colm
The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.
CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.
Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.
CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.
Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.
CMD-003 prototype
Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.
In their most recent study, published in the Journal of Clinical Oncology, the 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 from their disease at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of them 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.
Photo by Graham Colm
The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.
CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.
Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.
CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.
Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.
CMD-003 prototype
Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.
In their most recent study, published in the Journal of Clinical Oncology, the 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 from their disease at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of them 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.
Pesticides may cause NHL, other cancers
Photo by John Messina
The International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization, has found evidence suggesting that 5 organophosphate pesticides may be carcinogenic.
The IARC classified the herbicide glyphosate and the insecticides malathion and diazinon as “probably carcinogenic” to humans and the insecticides tetrachlorvinphos and parathion as “possibly carcinogenic” to humans.
A summary of these findings has been published in The Lancet Oncology.
Glyphosate
For the herbicide glyphosate, the IARC found limited evidence of carcinogenicity in humans. Case-control studies of occupational exposure to glyphosate in the US, Canada, and Sweden showed increased risks for non-Hodgkin lymphoma (NHL).
However, the Agricultural Health Study (AHS) showed no significantly increased risk of NHL in subjects exposed to glyphosate.
A study of community residents showed increases in blood markers of chromosomal damage after glyphosate formulations were sprayed nearby. And glyphosate was shown to cause DNA and chromosomal damage in human cells, although bacterial mutagenesis tests were negative.
In studies of male mice, glyphosate increased the incidence of renal tubule carcinoma and hemangiosarcoma. Glyphosate also increased the incidence of pancreatic islet-cell adenoma in male rats, and a glyphosate formulation promoted skin tumors in mice.
The IARC said glyphosate has the highest global production volume of all herbicides. It is used in agriculture, forestry, urban, and home applications.
Glyphosate has been detected in the air during spraying, in water, and in food. The general population is exposed to the chemical primarily by living near sprayed areas, home use, and diet. But the IARC said the level of exposure observed is generally low.
Malathion
The IARC classified malathion as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL and prostate cancer. Occupational use of malathion was associated with an increased risk of prostate cancer in a Canadian case-control study and in the AHS.
Studies of occupational exposures in the US, Canada, and Sweden revealed positive associations between malathion and NHL. However, results of the AHS did not show an association between the insecticide and NHL.
Studies showed that malathion induced DNA and chromosomal damage in humans and animals, although bacterial mutagenesis tests were negative. Results also suggested malathion disrupts hormone pathways.
Experiments in mice showed malathion increased the incidence of hepatocellular adenoma or carcinoma (combined). In rats, the insecticide increased the incidence of thyroid carcinoma in males, hepatocellular adenoma or carcinoma (combined) in females, and mammary gland adenocarcinoma after subcutaneous injection in females.
The IARC said malathion is used in “substantial volumes throughout the world” to control insects in agricultural and residential areas.
Workers may be exposed to malathion during the use and production of the product. The general population may be exposed if they live near sprayed areas, use the product at home, or consume food exposed to the chemical.
Diazinon
The IARC classified diazinon as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL, leukemia, and lung cancer.
Two multicenter, case-control studies of agricultural exposures suggested a positive association between diazinon and NHL. The AHS showed positive associations with specific subtypes of NHL but no overall increased risk of NHL. The AHS also suggested an increased risk of leukemia and lung cancer in subjects exposed to diazinon.
Evidence suggested that diazinon induced DNA or chromosomal damage in human and mammalian cells in vitro. In vivo, diazinon increased the incidence of hepatocellular carcinoma in mice and leukemia or lymphoma (combined) in rats, but only in males receiving the low dose in each study.
Diazinon has been used to control insects in agricultural and residential areas. The IARC said production volumes have been relatively low and decreased further after 2006 due to restrictions in the US and the European Union (EU). There was limited information on the use of this pesticide in other countries.
Tetrachlorvinphos
The insecticide tetrachlorvinphos was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals. The IARC said the evidence in humans was inadequate.
However, tetrachlorvinphos was shown to induce hepatocellular tumors (benign or malignant) in mice, renal tubule tumors (benign or malignant) in male mice, and spleen hemangioma in male rats.
Tetrachlorvinphos is banned in the EU. In the US, the insecticide is still used on livestock and pets (in flea collars). The IARC said there was no information available on tetrachlorvinphos use in other countries.
Parathion
The insecticide parathion was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals.
Researchers have observed associations between the insecticide and cancers in several tissues in occupational studies. But the IARC said the evidence that parathion is carcinogenic in humans remains sparse.
Experiments in mice showed that parathion increased the incidence of bronchioloalveolar adenoma and/or carcinoma in males and lymphoma in females. In rats, parathion induced adrenal cortical adenoma or carcinoma (combined), malignant pancreatic tumors, and thyroid follicular cell adenoma in males, and mammary gland adenocarcinoma (after subcutaneous injection in females).
Parathion use has been severely restricted since the 1980s, and all authorized uses of this chemical were cancelled in the EU and the US by 2003.
Photo by John Messina
The International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization, has found evidence suggesting that 5 organophosphate pesticides may be carcinogenic.
The IARC classified the herbicide glyphosate and the insecticides malathion and diazinon as “probably carcinogenic” to humans and the insecticides tetrachlorvinphos and parathion as “possibly carcinogenic” to humans.
A summary of these findings has been published in The Lancet Oncology.
Glyphosate
For the herbicide glyphosate, the IARC found limited evidence of carcinogenicity in humans. Case-control studies of occupational exposure to glyphosate in the US, Canada, and Sweden showed increased risks for non-Hodgkin lymphoma (NHL).
However, the Agricultural Health Study (AHS) showed no significantly increased risk of NHL in subjects exposed to glyphosate.
A study of community residents showed increases in blood markers of chromosomal damage after glyphosate formulations were sprayed nearby. And glyphosate was shown to cause DNA and chromosomal damage in human cells, although bacterial mutagenesis tests were negative.
In studies of male mice, glyphosate increased the incidence of renal tubule carcinoma and hemangiosarcoma. Glyphosate also increased the incidence of pancreatic islet-cell adenoma in male rats, and a glyphosate formulation promoted skin tumors in mice.
The IARC said glyphosate has the highest global production volume of all herbicides. It is used in agriculture, forestry, urban, and home applications.
Glyphosate has been detected in the air during spraying, in water, and in food. The general population is exposed to the chemical primarily by living near sprayed areas, home use, and diet. But the IARC said the level of exposure observed is generally low.
Malathion
The IARC classified malathion as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL and prostate cancer. Occupational use of malathion was associated with an increased risk of prostate cancer in a Canadian case-control study and in the AHS.
Studies of occupational exposures in the US, Canada, and Sweden revealed positive associations between malathion and NHL. However, results of the AHS did not show an association between the insecticide and NHL.
Studies showed that malathion induced DNA and chromosomal damage in humans and animals, although bacterial mutagenesis tests were negative. Results also suggested malathion disrupts hormone pathways.
Experiments in mice showed malathion increased the incidence of hepatocellular adenoma or carcinoma (combined). In rats, the insecticide increased the incidence of thyroid carcinoma in males, hepatocellular adenoma or carcinoma (combined) in females, and mammary gland adenocarcinoma after subcutaneous injection in females.
The IARC said malathion is used in “substantial volumes throughout the world” to control insects in agricultural and residential areas.
Workers may be exposed to malathion during the use and production of the product. The general population may be exposed if they live near sprayed areas, use the product at home, or consume food exposed to the chemical.
Diazinon
The IARC classified diazinon as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL, leukemia, and lung cancer.
Two multicenter, case-control studies of agricultural exposures suggested a positive association between diazinon and NHL. The AHS showed positive associations with specific subtypes of NHL but no overall increased risk of NHL. The AHS also suggested an increased risk of leukemia and lung cancer in subjects exposed to diazinon.
Evidence suggested that diazinon induced DNA or chromosomal damage in human and mammalian cells in vitro. In vivo, diazinon increased the incidence of hepatocellular carcinoma in mice and leukemia or lymphoma (combined) in rats, but only in males receiving the low dose in each study.
Diazinon has been used to control insects in agricultural and residential areas. The IARC said production volumes have been relatively low and decreased further after 2006 due to restrictions in the US and the European Union (EU). There was limited information on the use of this pesticide in other countries.
Tetrachlorvinphos
The insecticide tetrachlorvinphos was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals. The IARC said the evidence in humans was inadequate.
However, tetrachlorvinphos was shown to induce hepatocellular tumors (benign or malignant) in mice, renal tubule tumors (benign or malignant) in male mice, and spleen hemangioma in male rats.
Tetrachlorvinphos is banned in the EU. In the US, the insecticide is still used on livestock and pets (in flea collars). The IARC said there was no information available on tetrachlorvinphos use in other countries.
Parathion
The insecticide parathion was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals.
Researchers have observed associations between the insecticide and cancers in several tissues in occupational studies. But the IARC said the evidence that parathion is carcinogenic in humans remains sparse.
Experiments in mice showed that parathion increased the incidence of bronchioloalveolar adenoma and/or carcinoma in males and lymphoma in females. In rats, parathion induced adrenal cortical adenoma or carcinoma (combined), malignant pancreatic tumors, and thyroid follicular cell adenoma in males, and mammary gland adenocarcinoma (after subcutaneous injection in females).
Parathion use has been severely restricted since the 1980s, and all authorized uses of this chemical were cancelled in the EU and the US by 2003.
Photo by John Messina
The International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization, has found evidence suggesting that 5 organophosphate pesticides may be carcinogenic.
The IARC classified the herbicide glyphosate and the insecticides malathion and diazinon as “probably carcinogenic” to humans and the insecticides tetrachlorvinphos and parathion as “possibly carcinogenic” to humans.
A summary of these findings has been published in The Lancet Oncology.
Glyphosate
For the herbicide glyphosate, the IARC found limited evidence of carcinogenicity in humans. Case-control studies of occupational exposure to glyphosate in the US, Canada, and Sweden showed increased risks for non-Hodgkin lymphoma (NHL).
However, the Agricultural Health Study (AHS) showed no significantly increased risk of NHL in subjects exposed to glyphosate.
A study of community residents showed increases in blood markers of chromosomal damage after glyphosate formulations were sprayed nearby. And glyphosate was shown to cause DNA and chromosomal damage in human cells, although bacterial mutagenesis tests were negative.
In studies of male mice, glyphosate increased the incidence of renal tubule carcinoma and hemangiosarcoma. Glyphosate also increased the incidence of pancreatic islet-cell adenoma in male rats, and a glyphosate formulation promoted skin tumors in mice.
The IARC said glyphosate has the highest global production volume of all herbicides. It is used in agriculture, forestry, urban, and home applications.
Glyphosate has been detected in the air during spraying, in water, and in food. The general population is exposed to the chemical primarily by living near sprayed areas, home use, and diet. But the IARC said the level of exposure observed is generally low.
Malathion
The IARC classified malathion as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL and prostate cancer. Occupational use of malathion was associated with an increased risk of prostate cancer in a Canadian case-control study and in the AHS.
Studies of occupational exposures in the US, Canada, and Sweden revealed positive associations between malathion and NHL. However, results of the AHS did not show an association between the insecticide and NHL.
Studies showed that malathion induced DNA and chromosomal damage in humans and animals, although bacterial mutagenesis tests were negative. Results also suggested malathion disrupts hormone pathways.
Experiments in mice showed malathion increased the incidence of hepatocellular adenoma or carcinoma (combined). In rats, the insecticide increased the incidence of thyroid carcinoma in males, hepatocellular adenoma or carcinoma (combined) in females, and mammary gland adenocarcinoma after subcutaneous injection in females.
The IARC said malathion is used in “substantial volumes throughout the world” to control insects in agricultural and residential areas.
Workers may be exposed to malathion during the use and production of the product. The general population may be exposed if they live near sprayed areas, use the product at home, or consume food exposed to the chemical.
Diazinon
The IARC classified diazinon as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL, leukemia, and lung cancer.
Two multicenter, case-control studies of agricultural exposures suggested a positive association between diazinon and NHL. The AHS showed positive associations with specific subtypes of NHL but no overall increased risk of NHL. The AHS also suggested an increased risk of leukemia and lung cancer in subjects exposed to diazinon.
Evidence suggested that diazinon induced DNA or chromosomal damage in human and mammalian cells in vitro. In vivo, diazinon increased the incidence of hepatocellular carcinoma in mice and leukemia or lymphoma (combined) in rats, but only in males receiving the low dose in each study.
Diazinon has been used to control insects in agricultural and residential areas. The IARC said production volumes have been relatively low and decreased further after 2006 due to restrictions in the US and the European Union (EU). There was limited information on the use of this pesticide in other countries.
Tetrachlorvinphos
The insecticide tetrachlorvinphos was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals. The IARC said the evidence in humans was inadequate.
However, tetrachlorvinphos was shown to induce hepatocellular tumors (benign or malignant) in mice, renal tubule tumors (benign or malignant) in male mice, and spleen hemangioma in male rats.
Tetrachlorvinphos is banned in the EU. In the US, the insecticide is still used on livestock and pets (in flea collars). The IARC said there was no information available on tetrachlorvinphos use in other countries.
Parathion
The insecticide parathion was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals.
Researchers have observed associations between the insecticide and cancers in several tissues in occupational studies. But the IARC said the evidence that parathion is carcinogenic in humans remains sparse.
Experiments in mice showed that parathion increased the incidence of bronchioloalveolar adenoma and/or carcinoma in males and lymphoma in females. In rats, parathion induced adrenal cortical adenoma or carcinoma (combined), malignant pancreatic tumors, and thyroid follicular cell adenoma in males, and mammary gland adenocarcinoma (after subcutaneous injection in females).
Parathion use has been severely restricted since the 1980s, and all authorized uses of this chemical were cancelled in the EU and the US by 2003.
Immunotoxin could treat B-cell malignancies, team says
Photo courtesy of the
University of Minnesota
A bispecific ligand-directed diphtheria toxin known as DT2219 shows promise for treating patients with relapsed/refractory B-cell malignancies, according to researchers.
DT2219 produced responses in 2 of 25 patients analyzed in a phase 1 study. The maximum tolerated dose of DT2219 was not reached, although 2 patients experienced dose-limiting toxicities.
“In this phase 1 trial, we found a safe dose of the drug that has biological activity,” said Daniel Vallera, PhD, of the University of Minnesota in Minneapolis.
“We are planning a phase 2 trial with this drug. It will focus on giving more cycles of treatment, which we believe will dramatically enhance the response rates.”
Dr Vallera and his colleagues detailed the phase 1 results in Clinical Cancer Research.
To develop DT2219, the researchers chose 2 antibody fragments that each selectively bind to CD19 and CD22. They used genetic engineering to attach these two antibodies to the bacterial diphtheria toxin.
When the antibody fragments bind to the two targets on the cancer cell, the entire drug enters the cell, and the toxin kills the cell.
To test DT2219, the researchers enrolled 25 patients with chemo-refractory pre-B acute lymphoblastic leukemia (n=10), chronic lymphocytic leukemia (n=5), or non-Hodgkin lymphoma (n=10). All tumors had CD19 and/or CD22 proteins.
Patients had received a median of 3 prior therapies (range, 2 to 5), and 8 patients had undergone an unsuccessful stem cell transplant (5 autologous and 3 allogeneic).
Patients received DT2219 intravenously over 2 hours every other day for 4 total doses. The dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in 9 dose cohorts until a dose-limiting toxicity occurred.
All but 1 patient received a single course of DT2219. That patient received a second, 4-dose course after attaining a partial response.
Outcomes
The 12 patients who received doses ranging from 0.5 mg/kg/day to 20 mg/kg/day had minimal or no adverse events (AEs). But all 13 patients who received 4 doses of DT2219 at 40 mg/kg or greater every other day experienced treatment-related AEs.
Grade 1-2 treatment-related AEs included capillary leak syndrome (n=7), ALT/AST elevation (n=4), fatigue (n=3), fever (n=3), hypokalemia (n=2), hypoalbuminemia (n=1), hearing loss (n=1), hypocalcemia (n=1), anemia (n=1), and vomiting (n=1).
Grade 3-4 treatment-related AEs were thrombocytopenia (n=2), neutropenia (n=1), neutropenic fever (n=1), capillary leak syndrome (n=1), hypokalemia (n=1), and leg weakness (n=1). The grade 3 leg weakness and grade 3 capillary leak syndrome were dose-limiting toxicities.
The maximum tolerated dose was not reached, but clinical responses occurred between doses of 40 to 80 µg/kg.
All 25 patients were evaluable for response, but only 9 patients in the highest dose cohorts had measurable drug levels.
Two patients had durable, objective responses. One patient had chronic lymphocytic leukemia, and the other had diffuse large B-cell lymphoma. The latter patient’s response was a complete remission that occurred after 2 treatment cycles.
“We were surprised that the drug was effective enough to entirely eliminate the cancer in one of our patients,” Dr Vallera said. “Further, we expected the patients to make antibodies against the bacterial toxin and, thus, reject our drug. Surprisingly, this did not occur in the majority of our patients [70%].”
“We need to study more patients to understand why they did not produce neutralizing antibodies. However, we also have been working to create a less immunogenic form of the toxin for the next-generation drug.”
“Another important fact about our drug is that it was home-grown, meaning there was no commercial partner, which is rare. The drug was funded mostly with private donations, including individuals that have lost loved ones to cancer.”
Photo courtesy of the
University of Minnesota
A bispecific ligand-directed diphtheria toxin known as DT2219 shows promise for treating patients with relapsed/refractory B-cell malignancies, according to researchers.
DT2219 produced responses in 2 of 25 patients analyzed in a phase 1 study. The maximum tolerated dose of DT2219 was not reached, although 2 patients experienced dose-limiting toxicities.
“In this phase 1 trial, we found a safe dose of the drug that has biological activity,” said Daniel Vallera, PhD, of the University of Minnesota in Minneapolis.
“We are planning a phase 2 trial with this drug. It will focus on giving more cycles of treatment, which we believe will dramatically enhance the response rates.”
Dr Vallera and his colleagues detailed the phase 1 results in Clinical Cancer Research.
To develop DT2219, the researchers chose 2 antibody fragments that each selectively bind to CD19 and CD22. They used genetic engineering to attach these two antibodies to the bacterial diphtheria toxin.
When the antibody fragments bind to the two targets on the cancer cell, the entire drug enters the cell, and the toxin kills the cell.
To test DT2219, the researchers enrolled 25 patients with chemo-refractory pre-B acute lymphoblastic leukemia (n=10), chronic lymphocytic leukemia (n=5), or non-Hodgkin lymphoma (n=10). All tumors had CD19 and/or CD22 proteins.
Patients had received a median of 3 prior therapies (range, 2 to 5), and 8 patients had undergone an unsuccessful stem cell transplant (5 autologous and 3 allogeneic).
Patients received DT2219 intravenously over 2 hours every other day for 4 total doses. The dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in 9 dose cohorts until a dose-limiting toxicity occurred.
All but 1 patient received a single course of DT2219. That patient received a second, 4-dose course after attaining a partial response.
Outcomes
The 12 patients who received doses ranging from 0.5 mg/kg/day to 20 mg/kg/day had minimal or no adverse events (AEs). But all 13 patients who received 4 doses of DT2219 at 40 mg/kg or greater every other day experienced treatment-related AEs.
Grade 1-2 treatment-related AEs included capillary leak syndrome (n=7), ALT/AST elevation (n=4), fatigue (n=3), fever (n=3), hypokalemia (n=2), hypoalbuminemia (n=1), hearing loss (n=1), hypocalcemia (n=1), anemia (n=1), and vomiting (n=1).
Grade 3-4 treatment-related AEs were thrombocytopenia (n=2), neutropenia (n=1), neutropenic fever (n=1), capillary leak syndrome (n=1), hypokalemia (n=1), and leg weakness (n=1). The grade 3 leg weakness and grade 3 capillary leak syndrome were dose-limiting toxicities.
The maximum tolerated dose was not reached, but clinical responses occurred between doses of 40 to 80 µg/kg.
All 25 patients were evaluable for response, but only 9 patients in the highest dose cohorts had measurable drug levels.
Two patients had durable, objective responses. One patient had chronic lymphocytic leukemia, and the other had diffuse large B-cell lymphoma. The latter patient’s response was a complete remission that occurred after 2 treatment cycles.
“We were surprised that the drug was effective enough to entirely eliminate the cancer in one of our patients,” Dr Vallera said. “Further, we expected the patients to make antibodies against the bacterial toxin and, thus, reject our drug. Surprisingly, this did not occur in the majority of our patients [70%].”
“We need to study more patients to understand why they did not produce neutralizing antibodies. However, we also have been working to create a less immunogenic form of the toxin for the next-generation drug.”
“Another important fact about our drug is that it was home-grown, meaning there was no commercial partner, which is rare. The drug was funded mostly with private donations, including individuals that have lost loved ones to cancer.”
Photo courtesy of the
University of Minnesota
A bispecific ligand-directed diphtheria toxin known as DT2219 shows promise for treating patients with relapsed/refractory B-cell malignancies, according to researchers.
DT2219 produced responses in 2 of 25 patients analyzed in a phase 1 study. The maximum tolerated dose of DT2219 was not reached, although 2 patients experienced dose-limiting toxicities.
“In this phase 1 trial, we found a safe dose of the drug that has biological activity,” said Daniel Vallera, PhD, of the University of Minnesota in Minneapolis.
“We are planning a phase 2 trial with this drug. It will focus on giving more cycles of treatment, which we believe will dramatically enhance the response rates.”
Dr Vallera and his colleagues detailed the phase 1 results in Clinical Cancer Research.
To develop DT2219, the researchers chose 2 antibody fragments that each selectively bind to CD19 and CD22. They used genetic engineering to attach these two antibodies to the bacterial diphtheria toxin.
When the antibody fragments bind to the two targets on the cancer cell, the entire drug enters the cell, and the toxin kills the cell.
To test DT2219, the researchers enrolled 25 patients with chemo-refractory pre-B acute lymphoblastic leukemia (n=10), chronic lymphocytic leukemia (n=5), or non-Hodgkin lymphoma (n=10). All tumors had CD19 and/or CD22 proteins.
Patients had received a median of 3 prior therapies (range, 2 to 5), and 8 patients had undergone an unsuccessful stem cell transplant (5 autologous and 3 allogeneic).
Patients received DT2219 intravenously over 2 hours every other day for 4 total doses. The dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in 9 dose cohorts until a dose-limiting toxicity occurred.
All but 1 patient received a single course of DT2219. That patient received a second, 4-dose course after attaining a partial response.
Outcomes
The 12 patients who received doses ranging from 0.5 mg/kg/day to 20 mg/kg/day had minimal or no adverse events (AEs). But all 13 patients who received 4 doses of DT2219 at 40 mg/kg or greater every other day experienced treatment-related AEs.
Grade 1-2 treatment-related AEs included capillary leak syndrome (n=7), ALT/AST elevation (n=4), fatigue (n=3), fever (n=3), hypokalemia (n=2), hypoalbuminemia (n=1), hearing loss (n=1), hypocalcemia (n=1), anemia (n=1), and vomiting (n=1).
Grade 3-4 treatment-related AEs were thrombocytopenia (n=2), neutropenia (n=1), neutropenic fever (n=1), capillary leak syndrome (n=1), hypokalemia (n=1), and leg weakness (n=1). The grade 3 leg weakness and grade 3 capillary leak syndrome were dose-limiting toxicities.
The maximum tolerated dose was not reached, but clinical responses occurred between doses of 40 to 80 µg/kg.
All 25 patients were evaluable for response, but only 9 patients in the highest dose cohorts had measurable drug levels.
Two patients had durable, objective responses. One patient had chronic lymphocytic leukemia, and the other had diffuse large B-cell lymphoma. The latter patient’s response was a complete remission that occurred after 2 treatment cycles.
“We were surprised that the drug was effective enough to entirely eliminate the cancer in one of our patients,” Dr Vallera said. “Further, we expected the patients to make antibodies against the bacterial toxin and, thus, reject our drug. Surprisingly, this did not occur in the majority of our patients [70%].”
“We need to study more patients to understand why they did not produce neutralizing antibodies. However, we also have been working to create a less immunogenic form of the toxin for the next-generation drug.”
“Another important fact about our drug is that it was home-grown, meaning there was no commercial partner, which is rare. The drug was funded mostly with private donations, including individuals that have lost loved ones to cancer.”
Group uses gene editing to fight lymphoma
Aubrey, Gemma Kelly,
and Marco Herold
Photo courtesy of the
Walter and Eliza Hall Institute
The gene-editing technique CRISPR/Cas9 can be used to target and kill lymphoma cells with high accuracy, according to preclinical research published in Cell Reports.
Using a lentiviral CRISPR/Cas9 platform, researchers were able to kill human Burkitt lymphoma cells by locating and deleting MCL-1, a gene known to be essential for cancer cell survival.
These results suggest the technology could be used as a direct treatment for diseases arising from genetic errors.
“Our study showed that the CRISPR technology can directly kill cancer cells by targeting factors that are essential for their survival and growth,” said study author Brandon Aubrey, a PhD candidate at the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
Aubrey and his colleagues said they engineered a lentiviral vector platform that allows for efficient cell transduction and subsequent inducible expression of small guide RNAs with concomitant constitutive expression of Cas9.
After finding they could use this system to knock out the pro-apoptotic BH3-only protein BIM in human and mouse cell lines, the team wanted to determine if it could target genes that are essential for sustained cell growth.
So they used the technique to delete MCL-1 in human Burkitt lymphoma cells. And they observed a “very high frequency” of cell killing.
The researchers also used their system to produce hematopoietic-cell-restricted TRP53-knockout mice. Along with mutations that caused loss of the TRP53 protein, the team found they had generated novel mutant TRP53 proteins that could promote lymphoma development.
“[W]e showed, for the first time, that it is possible for CRISPR technology to be used in cancer therapy,” said Marco Herold, PhD, of the Walter and Eliza Hall Institute.
“In addition to its very exciting potential for disease treatment, we have shown that it has the potential to identify novel mutations in cancer-causing genes and genes that ‘suppress’ cancer development, which will help us to identify how they initiate or accelerate the development of cancer.”
Aubrey, Gemma Kelly,
and Marco Herold
Photo courtesy of the
Walter and Eliza Hall Institute
The gene-editing technique CRISPR/Cas9 can be used to target and kill lymphoma cells with high accuracy, according to preclinical research published in Cell Reports.
Using a lentiviral CRISPR/Cas9 platform, researchers were able to kill human Burkitt lymphoma cells by locating and deleting MCL-1, a gene known to be essential for cancer cell survival.
These results suggest the technology could be used as a direct treatment for diseases arising from genetic errors.
“Our study showed that the CRISPR technology can directly kill cancer cells by targeting factors that are essential for their survival and growth,” said study author Brandon Aubrey, a PhD candidate at the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
Aubrey and his colleagues said they engineered a lentiviral vector platform that allows for efficient cell transduction and subsequent inducible expression of small guide RNAs with concomitant constitutive expression of Cas9.
After finding they could use this system to knock out the pro-apoptotic BH3-only protein BIM in human and mouse cell lines, the team wanted to determine if it could target genes that are essential for sustained cell growth.
So they used the technique to delete MCL-1 in human Burkitt lymphoma cells. And they observed a “very high frequency” of cell killing.
The researchers also used their system to produce hematopoietic-cell-restricted TRP53-knockout mice. Along with mutations that caused loss of the TRP53 protein, the team found they had generated novel mutant TRP53 proteins that could promote lymphoma development.
“[W]e showed, for the first time, that it is possible for CRISPR technology to be used in cancer therapy,” said Marco Herold, PhD, of the Walter and Eliza Hall Institute.
“In addition to its very exciting potential for disease treatment, we have shown that it has the potential to identify novel mutations in cancer-causing genes and genes that ‘suppress’ cancer development, which will help us to identify how they initiate or accelerate the development of cancer.”
Aubrey, Gemma Kelly,
and Marco Herold
Photo courtesy of the
Walter and Eliza Hall Institute
The gene-editing technique CRISPR/Cas9 can be used to target and kill lymphoma cells with high accuracy, according to preclinical research published in Cell Reports.
Using a lentiviral CRISPR/Cas9 platform, researchers were able to kill human Burkitt lymphoma cells by locating and deleting MCL-1, a gene known to be essential for cancer cell survival.
These results suggest the technology could be used as a direct treatment for diseases arising from genetic errors.
“Our study showed that the CRISPR technology can directly kill cancer cells by targeting factors that are essential for their survival and growth,” said study author Brandon Aubrey, a PhD candidate at the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
Aubrey and his colleagues said they engineered a lentiviral vector platform that allows for efficient cell transduction and subsequent inducible expression of small guide RNAs with concomitant constitutive expression of Cas9.
After finding they could use this system to knock out the pro-apoptotic BH3-only protein BIM in human and mouse cell lines, the team wanted to determine if it could target genes that are essential for sustained cell growth.
So they used the technique to delete MCL-1 in human Burkitt lymphoma cells. And they observed a “very high frequency” of cell killing.
The researchers also used their system to produce hematopoietic-cell-restricted TRP53-knockout mice. Along with mutations that caused loss of the TRP53 protein, the team found they had generated novel mutant TRP53 proteins that could promote lymphoma development.
“[W]e showed, for the first time, that it is possible for CRISPR technology to be used in cancer therapy,” said Marco Herold, PhD, of the Walter and Eliza Hall Institute.
“In addition to its very exciting potential for disease treatment, we have shown that it has the potential to identify novel mutations in cancer-causing genes and genes that ‘suppress’ cancer development, which will help us to identify how they initiate or accelerate the development of cancer.”
Drug incompatible with certain devices, FDA warns
The US Food and Drug Administration (FDA) is warning healthcare professionals not to use Treanda (bendamustine hydrochloride) solution with closed-system transfer devices (CSTD), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).
Most marketed CSTDs contain either polycarbonate or ABS. And these materials dissolve when they come into contact with N, N-dimethylacetamide (DMA), an ingredient in Treanda solution.
This can lead to device failure, possible product contamination, and potential serious adverse health consequences, including skin reactions in healthcare professionals preparing and administering this product and the risk of small blood vessel blockage in patients.
Discovering the incompatibility
Treanda, which is manufactured by Teva, is used to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
Treanda is available as a solution—Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution)—and a lyophilized powder—Treanda for Injection (25mg/vial or 100 mg/vial lyophilized powder).
The incompatibility of DMA with polycarbonate and ABS is only an issue with Treanda solution—not the lyophilized powder.
Since December 2014, Teva has received 40 complaints of the incompatibility issue, which was recently brought to the FDA’s attention. The agency also received a notification of device incompatibility with Treanda solution from a pharmacist.
These incompatibility issues included leaking of the CSTD, breaking or operational failure of the CSTD components, and a cloudy appearance or presence of particulate matter in the intravenous bag after dilution. To date, no adverse events have been reported related to the incompatibility.
FDA recommendations
The FDA has required label changes for both the solution and the powder formulations of Treanda to reflect the following safe preparation information.
The agency is recommending that healthcare professionals use Treanda solution only with polypropylene syringes containing a metal needle and a polypropylene hub. Polypropylene syringes are translucent in appearance.
Treanda solution should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The solution must be withdrawn and transferred for dilution in a biosafety cabinet or containment isolator.
If they aim to use a CSTD with Treanda solution, healthcare professionals should verify with the CSTD manufacturer or Teva US Medical Information (1-800-896-5855) that the CSTD is compatible with Treanda solution before preparing the drug.
Alternatively, healthcare professionals can use Treanda lyophilized powder with a CSTD. The solution and lyophilized powder formulations of Treanda should not be mixed.
For additional details on safe preparation of Treanda solution and lyophilized powder, see Teva’s Dear Health Care Provider letter.
Adverse events or quality problems associated with the use of Treanda products can be reported to the FDA’s MedWatch Adverse Event Reporting Program.
The US Food and Drug Administration (FDA) is warning healthcare professionals not to use Treanda (bendamustine hydrochloride) solution with closed-system transfer devices (CSTD), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).
Most marketed CSTDs contain either polycarbonate or ABS. And these materials dissolve when they come into contact with N, N-dimethylacetamide (DMA), an ingredient in Treanda solution.
This can lead to device failure, possible product contamination, and potential serious adverse health consequences, including skin reactions in healthcare professionals preparing and administering this product and the risk of small blood vessel blockage in patients.
Discovering the incompatibility
Treanda, which is manufactured by Teva, is used to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
Treanda is available as a solution—Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution)—and a lyophilized powder—Treanda for Injection (25mg/vial or 100 mg/vial lyophilized powder).
The incompatibility of DMA with polycarbonate and ABS is only an issue with Treanda solution—not the lyophilized powder.
Since December 2014, Teva has received 40 complaints of the incompatibility issue, which was recently brought to the FDA’s attention. The agency also received a notification of device incompatibility with Treanda solution from a pharmacist.
These incompatibility issues included leaking of the CSTD, breaking or operational failure of the CSTD components, and a cloudy appearance or presence of particulate matter in the intravenous bag after dilution. To date, no adverse events have been reported related to the incompatibility.
FDA recommendations
The FDA has required label changes for both the solution and the powder formulations of Treanda to reflect the following safe preparation information.
The agency is recommending that healthcare professionals use Treanda solution only with polypropylene syringes containing a metal needle and a polypropylene hub. Polypropylene syringes are translucent in appearance.
Treanda solution should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The solution must be withdrawn and transferred for dilution in a biosafety cabinet or containment isolator.
If they aim to use a CSTD with Treanda solution, healthcare professionals should verify with the CSTD manufacturer or Teva US Medical Information (1-800-896-5855) that the CSTD is compatible with Treanda solution before preparing the drug.
Alternatively, healthcare professionals can use Treanda lyophilized powder with a CSTD. The solution and lyophilized powder formulations of Treanda should not be mixed.
For additional details on safe preparation of Treanda solution and lyophilized powder, see Teva’s Dear Health Care Provider letter.
Adverse events or quality problems associated with the use of Treanda products can be reported to the FDA’s MedWatch Adverse Event Reporting Program.
The US Food and Drug Administration (FDA) is warning healthcare professionals not to use Treanda (bendamustine hydrochloride) solution with closed-system transfer devices (CSTD), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).
Most marketed CSTDs contain either polycarbonate or ABS. And these materials dissolve when they come into contact with N, N-dimethylacetamide (DMA), an ingredient in Treanda solution.
This can lead to device failure, possible product contamination, and potential serious adverse health consequences, including skin reactions in healthcare professionals preparing and administering this product and the risk of small blood vessel blockage in patients.
Discovering the incompatibility
Treanda, which is manufactured by Teva, is used to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
Treanda is available as a solution—Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution)—and a lyophilized powder—Treanda for Injection (25mg/vial or 100 mg/vial lyophilized powder).
The incompatibility of DMA with polycarbonate and ABS is only an issue with Treanda solution—not the lyophilized powder.
Since December 2014, Teva has received 40 complaints of the incompatibility issue, which was recently brought to the FDA’s attention. The agency also received a notification of device incompatibility with Treanda solution from a pharmacist.
These incompatibility issues included leaking of the CSTD, breaking or operational failure of the CSTD components, and a cloudy appearance or presence of particulate matter in the intravenous bag after dilution. To date, no adverse events have been reported related to the incompatibility.
FDA recommendations
The FDA has required label changes for both the solution and the powder formulations of Treanda to reflect the following safe preparation information.
The agency is recommending that healthcare professionals use Treanda solution only with polypropylene syringes containing a metal needle and a polypropylene hub. Polypropylene syringes are translucent in appearance.
Treanda solution should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The solution must be withdrawn and transferred for dilution in a biosafety cabinet or containment isolator.
If they aim to use a CSTD with Treanda solution, healthcare professionals should verify with the CSTD manufacturer or Teva US Medical Information (1-800-896-5855) that the CSTD is compatible with Treanda solution before preparing the drug.
Alternatively, healthcare professionals can use Treanda lyophilized powder with a CSTD. The solution and lyophilized powder formulations of Treanda should not be mixed.
For additional details on safe preparation of Treanda solution and lyophilized powder, see Teva’s Dear Health Care Provider letter.
Adverse events or quality problems associated with the use of Treanda products can be reported to the FDA’s MedWatch Adverse Event Reporting Program.
Regimen prolongs PFS, increases AEs in MCL
Results of a phase 3 study suggest the VR-CAP regimen is more effective but less safe than R-CHOP in patients with newly diagnosed mantle cell lymphoma (MCL).
Patients who received VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) had superior progression-free survival (PFS) when compared to patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
But VR-CAP was also associated with more adverse events (AEs), particularly hematologic toxicities.
Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues reported results from this trial, known as LYM-3002, in NEJM. The study was funded by Janssen Research and Development and Millennium Pharmaceuticals.
LYM-3002 included 487 patients newly diagnosed with MCL who were not eligible for stem cell transplant.
Patients were randomized to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (similar to the R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11).
The median follow-up was 40 months. The VR-CAP regimen significantly improved PFS, the primary endpoint, when compared to R-CHOP.
According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median PFS times of 24.7 months and 14.4 months, respectively (hazard ratio [HR]=0.63, P<0.001).
Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median PFS times of 30.7 months and 16.1 months, respectively (HR=0.51, P<0.001).
Patients in the VR-CAP arm also fared better with regard to some secondary endpoints. The complete response rate was higher in the VR-CAP arm than the R-CHOP arm—53% and 42%, respectively (HR=1.29, P=0.007).
And patients in the VR-CAP arm had a longer median treatment-free interval—40.6 months and 20.5 months, respectively (HR=0.50, P<0.001).
However, there was no significant difference in overall survival between the treatment arms. The median overall survival was not reached in the VR-CAP arm and was 56.3 months in the R-CHOP arm (HR=0.80, P=0.17). The 4-year overall survival rate was 64% and 54%, respectively.
The investigators said VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious AEs were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.
Hematologic toxicity was more common in the VR-CAP arm than the R-CHOP arm. This included thrombocytopenia (72% vs 19%), neutropenia (88% vs 74%), anemia (51% vs 37%), leukopenia (50% vs 38%), lymphocytopenia (31% vs 13%), and febrile neutropenia (17% vs 14%).
Treatment discontinuation due to AEs occurred in 8% of patients in the VR-CAP arm and 6% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.
It was based on these results that bortezomib was approved for use in patients with newly diagnosed MCL in the Europe Union and the US.
Results of a phase 3 study suggest the VR-CAP regimen is more effective but less safe than R-CHOP in patients with newly diagnosed mantle cell lymphoma (MCL).
Patients who received VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) had superior progression-free survival (PFS) when compared to patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
But VR-CAP was also associated with more adverse events (AEs), particularly hematologic toxicities.
Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues reported results from this trial, known as LYM-3002, in NEJM. The study was funded by Janssen Research and Development and Millennium Pharmaceuticals.
LYM-3002 included 487 patients newly diagnosed with MCL who were not eligible for stem cell transplant.
Patients were randomized to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (similar to the R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11).
The median follow-up was 40 months. The VR-CAP regimen significantly improved PFS, the primary endpoint, when compared to R-CHOP.
According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median PFS times of 24.7 months and 14.4 months, respectively (hazard ratio [HR]=0.63, P<0.001).
Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median PFS times of 30.7 months and 16.1 months, respectively (HR=0.51, P<0.001).
Patients in the VR-CAP arm also fared better with regard to some secondary endpoints. The complete response rate was higher in the VR-CAP arm than the R-CHOP arm—53% and 42%, respectively (HR=1.29, P=0.007).
And patients in the VR-CAP arm had a longer median treatment-free interval—40.6 months and 20.5 months, respectively (HR=0.50, P<0.001).
However, there was no significant difference in overall survival between the treatment arms. The median overall survival was not reached in the VR-CAP arm and was 56.3 months in the R-CHOP arm (HR=0.80, P=0.17). The 4-year overall survival rate was 64% and 54%, respectively.
The investigators said VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious AEs were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.
Hematologic toxicity was more common in the VR-CAP arm than the R-CHOP arm. This included thrombocytopenia (72% vs 19%), neutropenia (88% vs 74%), anemia (51% vs 37%), leukopenia (50% vs 38%), lymphocytopenia (31% vs 13%), and febrile neutropenia (17% vs 14%).
Treatment discontinuation due to AEs occurred in 8% of patients in the VR-CAP arm and 6% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.
It was based on these results that bortezomib was approved for use in patients with newly diagnosed MCL in the Europe Union and the US.
Results of a phase 3 study suggest the VR-CAP regimen is more effective but less safe than R-CHOP in patients with newly diagnosed mantle cell lymphoma (MCL).
Patients who received VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) had superior progression-free survival (PFS) when compared to patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
But VR-CAP was also associated with more adverse events (AEs), particularly hematologic toxicities.
Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues reported results from this trial, known as LYM-3002, in NEJM. The study was funded by Janssen Research and Development and Millennium Pharmaceuticals.
LYM-3002 included 487 patients newly diagnosed with MCL who were not eligible for stem cell transplant.
Patients were randomized to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (similar to the R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11).
The median follow-up was 40 months. The VR-CAP regimen significantly improved PFS, the primary endpoint, when compared to R-CHOP.
According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median PFS times of 24.7 months and 14.4 months, respectively (hazard ratio [HR]=0.63, P<0.001).
Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median PFS times of 30.7 months and 16.1 months, respectively (HR=0.51, P<0.001).
Patients in the VR-CAP arm also fared better with regard to some secondary endpoints. The complete response rate was higher in the VR-CAP arm than the R-CHOP arm—53% and 42%, respectively (HR=1.29, P=0.007).
And patients in the VR-CAP arm had a longer median treatment-free interval—40.6 months and 20.5 months, respectively (HR=0.50, P<0.001).
However, there was no significant difference in overall survival between the treatment arms. The median overall survival was not reached in the VR-CAP arm and was 56.3 months in the R-CHOP arm (HR=0.80, P=0.17). The 4-year overall survival rate was 64% and 54%, respectively.
The investigators said VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious AEs were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.
Hematologic toxicity was more common in the VR-CAP arm than the R-CHOP arm. This included thrombocytopenia (72% vs 19%), neutropenia (88% vs 74%), anemia (51% vs 37%), leukopenia (50% vs 38%), lymphocytopenia (31% vs 13%), and febrile neutropenia (17% vs 14%).
Treatment discontinuation due to AEs occurred in 8% of patients in the VR-CAP arm and 6% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.
It was based on these results that bortezomib was approved for use in patients with newly diagnosed MCL in the Europe Union and the US.
Cancer care spending doesn’t correlate to lives saved
Photo by Rhoda Baer
A new analysis suggests that although US spending on cancer treatment has increased greatly in recent years, cancer mortality rates have decreased only modestly.
The study showed that care in the US often failed to prevent cancer-related deaths as well as care in Western Europe.
And when deaths were averted in the US, there was a substantial cost attached, said study author Samir Soneji, PhD, of the Norris Cotton Cancer Center in Lebanon, New Hampshire.
He and JaeWon Yang, a former undergraduate at Dartmouth College in Hanover, New Hampshire, reported these findings in Health Affairs.
The researchers compared cancer deaths and money spent on cancer care in the US and Western Europe between 1982 and 2010. They found that costs were higher in the US than in Europe for all cancers analyzed.
And compared to Western Europe, the US had 64,560 excess leukemia deaths; 164,429 excess non-Hodgkin lymphoma (NHL) deaths; 1,119,599 excess lung cancer deaths; and 39,144 excess melanoma deaths.
On the other hand, the US averted 4859 Hodgkin lymphoma deaths; 66,797 breast cancer deaths; 4354 cervical/uterine cancer deaths; 264,632 colorectal cancer deaths; 59,882 prostate cancer deaths; 621,820 stomach cancer deaths; 3372 testicular cancer deaths; and 18,320 thyroid cancer deaths.
“The greatest number of deaths averted occurred in cancers for which decreasing mortality rates were more likely to be the result of successful prevention and screening rather than advancements in treatment,” Dr Soneji noted.
He and Yang also found that the ratio of incremental cost to quality-adjusted life years (QALYs) saved in the US was $156,045 for Hodgkin lymphoma; $402,369 for breast cancer; $110,009 for colorectal cancer; $1,978,542 for prostate cancer; $4635 for stomach cancer; $222,839 for testicular cancer; and $139,681 for thyroid cancer.
But the US lost QALYs despite additional spending for leukemia, NHL, and a few other cancers. The incremental cost divided by QALYs saved was -$30,790 for leukemia; -$41,362 for NHL; -$855,019 for cervical/uterine cancer; -$18,815 for lung cancer, and -$136,592 for melanoma.
Dr Soneji described these results as, “substantially contrary to previous findings, especially for breast and prostate cancer, despite using the same data” as a previous study published in Health Affairs.
Non-replicability is a serious problem throughout academia, Dr Soneji noted. So to promote open discussion, he makes his data and procedures available to all scholars on an open-access repository called Dataverse.
Photo by Rhoda Baer
A new analysis suggests that although US spending on cancer treatment has increased greatly in recent years, cancer mortality rates have decreased only modestly.
The study showed that care in the US often failed to prevent cancer-related deaths as well as care in Western Europe.
And when deaths were averted in the US, there was a substantial cost attached, said study author Samir Soneji, PhD, of the Norris Cotton Cancer Center in Lebanon, New Hampshire.
He and JaeWon Yang, a former undergraduate at Dartmouth College in Hanover, New Hampshire, reported these findings in Health Affairs.
The researchers compared cancer deaths and money spent on cancer care in the US and Western Europe between 1982 and 2010. They found that costs were higher in the US than in Europe for all cancers analyzed.
And compared to Western Europe, the US had 64,560 excess leukemia deaths; 164,429 excess non-Hodgkin lymphoma (NHL) deaths; 1,119,599 excess lung cancer deaths; and 39,144 excess melanoma deaths.
On the other hand, the US averted 4859 Hodgkin lymphoma deaths; 66,797 breast cancer deaths; 4354 cervical/uterine cancer deaths; 264,632 colorectal cancer deaths; 59,882 prostate cancer deaths; 621,820 stomach cancer deaths; 3372 testicular cancer deaths; and 18,320 thyroid cancer deaths.
“The greatest number of deaths averted occurred in cancers for which decreasing mortality rates were more likely to be the result of successful prevention and screening rather than advancements in treatment,” Dr Soneji noted.
He and Yang also found that the ratio of incremental cost to quality-adjusted life years (QALYs) saved in the US was $156,045 for Hodgkin lymphoma; $402,369 for breast cancer; $110,009 for colorectal cancer; $1,978,542 for prostate cancer; $4635 for stomach cancer; $222,839 for testicular cancer; and $139,681 for thyroid cancer.
But the US lost QALYs despite additional spending for leukemia, NHL, and a few other cancers. The incremental cost divided by QALYs saved was -$30,790 for leukemia; -$41,362 for NHL; -$855,019 for cervical/uterine cancer; -$18,815 for lung cancer, and -$136,592 for melanoma.
Dr Soneji described these results as, “substantially contrary to previous findings, especially for breast and prostate cancer, despite using the same data” as a previous study published in Health Affairs.
Non-replicability is a serious problem throughout academia, Dr Soneji noted. So to promote open discussion, he makes his data and procedures available to all scholars on an open-access repository called Dataverse.
Photo by Rhoda Baer
A new analysis suggests that although US spending on cancer treatment has increased greatly in recent years, cancer mortality rates have decreased only modestly.
The study showed that care in the US often failed to prevent cancer-related deaths as well as care in Western Europe.
And when deaths were averted in the US, there was a substantial cost attached, said study author Samir Soneji, PhD, of the Norris Cotton Cancer Center in Lebanon, New Hampshire.
He and JaeWon Yang, a former undergraduate at Dartmouth College in Hanover, New Hampshire, reported these findings in Health Affairs.
The researchers compared cancer deaths and money spent on cancer care in the US and Western Europe between 1982 and 2010. They found that costs were higher in the US than in Europe for all cancers analyzed.
And compared to Western Europe, the US had 64,560 excess leukemia deaths; 164,429 excess non-Hodgkin lymphoma (NHL) deaths; 1,119,599 excess lung cancer deaths; and 39,144 excess melanoma deaths.
On the other hand, the US averted 4859 Hodgkin lymphoma deaths; 66,797 breast cancer deaths; 4354 cervical/uterine cancer deaths; 264,632 colorectal cancer deaths; 59,882 prostate cancer deaths; 621,820 stomach cancer deaths; 3372 testicular cancer deaths; and 18,320 thyroid cancer deaths.
“The greatest number of deaths averted occurred in cancers for which decreasing mortality rates were more likely to be the result of successful prevention and screening rather than advancements in treatment,” Dr Soneji noted.
He and Yang also found that the ratio of incremental cost to quality-adjusted life years (QALYs) saved in the US was $156,045 for Hodgkin lymphoma; $402,369 for breast cancer; $110,009 for colorectal cancer; $1,978,542 for prostate cancer; $4635 for stomach cancer; $222,839 for testicular cancer; and $139,681 for thyroid cancer.
But the US lost QALYs despite additional spending for leukemia, NHL, and a few other cancers. The incremental cost divided by QALYs saved was -$30,790 for leukemia; -$41,362 for NHL; -$855,019 for cervical/uterine cancer; -$18,815 for lung cancer, and -$136,592 for melanoma.
Dr Soneji described these results as, “substantially contrary to previous findings, especially for breast and prostate cancer, despite using the same data” as a previous study published in Health Affairs.
Non-replicability is a serious problem throughout academia, Dr Soneji noted. So to promote open discussion, he makes his data and procedures available to all scholars on an open-access repository called Dataverse.
Why CLL patients stop taking ibrutinib
Photo courtesy of CDC
In reviewing 4 clinical trials of ibrutinib, researchers found that a quarter of chronic lymphocytic leukemia (CLL) patients discontinued treatment with the Bruton tyrosine kinase (BTK) inhibitor.
Ten percent of patients stopped taking the drug due to disease progression, and 15% stopped because of adverse and medical events.
Sequencing data indicated that mutations in BTK and PLCG2 were associated with CLL progression but not Richter’s transformation (RT).
Jennifer A. Woyach, MD, of Ohio State University in Columbus, and her colleagues detailed these discoveries in JAMA Oncology.
The researchers evaluated 308 patients participating in 4 trials conducted at a single institution. The team described the characteristics and outcomes of the patients who discontinued treatment with ibrutinib.
At a median follow-up of 20 months, 232 of the patients studied (75%) remained on therapy, including 7 patients who went off study to undergo stem cell transplant or receive ibrutinib commercially at another center.
Forty-five patients (15%) discontinued treatment following adverse or medical events—28 due to infection, 8 for other adverse events, and 9 due to other medical events. This included 2 patients who needed anticoagulation, 2 with comorbid medical conditions, 1 case of progressive multifocal leukoencephalopathy in a patient who had received rituximab, 1 case of noncompliance, 1 failure to thrive, 1 sudden cardiac death, and 1 cerebrovascular event.
Thirty-one patients (10%) discontinued treatment due to disease progression. Progression included RT or progressive CLL. RT appeared to occur early and CLL progression later. The median survival was 3.5 months after RT and 17.6 months after CLL progression.
Deep sequencing performed on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all of them. But sequencing data on peripheral blood from 8 patients with RT showed that only 2 patients had mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2.
Photo courtesy of CDC
In reviewing 4 clinical trials of ibrutinib, researchers found that a quarter of chronic lymphocytic leukemia (CLL) patients discontinued treatment with the Bruton tyrosine kinase (BTK) inhibitor.
Ten percent of patients stopped taking the drug due to disease progression, and 15% stopped because of adverse and medical events.
Sequencing data indicated that mutations in BTK and PLCG2 were associated with CLL progression but not Richter’s transformation (RT).
Jennifer A. Woyach, MD, of Ohio State University in Columbus, and her colleagues detailed these discoveries in JAMA Oncology.
The researchers evaluated 308 patients participating in 4 trials conducted at a single institution. The team described the characteristics and outcomes of the patients who discontinued treatment with ibrutinib.
At a median follow-up of 20 months, 232 of the patients studied (75%) remained on therapy, including 7 patients who went off study to undergo stem cell transplant or receive ibrutinib commercially at another center.
Forty-five patients (15%) discontinued treatment following adverse or medical events—28 due to infection, 8 for other adverse events, and 9 due to other medical events. This included 2 patients who needed anticoagulation, 2 with comorbid medical conditions, 1 case of progressive multifocal leukoencephalopathy in a patient who had received rituximab, 1 case of noncompliance, 1 failure to thrive, 1 sudden cardiac death, and 1 cerebrovascular event.
Thirty-one patients (10%) discontinued treatment due to disease progression. Progression included RT or progressive CLL. RT appeared to occur early and CLL progression later. The median survival was 3.5 months after RT and 17.6 months after CLL progression.
Deep sequencing performed on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all of them. But sequencing data on peripheral blood from 8 patients with RT showed that only 2 patients had mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2.
Photo courtesy of CDC
In reviewing 4 clinical trials of ibrutinib, researchers found that a quarter of chronic lymphocytic leukemia (CLL) patients discontinued treatment with the Bruton tyrosine kinase (BTK) inhibitor.
Ten percent of patients stopped taking the drug due to disease progression, and 15% stopped because of adverse and medical events.
Sequencing data indicated that mutations in BTK and PLCG2 were associated with CLL progression but not Richter’s transformation (RT).
Jennifer A. Woyach, MD, of Ohio State University in Columbus, and her colleagues detailed these discoveries in JAMA Oncology.
The researchers evaluated 308 patients participating in 4 trials conducted at a single institution. The team described the characteristics and outcomes of the patients who discontinued treatment with ibrutinib.
At a median follow-up of 20 months, 232 of the patients studied (75%) remained on therapy, including 7 patients who went off study to undergo stem cell transplant or receive ibrutinib commercially at another center.
Forty-five patients (15%) discontinued treatment following adverse or medical events—28 due to infection, 8 for other adverse events, and 9 due to other medical events. This included 2 patients who needed anticoagulation, 2 with comorbid medical conditions, 1 case of progressive multifocal leukoencephalopathy in a patient who had received rituximab, 1 case of noncompliance, 1 failure to thrive, 1 sudden cardiac death, and 1 cerebrovascular event.
Thirty-one patients (10%) discontinued treatment due to disease progression. Progression included RT or progressive CLL. RT appeared to occur early and CLL progression later. The median survival was 3.5 months after RT and 17.6 months after CLL progression.
Deep sequencing performed on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all of them. But sequencing data on peripheral blood from 8 patients with RT showed that only 2 patients had mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2.
Ibrutinib demonstrates efficacy in CLL after allo-HSCT
Photo courtesy of CDC
SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.
One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.
Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).
David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.
Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).
High response rate
The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.
All 16 patients analyzed had prior allogeneic
hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.
Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).
The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.
The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.
The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.
Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.
Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.
And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).
‘Promising’ donor immune modulation
Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.
Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.
Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.
The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.
Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.
And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.
Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of CDC
SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.
One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.
Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).
David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.
Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).
High response rate
The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.
All 16 patients analyzed had prior allogeneic
hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.
Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).
The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.
The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.
The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.
Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.
Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.
And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).
‘Promising’ donor immune modulation
Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.
Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.
Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.
The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.
Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.
And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.
Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of CDC
SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.
One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.
Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).
David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.
Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).
High response rate
The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.
All 16 patients analyzed had prior allogeneic
hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.
Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).
The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.
The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.
The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.
Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.
Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.
And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).
‘Promising’ donor immune modulation
Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.
Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.
Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.
The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.
Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.
And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.
Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.
*Information in the abstract differs from that presented at the meeting.
Antibodies can fight lymphoma
Researchers say they have developed a method that simulates Epstein-Barr virus (EBV) infection, and the immune cells that are activated as a result can kill non-Hodgkin lymphoma cells efficiently.
The team made use of antibodies that exhibit a piece of viral protein. The antibodies contain binding sites that target molecules on the surface of lymphoma cells.
The researchers used genetic engineering methods to fuse protein pieces of EBV to the “rear” end of the antibody protein.
As exposure to EBV is common, many people already have memory T cells that can mount a rapid immune response upon a new encounter with this pathogen.
The antibodies attach to the cancerous B cells and are subsequently engulfed into the cell interior. There, the antibody protein is degraded, and the individual fragments are presented by molecules on the surface of the cancer cells.
As a result, the viral protein is also exhibited on the cell surface, thus making it look like an EBV infection to the immune system.
The researchers found that T cells effectively killed the “infected” lymphoma cells in vitro. In blood cells from individuals who had been infected with EBV in the past, the antigen-armed antibodies successfully activated memory T cells.
“This is a clear indication that our antigen-armed antibodies can also induce an immune response against lymphoma cells in a living organism,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.
To activate the immune system in as many people as possible, Dr Delecluse and his colleagues also inserted larger pieces of EBV proteins into their antibodies.
Depending on a person’s genetic makeup, the cells could then cut out various smaller protein segments and present them on their surface.
“A problem with antibody-based cancer therapies is that the tumor cells make the surface molecule targeted by the antibody disappear from their surface,” Dr Delecluse said. “To prevent this situation, we used a mixture of antibodies that target 4 different B-cell surface molecules.”
For more details, see the researchers’ article in Blood.
Researchers say they have developed a method that simulates Epstein-Barr virus (EBV) infection, and the immune cells that are activated as a result can kill non-Hodgkin lymphoma cells efficiently.
The team made use of antibodies that exhibit a piece of viral protein. The antibodies contain binding sites that target molecules on the surface of lymphoma cells.
The researchers used genetic engineering methods to fuse protein pieces of EBV to the “rear” end of the antibody protein.
As exposure to EBV is common, many people already have memory T cells that can mount a rapid immune response upon a new encounter with this pathogen.
The antibodies attach to the cancerous B cells and are subsequently engulfed into the cell interior. There, the antibody protein is degraded, and the individual fragments are presented by molecules on the surface of the cancer cells.
As a result, the viral protein is also exhibited on the cell surface, thus making it look like an EBV infection to the immune system.
The researchers found that T cells effectively killed the “infected” lymphoma cells in vitro. In blood cells from individuals who had been infected with EBV in the past, the antigen-armed antibodies successfully activated memory T cells.
“This is a clear indication that our antigen-armed antibodies can also induce an immune response against lymphoma cells in a living organism,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.
To activate the immune system in as many people as possible, Dr Delecluse and his colleagues also inserted larger pieces of EBV proteins into their antibodies.
Depending on a person’s genetic makeup, the cells could then cut out various smaller protein segments and present them on their surface.
“A problem with antibody-based cancer therapies is that the tumor cells make the surface molecule targeted by the antibody disappear from their surface,” Dr Delecluse said. “To prevent this situation, we used a mixture of antibodies that target 4 different B-cell surface molecules.”
For more details, see the researchers’ article in Blood.
Researchers say they have developed a method that simulates Epstein-Barr virus (EBV) infection, and the immune cells that are activated as a result can kill non-Hodgkin lymphoma cells efficiently.
The team made use of antibodies that exhibit a piece of viral protein. The antibodies contain binding sites that target molecules on the surface of lymphoma cells.
The researchers used genetic engineering methods to fuse protein pieces of EBV to the “rear” end of the antibody protein.
As exposure to EBV is common, many people already have memory T cells that can mount a rapid immune response upon a new encounter with this pathogen.
The antibodies attach to the cancerous B cells and are subsequently engulfed into the cell interior. There, the antibody protein is degraded, and the individual fragments are presented by molecules on the surface of the cancer cells.
As a result, the viral protein is also exhibited on the cell surface, thus making it look like an EBV infection to the immune system.
The researchers found that T cells effectively killed the “infected” lymphoma cells in vitro. In blood cells from individuals who had been infected with EBV in the past, the antigen-armed antibodies successfully activated memory T cells.
“This is a clear indication that our antigen-armed antibodies can also induce an immune response against lymphoma cells in a living organism,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.
To activate the immune system in as many people as possible, Dr Delecluse and his colleagues also inserted larger pieces of EBV proteins into their antibodies.
Depending on a person’s genetic makeup, the cells could then cut out various smaller protein segments and present them on their surface.
“A problem with antibody-based cancer therapies is that the tumor cells make the surface molecule targeted by the antibody disappear from their surface,” Dr Delecluse said. “To prevent this situation, we used a mixture of antibodies that target 4 different B-cell surface molecules.”
For more details, see the researchers’ article in Blood.