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FDA approves reversal agent for dabigatran
treating a patient
Photo by Tom Watanabe
The US Food and Drug Administration (FDA) has granted accelerated approval for idarucizumab (Praxbind), the first reversal agent for the direct thrombin inhibitor dabigatran (Pradaxa).
Idarucizumab is now approved for use in emergency situations when there is a need to reverse the anticoagulant effect of dabigatran.
The FDA’s accelerated approval program allows the agency to approve drugs for serious conditions that fill an unmet medical need.
Accelerated approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a clinical benefit to patients. So the company developing the drug is required to submit additional information after approval to confirm the drug’s clinical benefit.
About dabigatran and idarucizumab
Dabigatran is FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, as well as for the treatment and prevention of deep vein thrombosis and pulmonary embolism.
Idarucizumab is the first reversal agent approved specifically for dabigatran and works by binding to the drug compound to neutralize its effect. Idarucizumab is administered via intravenous injection.
Both idarucizumab and dabigatran are under development by Boehringer Ingelheim.
Idarucizumab has been studied in 3 randomized, double-blind, phase 1 trials of subjects who were not previously taking dabigatran and a phase 3 trial (RE-VERSE AD) of patients who were taking dabigatran and required reversal in an emergency setting.
Phase 1 trials
One phase 1 study (NCT01688830) enrolled 157 healthy male volunteers and consisted of 3 parts. Part 1 included 110 subjects who received placebo or idarucizumab at doses ranging from 20 mg to 8 g.
Idarucizumab (in the absence of dabigatran) was deemed safe and well tolerated. These results were published in Thrombosis and Haemostasis.
Parts 2 and 3 of the study included 47 subjects (part 2, n=35; part 3, n=12), and researchers investigated how well various doses of idarucizumab reversed the anticoagulant effect of dabigatran.
Results from parts 2 and 3 were published in The Lancet. The researchers said idarucizumab (given at 2 g or greater) provided immediate, complete, and sustained reversal of the anticoagulant effect of dabigatran, without producing serious adverse events.
In a second phase 1 study (NCT01955720), researchers evaluated idarucizumab in 46 subjects (males and females). This included healthy volunteers, elderly subjects, and participants with pre-existing mild or moderate kidney impairment.
Idarucizumab immediately and completely reversed dabigatran’s anticoagulant effect in these subjects, and they were able to restart dabigatran within 24 hours of receiving idarucizumab.
In addition, the researchers said there were no clinically relevant adverse events related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. These results were presented at the 2014 ASH Annual Meeting.
A third phase 1 study (NCT02028780) enrolled 80 healthy Japanese subjects. Researchers assessed the safety, tolerability, and pharmacokinetics of single, increasing doses of idarucizumab, administered both alone and after dabigatran.
Phase 3 trial
In the ongoing phase 3 trial, RE-VERSE AD, researchers are evaluating idarucizumab in emergency settings. The team reported interim results in 90 patients in NEJM and at the 2015 ISTH Congress.
Idarucizumab normalized diluted thrombin time and ecarin clotting time in a majority of patients who had uncontrolled or life-threatening bleeding complications while on dabigatran and in most patients who had to reverse dabigatran’s effects because they required emergency surgery or an invasive procedure.
The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients experienced serious adverse events, 20% died, and several patients had thrombotic or bleeding events after receiving idarucizumab. 
treating a patient
Photo by Tom Watanabe
The US Food and Drug Administration (FDA) has granted accelerated approval for idarucizumab (Praxbind), the first reversal agent for the direct thrombin inhibitor dabigatran (Pradaxa).
Idarucizumab is now approved for use in emergency situations when there is a need to reverse the anticoagulant effect of dabigatran.
The FDA’s accelerated approval program allows the agency to approve drugs for serious conditions that fill an unmet medical need.
Accelerated approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a clinical benefit to patients. So the company developing the drug is required to submit additional information after approval to confirm the drug’s clinical benefit.
About dabigatran and idarucizumab
Dabigatran is FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, as well as for the treatment and prevention of deep vein thrombosis and pulmonary embolism.
Idarucizumab is the first reversal agent approved specifically for dabigatran and works by binding to the drug compound to neutralize its effect. Idarucizumab is administered via intravenous injection.
Both idarucizumab and dabigatran are under development by Boehringer Ingelheim.
Idarucizumab has been studied in 3 randomized, double-blind, phase 1 trials of subjects who were not previously taking dabigatran and a phase 3 trial (RE-VERSE AD) of patients who were taking dabigatran and required reversal in an emergency setting.
Phase 1 trials
One phase 1 study (NCT01688830) enrolled 157 healthy male volunteers and consisted of 3 parts. Part 1 included 110 subjects who received placebo or idarucizumab at doses ranging from 20 mg to 8 g.
Idarucizumab (in the absence of dabigatran) was deemed safe and well tolerated. These results were published in Thrombosis and Haemostasis.
Parts 2 and 3 of the study included 47 subjects (part 2, n=35; part 3, n=12), and researchers investigated how well various doses of idarucizumab reversed the anticoagulant effect of dabigatran.
Results from parts 2 and 3 were published in The Lancet. The researchers said idarucizumab (given at 2 g or greater) provided immediate, complete, and sustained reversal of the anticoagulant effect of dabigatran, without producing serious adverse events.
In a second phase 1 study (NCT01955720), researchers evaluated idarucizumab in 46 subjects (males and females). This included healthy volunteers, elderly subjects, and participants with pre-existing mild or moderate kidney impairment.
Idarucizumab immediately and completely reversed dabigatran’s anticoagulant effect in these subjects, and they were able to restart dabigatran within 24 hours of receiving idarucizumab.
In addition, the researchers said there were no clinically relevant adverse events related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. These results were presented at the 2014 ASH Annual Meeting.
A third phase 1 study (NCT02028780) enrolled 80 healthy Japanese subjects. Researchers assessed the safety, tolerability, and pharmacokinetics of single, increasing doses of idarucizumab, administered both alone and after dabigatran.
Phase 3 trial
In the ongoing phase 3 trial, RE-VERSE AD, researchers are evaluating idarucizumab in emergency settings. The team reported interim results in 90 patients in NEJM and at the 2015 ISTH Congress.
Idarucizumab normalized diluted thrombin time and ecarin clotting time in a majority of patients who had uncontrolled or life-threatening bleeding complications while on dabigatran and in most patients who had to reverse dabigatran’s effects because they required emergency surgery or an invasive procedure.
The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients experienced serious adverse events, 20% died, and several patients had thrombotic or bleeding events after receiving idarucizumab.
treating a patient
Photo by Tom Watanabe
The US Food and Drug Administration (FDA) has granted accelerated approval for idarucizumab (Praxbind), the first reversal agent for the direct thrombin inhibitor dabigatran (Pradaxa).
Idarucizumab is now approved for use in emergency situations when there is a need to reverse the anticoagulant effect of dabigatran.
The FDA’s accelerated approval program allows the agency to approve drugs for serious conditions that fill an unmet medical need.
Accelerated approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a clinical benefit to patients. So the company developing the drug is required to submit additional information after approval to confirm the drug’s clinical benefit.
About dabigatran and idarucizumab
Dabigatran is FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, as well as for the treatment and prevention of deep vein thrombosis and pulmonary embolism.
Idarucizumab is the first reversal agent approved specifically for dabigatran and works by binding to the drug compound to neutralize its effect. Idarucizumab is administered via intravenous injection.
Both idarucizumab and dabigatran are under development by Boehringer Ingelheim.
Idarucizumab has been studied in 3 randomized, double-blind, phase 1 trials of subjects who were not previously taking dabigatran and a phase 3 trial (RE-VERSE AD) of patients who were taking dabigatran and required reversal in an emergency setting.
Phase 1 trials
One phase 1 study (NCT01688830) enrolled 157 healthy male volunteers and consisted of 3 parts. Part 1 included 110 subjects who received placebo or idarucizumab at doses ranging from 20 mg to 8 g.
Idarucizumab (in the absence of dabigatran) was deemed safe and well tolerated. These results were published in Thrombosis and Haemostasis.
Parts 2 and 3 of the study included 47 subjects (part 2, n=35; part 3, n=12), and researchers investigated how well various doses of idarucizumab reversed the anticoagulant effect of dabigatran.
Results from parts 2 and 3 were published in The Lancet. The researchers said idarucizumab (given at 2 g or greater) provided immediate, complete, and sustained reversal of the anticoagulant effect of dabigatran, without producing serious adverse events.
In a second phase 1 study (NCT01955720), researchers evaluated idarucizumab in 46 subjects (males and females). This included healthy volunteers, elderly subjects, and participants with pre-existing mild or moderate kidney impairment.
Idarucizumab immediately and completely reversed dabigatran’s anticoagulant effect in these subjects, and they were able to restart dabigatran within 24 hours of receiving idarucizumab.
In addition, the researchers said there were no clinically relevant adverse events related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. These results were presented at the 2014 ASH Annual Meeting.
A third phase 1 study (NCT02028780) enrolled 80 healthy Japanese subjects. Researchers assessed the safety, tolerability, and pharmacokinetics of single, increasing doses of idarucizumab, administered both alone and after dabigatran.
Phase 3 trial
In the ongoing phase 3 trial, RE-VERSE AD, researchers are evaluating idarucizumab in emergency settings. The team reported interim results in 90 patients in NEJM and at the 2015 ISTH Congress.
Idarucizumab normalized diluted thrombin time and ecarin clotting time in a majority of patients who had uncontrolled or life-threatening bleeding complications while on dabigatran and in most patients who had to reverse dabigatran’s effects because they required emergency surgery or an invasive procedure.
The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients experienced serious adverse events, 20% died, and several patients had thrombotic or bleeding events after receiving idarucizumab.
In ALL, early treatment decisions have “irrevocable” implications
SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.
Cytogenetics and genomics help risk-adapt therapy
“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.
Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.
“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.
Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).
Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.
A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.
“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”
Demographics can guide treatment choices as well
Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.
“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”
AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).
“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”
At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.
He recommended consideration of comorbidities and use of a comprehensive geriatric assessment when contemplating care options for this age group. “We want to make sure that the therapy used matches the patient before us,” he added, pointing to an algorithm that is helpful in this setting (Blood. 2013;122:1366-75).
“Where it’s possible, I would encourage the use of clinical trials, particularly geared to the older age population. And that said, in the older, fitter patient with a good initial response to therapy, do not discount the appropriateness of allogeneic stem cell transplant,” Dr. Alvarnas advised.
At the same time, hematologists should have a frank discussion with these older patients about the goals of care and advanced directives, and should involve supportive care early.
“NCCN has an absolutely beautiful document on the care of older oncology patients as well as a beautiful set of guidelines regarding supportive care,” he added. “Please look at those. I think are an invaluable resource.”
Immunotherapy shows promise in the salvage setting
“At the time of salvage, immunotherapy-based approaches are very powerful, so don’t overtreat the patient with modalities that aren’t going to work,” Dr. Alvarnas recommended.
“Immunotherapeutic approaches are going to play an increasingly important role in patients with ALL, and we see these novel therapeutics completely upending what we knew about this disease even a year or two ago,” he said. A variety of monoclonal antibodies against CD20, CD19, CD22, and CD52 have shown promise when tested in various patient populations (Blood. 2015;125:4010-6).
This concept has been taken a step further with blinatumomab (Blincyto), an antibody having two antigen recognition sites that brings CD19-positive tumor cells in contact with T lymphocytes. It is the first such agent to be approved by the FDA for an ALL indication (currently for refractory or relapsed Ph-negative B-cell ALL). “It has nonoverlapping activity with cytotoxic chemotherapy, which makes it an ideal agent,” Dr. Alvarnas noted.
The main risk with blinatumomab is a cytokine release syndrome, which is most common in patients with a high disease burden and requires drug discontinuation and treatment with high-dose dexamethasone. Neurotoxicity is also noteworthy as it can be fatal.
Responses to blinatumomab tend to be dramatic and deep, but brief, according to Dr. Alvarnas. “Even though it’s profoundly powerful, it’s not a curative agent. It really provides a bridge towards cure, with that cure coming through the use of allogeneic stem cell transplant,” he elaborated. “So if someone relapses and you begin blinatumomab, get them referred very quickly to a transplant center.”
Another promising immunotherapy is inotuzumab ozagamicin, an antibody-drug conjugate that targets CD22-expressing cells. It has been associated with a complete response rate of 19%, although veno-occlusive toxicity has been problematic (Cancer. 2013;119:2728-36). “This agent has not yet received FDA approval, but it’s one that we are awaiting expectantly,” he said.
Finally, phase 1 trials from various academic centers have shown that chimeric antigen receptor (CAR) T-cell therapy achieves complete response rates of 67%-90% in patients with high-risk refractory disease, according to Dr. Alvarnas, who disclosed that he had no relevant financial relationships.
“This has lead to culmination in phase 2 trials, and I really do see this as an important component in the management of patients with relapsed and refractory ALL,” he concluded. “It’s not something that is available at every center. Right now it’s restricted largely to academic centers capable of producing these therapeutics in their own GLP [Good Laboratory Practice] facility.”
SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.
Cytogenetics and genomics help risk-adapt therapy
“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.
Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.
“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.
Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).
Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.
A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.
“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”
Demographics can guide treatment choices as well
Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.
“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”
AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).
“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”
At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.
He recommended consideration of comorbidities and use of a comprehensive geriatric assessment when contemplating care options for this age group. “We want to make sure that the therapy used matches the patient before us,” he added, pointing to an algorithm that is helpful in this setting (Blood. 2013;122:1366-75).
“Where it’s possible, I would encourage the use of clinical trials, particularly geared to the older age population. And that said, in the older, fitter patient with a good initial response to therapy, do not discount the appropriateness of allogeneic stem cell transplant,” Dr. Alvarnas advised.
At the same time, hematologists should have a frank discussion with these older patients about the goals of care and advanced directives, and should involve supportive care early.
“NCCN has an absolutely beautiful document on the care of older oncology patients as well as a beautiful set of guidelines regarding supportive care,” he added. “Please look at those. I think are an invaluable resource.”
Immunotherapy shows promise in the salvage setting
“At the time of salvage, immunotherapy-based approaches are very powerful, so don’t overtreat the patient with modalities that aren’t going to work,” Dr. Alvarnas recommended.
“Immunotherapeutic approaches are going to play an increasingly important role in patients with ALL, and we see these novel therapeutics completely upending what we knew about this disease even a year or two ago,” he said. A variety of monoclonal antibodies against CD20, CD19, CD22, and CD52 have shown promise when tested in various patient populations (Blood. 2015;125:4010-6).
This concept has been taken a step further with blinatumomab (Blincyto), an antibody having two antigen recognition sites that brings CD19-positive tumor cells in contact with T lymphocytes. It is the first such agent to be approved by the FDA for an ALL indication (currently for refractory or relapsed Ph-negative B-cell ALL). “It has nonoverlapping activity with cytotoxic chemotherapy, which makes it an ideal agent,” Dr. Alvarnas noted.
The main risk with blinatumomab is a cytokine release syndrome, which is most common in patients with a high disease burden and requires drug discontinuation and treatment with high-dose dexamethasone. Neurotoxicity is also noteworthy as it can be fatal.
Responses to blinatumomab tend to be dramatic and deep, but brief, according to Dr. Alvarnas. “Even though it’s profoundly powerful, it’s not a curative agent. It really provides a bridge towards cure, with that cure coming through the use of allogeneic stem cell transplant,” he elaborated. “So if someone relapses and you begin blinatumomab, get them referred very quickly to a transplant center.”
Another promising immunotherapy is inotuzumab ozagamicin, an antibody-drug conjugate that targets CD22-expressing cells. It has been associated with a complete response rate of 19%, although veno-occlusive toxicity has been problematic (Cancer. 2013;119:2728-36). “This agent has not yet received FDA approval, but it’s one that we are awaiting expectantly,” he said.
Finally, phase 1 trials from various academic centers have shown that chimeric antigen receptor (CAR) T-cell therapy achieves complete response rates of 67%-90% in patients with high-risk refractory disease, according to Dr. Alvarnas, who disclosed that he had no relevant financial relationships.
“This has lead to culmination in phase 2 trials, and I really do see this as an important component in the management of patients with relapsed and refractory ALL,” he concluded. “It’s not something that is available at every center. Right now it’s restricted largely to academic centers capable of producing these therapeutics in their own GLP [Good Laboratory Practice] facility.”
SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.
Cytogenetics and genomics help risk-adapt therapy
“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.
Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.
“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.
Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).
Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.
A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.
“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”
Demographics can guide treatment choices as well
Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.
“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”
AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).
“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”
At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.
He recommended consideration of comorbidities and use of a comprehensive geriatric assessment when contemplating care options for this age group. “We want to make sure that the therapy used matches the patient before us,” he added, pointing to an algorithm that is helpful in this setting (Blood. 2013;122:1366-75).
“Where it’s possible, I would encourage the use of clinical trials, particularly geared to the older age population. And that said, in the older, fitter patient with a good initial response to therapy, do not discount the appropriateness of allogeneic stem cell transplant,” Dr. Alvarnas advised.
At the same time, hematologists should have a frank discussion with these older patients about the goals of care and advanced directives, and should involve supportive care early.
“NCCN has an absolutely beautiful document on the care of older oncology patients as well as a beautiful set of guidelines regarding supportive care,” he added. “Please look at those. I think are an invaluable resource.”
Immunotherapy shows promise in the salvage setting
“At the time of salvage, immunotherapy-based approaches are very powerful, so don’t overtreat the patient with modalities that aren’t going to work,” Dr. Alvarnas recommended.
“Immunotherapeutic approaches are going to play an increasingly important role in patients with ALL, and we see these novel therapeutics completely upending what we knew about this disease even a year or two ago,” he said. A variety of monoclonal antibodies against CD20, CD19, CD22, and CD52 have shown promise when tested in various patient populations (Blood. 2015;125:4010-6).
This concept has been taken a step further with blinatumomab (Blincyto), an antibody having two antigen recognition sites that brings CD19-positive tumor cells in contact with T lymphocytes. It is the first such agent to be approved by the FDA for an ALL indication (currently for refractory or relapsed Ph-negative B-cell ALL). “It has nonoverlapping activity with cytotoxic chemotherapy, which makes it an ideal agent,” Dr. Alvarnas noted.
The main risk with blinatumomab is a cytokine release syndrome, which is most common in patients with a high disease burden and requires drug discontinuation and treatment with high-dose dexamethasone. Neurotoxicity is also noteworthy as it can be fatal.
Responses to blinatumomab tend to be dramatic and deep, but brief, according to Dr. Alvarnas. “Even though it’s profoundly powerful, it’s not a curative agent. It really provides a bridge towards cure, with that cure coming through the use of allogeneic stem cell transplant,” he elaborated. “So if someone relapses and you begin blinatumomab, get them referred very quickly to a transplant center.”
Another promising immunotherapy is inotuzumab ozagamicin, an antibody-drug conjugate that targets CD22-expressing cells. It has been associated with a complete response rate of 19%, although veno-occlusive toxicity has been problematic (Cancer. 2013;119:2728-36). “This agent has not yet received FDA approval, but it’s one that we are awaiting expectantly,” he said.
Finally, phase 1 trials from various academic centers have shown that chimeric antigen receptor (CAR) T-cell therapy achieves complete response rates of 67%-90% in patients with high-risk refractory disease, according to Dr. Alvarnas, who disclosed that he had no relevant financial relationships.
“This has lead to culmination in phase 2 trials, and I really do see this as an important component in the management of patients with relapsed and refractory ALL,” he concluded. “It’s not something that is available at every center. Right now it’s restricted largely to academic centers capable of producing these therapeutics in their own GLP [Good Laboratory Practice] facility.”
EXPERT ANALYSIS AT NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
Idarucizumab approved as first agent to reverse a novel oral anticoagulant
Idarucizumab has been approved by the Food and Drug Administration for reversing the effects of dabigatran, a novel oral anticoagulant.
Specifically, idarucizumab (Praxbind) is intended for use in patients who are taking dabigatran (Pradaxa) during emergency situations when there is a need to reverse its blood-thinning effects, according to an FDA statement. Both drugs are marketed by Boehringer Ingelheim.
“The anticoagulant effects of Pradaxa are important and life-saving for some patients, but there are situations where reversal of the drug’s effects is medically necessary,” said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval offers the medical community an important tool for managing patients taking Pradaxa in emergency or life-threatening situations when bleeding can’t be controlled.”
The decision, released on Oct. 16, was based on efficacy and safety observed in three randomized trials, the largest of which is the ongoing phase III RE-VERSE AD.
Patients were enrolled into two distinct groups in RE-VERSE AD. Group A, with 51 patients, comprised patients on dabigatran experiencing a serious bleeding episode. Group B, with 39 patients, comprised patients on dabigatran who required an urgent surgical procedure. In both, 5 g of idarucizumab solution was administered intravenously. The primary endpoint was maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours.
In both groups, the median maximum percentage reversal was 100%. Other measures corroborated a rapid and highly effective reversal of anticoagulation. For example, the dilute thrombin time in those who could be evaluated was normalized in 98% of group A and 93% of group B (N Engl J Med. 2015 Aug 6. doi:10.1056/NEJMoa1502000).
Interim results of RE-VERSE AD “show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes,” said the lead author, Dr. Charles V. Pollack Jr., chairman of the department of emergency medicine at the University of Pennsylvania, Philadelphia. Dr. Pollack presented the findings at the 2015 International Society of Thrombosis and Haemostatis (ISTH) Congress in June.
Idarucizumab is the first reversal agent for any of the novel oral anticoagulants used as an alternative to warfarin. Unlike warfarin, which can be reversed with vitamin K, the lack of a reversal agent for dabigatran, a direct thrombin inhibitor, and other novel agents, such as rivaroxaban and apixaban, which are direct factor Xa inhibitors, has been a concern for patients who experience unexpected bleeding or face a risk of bleeding because of the need for urgent surgery. The laboratory findings were supported by the clinical findings, according to Dr. Pollack.
“Clinical outcomes were quite good in this multimorbid patient population,” he said. “Restoration of hemostasis as reported by local investigators was achieved in less than 12 hours when assessable, and 92% of the surgical patients were reported to have normal hemostasis at the time of the procedure.”
Idarucizumab was also found safe in this and the two previous randomized studies. In the 237 healthy volunteers evaluated previously, no serious adverse events were reported. In RE-VERSE AD, serious adverse events leading to death included hemorrhagic and thrombotic complications, but there were no off-target side effects, and the deaths occurred in a highly unstable patient population.
“Only one patient experienced a thrombotic complication within 72 hours [of initiating idarucizumab], and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack reported. He noted that no safety concerns arose in patients who were enrolled in the study, but later were found to have normal clotting parameters.
Idarucizumab binds to dabigatran to neutralize its activity. It was given priority review status by the FDA in April 2015. Priority review is now being sought for andexanet, which is a potential reversal agent for the factor Xa inhibitors, according to press releases from the developer, Portola Pharmaceuticals. Idarucizumab and other effective reversal agents – if approved – are expected to increase the utility of novel oral anticoagulants.
The FDA cautioned in its statement that reversing the effect of dabigatran exposes patients to the risk of blood clots and stroke from their underlying disease, and said that the idarucizumab labeling recommends patients resume their anticoagulant therapy as soon as medically appropriate.
Dr. Pollack disclosed that he has financial relationships with Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, and Pfizer. RE-VERSE AD was supported by Boehringer Ingelheim.
Idarucizumab has been approved by the Food and Drug Administration for reversing the effects of dabigatran, a novel oral anticoagulant.
Specifically, idarucizumab (Praxbind) is intended for use in patients who are taking dabigatran (Pradaxa) during emergency situations when there is a need to reverse its blood-thinning effects, according to an FDA statement. Both drugs are marketed by Boehringer Ingelheim.
“The anticoagulant effects of Pradaxa are important and life-saving for some patients, but there are situations where reversal of the drug’s effects is medically necessary,” said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval offers the medical community an important tool for managing patients taking Pradaxa in emergency or life-threatening situations when bleeding can’t be controlled.”
The decision, released on Oct. 16, was based on efficacy and safety observed in three randomized trials, the largest of which is the ongoing phase III RE-VERSE AD.
Patients were enrolled into two distinct groups in RE-VERSE AD. Group A, with 51 patients, comprised patients on dabigatran experiencing a serious bleeding episode. Group B, with 39 patients, comprised patients on dabigatran who required an urgent surgical procedure. In both, 5 g of idarucizumab solution was administered intravenously. The primary endpoint was maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours.
In both groups, the median maximum percentage reversal was 100%. Other measures corroborated a rapid and highly effective reversal of anticoagulation. For example, the dilute thrombin time in those who could be evaluated was normalized in 98% of group A and 93% of group B (N Engl J Med. 2015 Aug 6. doi:10.1056/NEJMoa1502000).
Interim results of RE-VERSE AD “show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes,” said the lead author, Dr. Charles V. Pollack Jr., chairman of the department of emergency medicine at the University of Pennsylvania, Philadelphia. Dr. Pollack presented the findings at the 2015 International Society of Thrombosis and Haemostatis (ISTH) Congress in June.
Idarucizumab is the first reversal agent for any of the novel oral anticoagulants used as an alternative to warfarin. Unlike warfarin, which can be reversed with vitamin K, the lack of a reversal agent for dabigatran, a direct thrombin inhibitor, and other novel agents, such as rivaroxaban and apixaban, which are direct factor Xa inhibitors, has been a concern for patients who experience unexpected bleeding or face a risk of bleeding because of the need for urgent surgery. The laboratory findings were supported by the clinical findings, according to Dr. Pollack.
“Clinical outcomes were quite good in this multimorbid patient population,” he said. “Restoration of hemostasis as reported by local investigators was achieved in less than 12 hours when assessable, and 92% of the surgical patients were reported to have normal hemostasis at the time of the procedure.”
Idarucizumab was also found safe in this and the two previous randomized studies. In the 237 healthy volunteers evaluated previously, no serious adverse events were reported. In RE-VERSE AD, serious adverse events leading to death included hemorrhagic and thrombotic complications, but there were no off-target side effects, and the deaths occurred in a highly unstable patient population.
“Only one patient experienced a thrombotic complication within 72 hours [of initiating idarucizumab], and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack reported. He noted that no safety concerns arose in patients who were enrolled in the study, but later were found to have normal clotting parameters.
Idarucizumab binds to dabigatran to neutralize its activity. It was given priority review status by the FDA in April 2015. Priority review is now being sought for andexanet, which is a potential reversal agent for the factor Xa inhibitors, according to press releases from the developer, Portola Pharmaceuticals. Idarucizumab and other effective reversal agents – if approved – are expected to increase the utility of novel oral anticoagulants.
The FDA cautioned in its statement that reversing the effect of dabigatran exposes patients to the risk of blood clots and stroke from their underlying disease, and said that the idarucizumab labeling recommends patients resume their anticoagulant therapy as soon as medically appropriate.
Dr. Pollack disclosed that he has financial relationships with Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, and Pfizer. RE-VERSE AD was supported by Boehringer Ingelheim.
Idarucizumab has been approved by the Food and Drug Administration for reversing the effects of dabigatran, a novel oral anticoagulant.
Specifically, idarucizumab (Praxbind) is intended for use in patients who are taking dabigatran (Pradaxa) during emergency situations when there is a need to reverse its blood-thinning effects, according to an FDA statement. Both drugs are marketed by Boehringer Ingelheim.
“The anticoagulant effects of Pradaxa are important and life-saving for some patients, but there are situations where reversal of the drug’s effects is medically necessary,” said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval offers the medical community an important tool for managing patients taking Pradaxa in emergency or life-threatening situations when bleeding can’t be controlled.”
The decision, released on Oct. 16, was based on efficacy and safety observed in three randomized trials, the largest of which is the ongoing phase III RE-VERSE AD.
Patients were enrolled into two distinct groups in RE-VERSE AD. Group A, with 51 patients, comprised patients on dabigatran experiencing a serious bleeding episode. Group B, with 39 patients, comprised patients on dabigatran who required an urgent surgical procedure. In both, 5 g of idarucizumab solution was administered intravenously. The primary endpoint was maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours.
In both groups, the median maximum percentage reversal was 100%. Other measures corroborated a rapid and highly effective reversal of anticoagulation. For example, the dilute thrombin time in those who could be evaluated was normalized in 98% of group A and 93% of group B (N Engl J Med. 2015 Aug 6. doi:10.1056/NEJMoa1502000).
Interim results of RE-VERSE AD “show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes,” said the lead author, Dr. Charles V. Pollack Jr., chairman of the department of emergency medicine at the University of Pennsylvania, Philadelphia. Dr. Pollack presented the findings at the 2015 International Society of Thrombosis and Haemostatis (ISTH) Congress in June.
Idarucizumab is the first reversal agent for any of the novel oral anticoagulants used as an alternative to warfarin. Unlike warfarin, which can be reversed with vitamin K, the lack of a reversal agent for dabigatran, a direct thrombin inhibitor, and other novel agents, such as rivaroxaban and apixaban, which are direct factor Xa inhibitors, has been a concern for patients who experience unexpected bleeding or face a risk of bleeding because of the need for urgent surgery. The laboratory findings were supported by the clinical findings, according to Dr. Pollack.
“Clinical outcomes were quite good in this multimorbid patient population,” he said. “Restoration of hemostasis as reported by local investigators was achieved in less than 12 hours when assessable, and 92% of the surgical patients were reported to have normal hemostasis at the time of the procedure.”
Idarucizumab was also found safe in this and the two previous randomized studies. In the 237 healthy volunteers evaluated previously, no serious adverse events were reported. In RE-VERSE AD, serious adverse events leading to death included hemorrhagic and thrombotic complications, but there were no off-target side effects, and the deaths occurred in a highly unstable patient population.
“Only one patient experienced a thrombotic complication within 72 hours [of initiating idarucizumab], and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack reported. He noted that no safety concerns arose in patients who were enrolled in the study, but later were found to have normal clotting parameters.
Idarucizumab binds to dabigatran to neutralize its activity. It was given priority review status by the FDA in April 2015. Priority review is now being sought for andexanet, which is a potential reversal agent for the factor Xa inhibitors, according to press releases from the developer, Portola Pharmaceuticals. Idarucizumab and other effective reversal agents – if approved – are expected to increase the utility of novel oral anticoagulants.
The FDA cautioned in its statement that reversing the effect of dabigatran exposes patients to the risk of blood clots and stroke from their underlying disease, and said that the idarucizumab labeling recommends patients resume their anticoagulant therapy as soon as medically appropriate.
Dr. Pollack disclosed that he has financial relationships with Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, and Pfizer. RE-VERSE AD was supported by Boehringer Ingelheim.
Endologix announces FDA approval of AFX2 Bifurcated Endograft
The U.S. Food and Drug Administration has approved the AFX2 Bifurcated Endograft System for the treatment of abdominal aortic aneurysms (AAA), the device’s manufacturer, Endologix, announced in a statement.
Endologix also touts the AFX2 as a way to facilitate percutaneous endovascular aneurysm repair (EVAR) by providing low-profile contralateral access through a 7F introducer. The device incorporates Endologix’s ActiveSeal technology, DuraPly expanded polytetrafluoroethylene graft material, and the Vela proximal endograft.
The AFX2 is expected to hit the market in the United States in the first quarter of 2016.
The U.S. Food and Drug Administration has approved the AFX2 Bifurcated Endograft System for the treatment of abdominal aortic aneurysms (AAA), the device’s manufacturer, Endologix, announced in a statement.
Endologix also touts the AFX2 as a way to facilitate percutaneous endovascular aneurysm repair (EVAR) by providing low-profile contralateral access through a 7F introducer. The device incorporates Endologix’s ActiveSeal technology, DuraPly expanded polytetrafluoroethylene graft material, and the Vela proximal endograft.
The AFX2 is expected to hit the market in the United States in the first quarter of 2016.
The U.S. Food and Drug Administration has approved the AFX2 Bifurcated Endograft System for the treatment of abdominal aortic aneurysms (AAA), the device’s manufacturer, Endologix, announced in a statement.
Endologix also touts the AFX2 as a way to facilitate percutaneous endovascular aneurysm repair (EVAR) by providing low-profile contralateral access through a 7F introducer. The device incorporates Endologix’s ActiveSeal technology, DuraPly expanded polytetrafluoroethylene graft material, and the Vela proximal endograft.
The AFX2 is expected to hit the market in the United States in the first quarter of 2016.
White tea
White tea, like green tea, is derived from the plant Camellia sinensis, a member of the Theaceae family and the source of all the globally popular “true tea” beverages.
Of the four main true teas, green and white are unfermented (white is the least processed), black tea is fermented, and oolong tea is semifermented.1,2,3 White tea actually comes from the tips of the green tea leaves or leaves that have not yet fully opened, with buds covered by fine white hair. As a commodity, white tea is more expensive than green tea because it is more difficult to obtain. EGCG [(-)epigallocatechin-3-O-gallate], the most abundant and biologically active polyphenolic catechin found in green tea, is also the constituent in white tea that accounts for its antioxidant properties.4,5 Indeed, white tea is included in topical products for its antioxidant as well as antiseptic activity, and is considered a more potent antioxidant additive medium than green tea.6,1
As an ingredient in a combination formula
White tea is included in the dietary supplement Imedeen Prime Renewal, along with fish protein polysaccharides, vitamins C and E, zinc, and extracts from soy, grape seed, chamomile, and tomato.
In 2006, Skovgaard et al. conducted a 6-month, double-blind, placebo-controlled randomized study on 80 healthy postmenopausal women (38 in the treatment group, 42 in the placebo group completed the study) to determine antiaging effects on the skin. Subjects took 2 tablets of the supplement or placebo twice daily. Clinical, photo, and ultrasound evaluations showed significantly greater improvements in the treatment group, compared with the placebo group, in the face (forehead, periocular, and perioral wrinkles; mottled pigmentation, laxity, sagging, dark circles under the eyes; and overall appearance), hands, and décolletage.7
Antioxidant and antiaging activity
In 2009, Thring et al. studied the antiaging and antioxidant characteristics of 23 plant extracts (from 21 species) by considering antielastase and anticollagenase activities. White tea was found to exhibit the greatest inhibitory activity against both elastase and collagenase, greater than burdock root and angelica in terms of antielastase activity, and greater than green tea, rose tincture, and lavender in relation to anticollagenase activity. The Trolox equivalent antioxidant capacity assay also showed that white tea displayed the highest antioxidant activity. The investigators noted the very high phenolic content of white tea in characterizing its potent inhibitory activity against enzymes that accelerate cutaneous aging.6
Earlier in 2009, Camouse et al. examined skin samples from volunteers or skin explants treated with topical white or green tea after ultraviolet exposure to ascertain that the antioxidant could prevent simulated solar radiation–induced damage to DNA and Langerhans cells. They noted that each product displayed a sun protection factor of 1, suggesting that the photoprotection conferred was not due to direct UV absorption. Both forms of topically applied tea extracts were equally effective and judged by the researchers to be potential photoprotective agents when used along with other substantiated approaches to skin protection. These findings provided the first reported evidence of topically applied white tea preventing UV-induced immunosuppression. The researchers further suggested that the color of white tea might render it more cosmetically desirable than green tea.8
It should be noted that a systematic review performed by Hunt et al. in 2010 of MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), CENTRAL (Cochrane Central Register of Controlled Trials), and AMED (Allied and Complementary Medicine Database) databases up to 2009 identified 11 randomized clinical or controlled clinical trials evaluating the effectiveness of botanical extracts for diminishing wrinkling and other signs of cutaneous aging. No significant reductions in wrinkling were associated with the use of green tea or Vitaphenol (a combination of green and white teas, mangosteen, and pomegranate extract). The authors noted, however, that all of the trials that they identified were characterized by poor methodologic quality.9
Thring et al. conducted an in vitro study in 2011 to evaluate the antioxidant and anti-inflammatory activity of white tea, rose, and witch hazel extracts in primary human skin fibroblasts. The investigators measured significant anticollagenase, antielastase, and antioxidant activities for the white tea extracts, which also spurred a significant reduction in the interleukin-8 amount synthesized by fibroblasts, compared with controls. They concluded that white tea (as well as the other extracts) yielded a protective effect on fibroblasts against damage induced by hydrogen peroxide exposure.10
In 2014, Azman et al. used the spin trap method and electron paramagnetic resonance (EPR) spectroscopy to show that among white tea constituents, EGCG and epicatechin-3-gallate (ECG) exhibit the greatest antiradical activity against the methoxy radical.1
Conclusion
Tea is one of the most popular beverages in the world and is touted for its antioxidant and anticancer properties. While the ingredients of green tea polyphenols have inspired a spate of recent research, much is yet to be learned about the potential health benefits of white tea, which is even less processed. Some evidence appears to suggest that white tea may be shown to be more effective overall, and in the dermatologic realm, than green tea. I look forward to seeing more research.
References
1. J Agric Food Chem. 2014;62(1):5743-8.
2. Dermatol Surg. 2005;31(7 Pt 2):873-80.
3. Oxid Med Cell Longev. 2012:2012:560682.
4. Mol Cell Biochem. 2000;206(1-2):125-32.
5. Free Radic Biol Med. 1999;26(11-12):1427-35.
6. BMC Complement Altern Med. 2009;9:27.
7. Eur J Clin Nutr. 2006;60(10):1201-6.
8. Exp Dermatol. 2009;18(6):522-6.
9. Drugs Aging. 2010;27(12):973-85.
10. J Inflamm (Lond). 2011;8(1):27).
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.
White tea, like green tea, is derived from the plant Camellia sinensis, a member of the Theaceae family and the source of all the globally popular “true tea” beverages.
Of the four main true teas, green and white are unfermented (white is the least processed), black tea is fermented, and oolong tea is semifermented.1,2,3 White tea actually comes from the tips of the green tea leaves or leaves that have not yet fully opened, with buds covered by fine white hair. As a commodity, white tea is more expensive than green tea because it is more difficult to obtain. EGCG [(-)epigallocatechin-3-O-gallate], the most abundant and biologically active polyphenolic catechin found in green tea, is also the constituent in white tea that accounts for its antioxidant properties.4,5 Indeed, white tea is included in topical products for its antioxidant as well as antiseptic activity, and is considered a more potent antioxidant additive medium than green tea.6,1
As an ingredient in a combination formula
White tea is included in the dietary supplement Imedeen Prime Renewal, along with fish protein polysaccharides, vitamins C and E, zinc, and extracts from soy, grape seed, chamomile, and tomato.
In 2006, Skovgaard et al. conducted a 6-month, double-blind, placebo-controlled randomized study on 80 healthy postmenopausal women (38 in the treatment group, 42 in the placebo group completed the study) to determine antiaging effects on the skin. Subjects took 2 tablets of the supplement or placebo twice daily. Clinical, photo, and ultrasound evaluations showed significantly greater improvements in the treatment group, compared with the placebo group, in the face (forehead, periocular, and perioral wrinkles; mottled pigmentation, laxity, sagging, dark circles under the eyes; and overall appearance), hands, and décolletage.7
Antioxidant and antiaging activity
In 2009, Thring et al. studied the antiaging and antioxidant characteristics of 23 plant extracts (from 21 species) by considering antielastase and anticollagenase activities. White tea was found to exhibit the greatest inhibitory activity against both elastase and collagenase, greater than burdock root and angelica in terms of antielastase activity, and greater than green tea, rose tincture, and lavender in relation to anticollagenase activity. The Trolox equivalent antioxidant capacity assay also showed that white tea displayed the highest antioxidant activity. The investigators noted the very high phenolic content of white tea in characterizing its potent inhibitory activity against enzymes that accelerate cutaneous aging.6
Earlier in 2009, Camouse et al. examined skin samples from volunteers or skin explants treated with topical white or green tea after ultraviolet exposure to ascertain that the antioxidant could prevent simulated solar radiation–induced damage to DNA and Langerhans cells. They noted that each product displayed a sun protection factor of 1, suggesting that the photoprotection conferred was not due to direct UV absorption. Both forms of topically applied tea extracts were equally effective and judged by the researchers to be potential photoprotective agents when used along with other substantiated approaches to skin protection. These findings provided the first reported evidence of topically applied white tea preventing UV-induced immunosuppression. The researchers further suggested that the color of white tea might render it more cosmetically desirable than green tea.8
It should be noted that a systematic review performed by Hunt et al. in 2010 of MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), CENTRAL (Cochrane Central Register of Controlled Trials), and AMED (Allied and Complementary Medicine Database) databases up to 2009 identified 11 randomized clinical or controlled clinical trials evaluating the effectiveness of botanical extracts for diminishing wrinkling and other signs of cutaneous aging. No significant reductions in wrinkling were associated with the use of green tea or Vitaphenol (a combination of green and white teas, mangosteen, and pomegranate extract). The authors noted, however, that all of the trials that they identified were characterized by poor methodologic quality.9
Thring et al. conducted an in vitro study in 2011 to evaluate the antioxidant and anti-inflammatory activity of white tea, rose, and witch hazel extracts in primary human skin fibroblasts. The investigators measured significant anticollagenase, antielastase, and antioxidant activities for the white tea extracts, which also spurred a significant reduction in the interleukin-8 amount synthesized by fibroblasts, compared with controls. They concluded that white tea (as well as the other extracts) yielded a protective effect on fibroblasts against damage induced by hydrogen peroxide exposure.10
In 2014, Azman et al. used the spin trap method and electron paramagnetic resonance (EPR) spectroscopy to show that among white tea constituents, EGCG and epicatechin-3-gallate (ECG) exhibit the greatest antiradical activity against the methoxy radical.1
Conclusion
Tea is one of the most popular beverages in the world and is touted for its antioxidant and anticancer properties. While the ingredients of green tea polyphenols have inspired a spate of recent research, much is yet to be learned about the potential health benefits of white tea, which is even less processed. Some evidence appears to suggest that white tea may be shown to be more effective overall, and in the dermatologic realm, than green tea. I look forward to seeing more research.
References
1. J Agric Food Chem. 2014;62(1):5743-8.
2. Dermatol Surg. 2005;31(7 Pt 2):873-80.
3. Oxid Med Cell Longev. 2012:2012:560682.
4. Mol Cell Biochem. 2000;206(1-2):125-32.
5. Free Radic Biol Med. 1999;26(11-12):1427-35.
6. BMC Complement Altern Med. 2009;9:27.
7. Eur J Clin Nutr. 2006;60(10):1201-6.
8. Exp Dermatol. 2009;18(6):522-6.
9. Drugs Aging. 2010;27(12):973-85.
10. J Inflamm (Lond). 2011;8(1):27).
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.
White tea, like green tea, is derived from the plant Camellia sinensis, a member of the Theaceae family and the source of all the globally popular “true tea” beverages.
Of the four main true teas, green and white are unfermented (white is the least processed), black tea is fermented, and oolong tea is semifermented.1,2,3 White tea actually comes from the tips of the green tea leaves or leaves that have not yet fully opened, with buds covered by fine white hair. As a commodity, white tea is more expensive than green tea because it is more difficult to obtain. EGCG [(-)epigallocatechin-3-O-gallate], the most abundant and biologically active polyphenolic catechin found in green tea, is also the constituent in white tea that accounts for its antioxidant properties.4,5 Indeed, white tea is included in topical products for its antioxidant as well as antiseptic activity, and is considered a more potent antioxidant additive medium than green tea.6,1
As an ingredient in a combination formula
White tea is included in the dietary supplement Imedeen Prime Renewal, along with fish protein polysaccharides, vitamins C and E, zinc, and extracts from soy, grape seed, chamomile, and tomato.
In 2006, Skovgaard et al. conducted a 6-month, double-blind, placebo-controlled randomized study on 80 healthy postmenopausal women (38 in the treatment group, 42 in the placebo group completed the study) to determine antiaging effects on the skin. Subjects took 2 tablets of the supplement or placebo twice daily. Clinical, photo, and ultrasound evaluations showed significantly greater improvements in the treatment group, compared with the placebo group, in the face (forehead, periocular, and perioral wrinkles; mottled pigmentation, laxity, sagging, dark circles under the eyes; and overall appearance), hands, and décolletage.7
Antioxidant and antiaging activity
In 2009, Thring et al. studied the antiaging and antioxidant characteristics of 23 plant extracts (from 21 species) by considering antielastase and anticollagenase activities. White tea was found to exhibit the greatest inhibitory activity against both elastase and collagenase, greater than burdock root and angelica in terms of antielastase activity, and greater than green tea, rose tincture, and lavender in relation to anticollagenase activity. The Trolox equivalent antioxidant capacity assay also showed that white tea displayed the highest antioxidant activity. The investigators noted the very high phenolic content of white tea in characterizing its potent inhibitory activity against enzymes that accelerate cutaneous aging.6
Earlier in 2009, Camouse et al. examined skin samples from volunteers or skin explants treated with topical white or green tea after ultraviolet exposure to ascertain that the antioxidant could prevent simulated solar radiation–induced damage to DNA and Langerhans cells. They noted that each product displayed a sun protection factor of 1, suggesting that the photoprotection conferred was not due to direct UV absorption. Both forms of topically applied tea extracts were equally effective and judged by the researchers to be potential photoprotective agents when used along with other substantiated approaches to skin protection. These findings provided the first reported evidence of topically applied white tea preventing UV-induced immunosuppression. The researchers further suggested that the color of white tea might render it more cosmetically desirable than green tea.8
It should be noted that a systematic review performed by Hunt et al. in 2010 of MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), CENTRAL (Cochrane Central Register of Controlled Trials), and AMED (Allied and Complementary Medicine Database) databases up to 2009 identified 11 randomized clinical or controlled clinical trials evaluating the effectiveness of botanical extracts for diminishing wrinkling and other signs of cutaneous aging. No significant reductions in wrinkling were associated with the use of green tea or Vitaphenol (a combination of green and white teas, mangosteen, and pomegranate extract). The authors noted, however, that all of the trials that they identified were characterized by poor methodologic quality.9
Thring et al. conducted an in vitro study in 2011 to evaluate the antioxidant and anti-inflammatory activity of white tea, rose, and witch hazel extracts in primary human skin fibroblasts. The investigators measured significant anticollagenase, antielastase, and antioxidant activities for the white tea extracts, which also spurred a significant reduction in the interleukin-8 amount synthesized by fibroblasts, compared with controls. They concluded that white tea (as well as the other extracts) yielded a protective effect on fibroblasts against damage induced by hydrogen peroxide exposure.10
In 2014, Azman et al. used the spin trap method and electron paramagnetic resonance (EPR) spectroscopy to show that among white tea constituents, EGCG and epicatechin-3-gallate (ECG) exhibit the greatest antiradical activity against the methoxy radical.1
Conclusion
Tea is one of the most popular beverages in the world and is touted for its antioxidant and anticancer properties. While the ingredients of green tea polyphenols have inspired a spate of recent research, much is yet to be learned about the potential health benefits of white tea, which is even less processed. Some evidence appears to suggest that white tea may be shown to be more effective overall, and in the dermatologic realm, than green tea. I look forward to seeing more research.
References
1. J Agric Food Chem. 2014;62(1):5743-8.
2. Dermatol Surg. 2005;31(7 Pt 2):873-80.
3. Oxid Med Cell Longev. 2012:2012:560682.
4. Mol Cell Biochem. 2000;206(1-2):125-32.
5. Free Radic Biol Med. 1999;26(11-12):1427-35.
6. BMC Complement Altern Med. 2009;9:27.
7. Eur J Clin Nutr. 2006;60(10):1201-6.
8. Exp Dermatol. 2009;18(6):522-6.
9. Drugs Aging. 2010;27(12):973-85.
10. J Inflamm (Lond). 2011;8(1):27).
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.
BMI negatively associated with acne lesion counts in postadolescent women
Body mass index was negatively associated with the number of acne lesions in a study of Taiwanese women, report Dr. P.H. Lu and coauthors at National Yang-Ming University in Taipei, Taiwan.
A study of 104 Taiwanese women aged 25-45 years with moderate to severe postadolescent acne vulgaris found a negative association between body mass index (BMI) and acne lesion count (P = .001).
In addition to BMI, other recorded measurements included blood pressure, fasting glucose, triglyceride levels, cholesterol levels, waist circumference, and hip circumference. Subjects were classified into four categories: BMI less than 18.5 kg/m2, BMI of 18.5 kg/m2–23.9 kg/m2, BMI of 24 kg/m2–26.9 kg/m2), or BMI greater than or equal to 27.
Acne severity was determined by the Investigator’s Global Assessment (IGA), with inclusion criteria being a score of 3 or 4 on a scale of 0 to 5. Inflammatory lesion counts were recorded by counting papules, pustules, nodules, and cysts. Noninflammatory lesions were recorded by counting comedones.
Women in the lowest BMI category had a mean of 35.5 inflammatory lesions, 7.4 noninflammatory lesions, and 42.9 total lesions, compared with patients in the 18.5-23.9 range (27.9 inflammatory, 6.6 noninflammatory, 34.0 total), and those who were in the two higher categories (18.1 inflammatory, 4.4 noninflammatory, 22.0 total), the authors reported.
“Further investigation is warranted into the association between BMI and acne in this subset of women,” Dr. Lu and associates concluded.
Read the full study in the Journal of the European Academy of Dermatology and Venereology.
Body mass index was negatively associated with the number of acne lesions in a study of Taiwanese women, report Dr. P.H. Lu and coauthors at National Yang-Ming University in Taipei, Taiwan.
A study of 104 Taiwanese women aged 25-45 years with moderate to severe postadolescent acne vulgaris found a negative association between body mass index (BMI) and acne lesion count (P = .001).
In addition to BMI, other recorded measurements included blood pressure, fasting glucose, triglyceride levels, cholesterol levels, waist circumference, and hip circumference. Subjects were classified into four categories: BMI less than 18.5 kg/m2, BMI of 18.5 kg/m2–23.9 kg/m2, BMI of 24 kg/m2–26.9 kg/m2), or BMI greater than or equal to 27.
Acne severity was determined by the Investigator’s Global Assessment (IGA), with inclusion criteria being a score of 3 or 4 on a scale of 0 to 5. Inflammatory lesion counts were recorded by counting papules, pustules, nodules, and cysts. Noninflammatory lesions were recorded by counting comedones.
Women in the lowest BMI category had a mean of 35.5 inflammatory lesions, 7.4 noninflammatory lesions, and 42.9 total lesions, compared with patients in the 18.5-23.9 range (27.9 inflammatory, 6.6 noninflammatory, 34.0 total), and those who were in the two higher categories (18.1 inflammatory, 4.4 noninflammatory, 22.0 total), the authors reported.
“Further investigation is warranted into the association between BMI and acne in this subset of women,” Dr. Lu and associates concluded.
Read the full study in the Journal of the European Academy of Dermatology and Venereology.
Body mass index was negatively associated with the number of acne lesions in a study of Taiwanese women, report Dr. P.H. Lu and coauthors at National Yang-Ming University in Taipei, Taiwan.
A study of 104 Taiwanese women aged 25-45 years with moderate to severe postadolescent acne vulgaris found a negative association between body mass index (BMI) and acne lesion count (P = .001).
In addition to BMI, other recorded measurements included blood pressure, fasting glucose, triglyceride levels, cholesterol levels, waist circumference, and hip circumference. Subjects were classified into four categories: BMI less than 18.5 kg/m2, BMI of 18.5 kg/m2–23.9 kg/m2, BMI of 24 kg/m2–26.9 kg/m2), or BMI greater than or equal to 27.
Acne severity was determined by the Investigator’s Global Assessment (IGA), with inclusion criteria being a score of 3 or 4 on a scale of 0 to 5. Inflammatory lesion counts were recorded by counting papules, pustules, nodules, and cysts. Noninflammatory lesions were recorded by counting comedones.
Women in the lowest BMI category had a mean of 35.5 inflammatory lesions, 7.4 noninflammatory lesions, and 42.9 total lesions, compared with patients in the 18.5-23.9 range (27.9 inflammatory, 6.6 noninflammatory, 34.0 total), and those who were in the two higher categories (18.1 inflammatory, 4.4 noninflammatory, 22.0 total), the authors reported.
“Further investigation is warranted into the association between BMI and acne in this subset of women,” Dr. Lu and associates concluded.
Read the full study in the Journal of the European Academy of Dermatology and Venereology.
Health Canada approves drug for acquired hemophilia A
Photo courtesy of
Baxter International Inc.
Health Canada has approved a recombinant porcine factor VIII (FVIII) product (Obizur) to treat bleeding episodes in patients with acquired hemophilia A caused by autoantibodies to FVIII.
Obizur is the first recombinant porcine treatment to be made available for acquired hemophilia A in Canada.
It is specifically designed so physicians can monitor treatment response by measuring FVIII activity levels in addition to making clinical assessments.
Health Canada’s approval is based on a phase 2/3 trial in which patients with acquired hemophilia A received Obizur as treatment for serious bleeding episodes.
Twenty-nine patients were enrolled in this trial and evaluated for safety. Researchers determined that one of the patients did not actually have acquired hemophilia A, so this patient could not be evaluated for efficacy.
At 24 hours after the initial infusion, all 28 patients in the efficacy analysis had a positive response to Obizur. This meant that bleeding stopped or decreased, the patients experienced clinical stabilization or improvement, and FVIII levels were 20% or higher.
Eighty-six percent of patients (24/28) had successful treatment of their initial bleeding episode. The overall treatment success was determined by the investigator based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.
The adverse event most frequently reported in the 29 patients in the safety analysis was the development of inhibitors to porcine FVIII.
Nineteen patients were negative for anti-porcine FVIII antibodies at baseline, and 5 of these patients (26%) developed anti-porcine FVIII antibodies following exposure to Obizur.
Of the 10 patients with detectable anti-porcine FVIII antibodies at baseline, 2 (20%) experienced an increase in titer, and 8 (80%) decreased to a non-detectable titer.
Obizur is under development by Baxalta Incorporated. The drug is currently approved for use in the US and is under regulatory review in the European Union, Switzerland, Australia, and Colombia.
Photo courtesy of
Baxter International Inc.
Health Canada has approved a recombinant porcine factor VIII (FVIII) product (Obizur) to treat bleeding episodes in patients with acquired hemophilia A caused by autoantibodies to FVIII.
Obizur is the first recombinant porcine treatment to be made available for acquired hemophilia A in Canada.
It is specifically designed so physicians can monitor treatment response by measuring FVIII activity levels in addition to making clinical assessments.
Health Canada’s approval is based on a phase 2/3 trial in which patients with acquired hemophilia A received Obizur as treatment for serious bleeding episodes.
Twenty-nine patients were enrolled in this trial and evaluated for safety. Researchers determined that one of the patients did not actually have acquired hemophilia A, so this patient could not be evaluated for efficacy.
At 24 hours after the initial infusion, all 28 patients in the efficacy analysis had a positive response to Obizur. This meant that bleeding stopped or decreased, the patients experienced clinical stabilization or improvement, and FVIII levels were 20% or higher.
Eighty-six percent of patients (24/28) had successful treatment of their initial bleeding episode. The overall treatment success was determined by the investigator based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.
The adverse event most frequently reported in the 29 patients in the safety analysis was the development of inhibitors to porcine FVIII.
Nineteen patients were negative for anti-porcine FVIII antibodies at baseline, and 5 of these patients (26%) developed anti-porcine FVIII antibodies following exposure to Obizur.
Of the 10 patients with detectable anti-porcine FVIII antibodies at baseline, 2 (20%) experienced an increase in titer, and 8 (80%) decreased to a non-detectable titer.
Obizur is under development by Baxalta Incorporated. The drug is currently approved for use in the US and is under regulatory review in the European Union, Switzerland, Australia, and Colombia.
Photo courtesy of
Baxter International Inc.
Health Canada has approved a recombinant porcine factor VIII (FVIII) product (Obizur) to treat bleeding episodes in patients with acquired hemophilia A caused by autoantibodies to FVIII.
Obizur is the first recombinant porcine treatment to be made available for acquired hemophilia A in Canada.
It is specifically designed so physicians can monitor treatment response by measuring FVIII activity levels in addition to making clinical assessments.
Health Canada’s approval is based on a phase 2/3 trial in which patients with acquired hemophilia A received Obizur as treatment for serious bleeding episodes.
Twenty-nine patients were enrolled in this trial and evaluated for safety. Researchers determined that one of the patients did not actually have acquired hemophilia A, so this patient could not be evaluated for efficacy.
At 24 hours after the initial infusion, all 28 patients in the efficacy analysis had a positive response to Obizur. This meant that bleeding stopped or decreased, the patients experienced clinical stabilization or improvement, and FVIII levels were 20% or higher.
Eighty-six percent of patients (24/28) had successful treatment of their initial bleeding episode. The overall treatment success was determined by the investigator based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.
The adverse event most frequently reported in the 29 patients in the safety analysis was the development of inhibitors to porcine FVIII.
Nineteen patients were negative for anti-porcine FVIII antibodies at baseline, and 5 of these patients (26%) developed anti-porcine FVIII antibodies following exposure to Obizur.
Of the 10 patients with detectable anti-porcine FVIII antibodies at baseline, 2 (20%) experienced an increase in titer, and 8 (80%) decreased to a non-detectable titer.
Obizur is under development by Baxalta Incorporated. The drug is currently approved for use in the US and is under regulatory review in the European Union, Switzerland, Australia, and Colombia.
COMP recommends orphan designations for KTE-C19
The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has adopted positive opinions recommending orphan designation for KTE-C19 to treat acute lymphoblastic leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma.
KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the surface of B cells.
The CAR T-cell therapy already has orphan designation for the treatment of diffuse large B-cell lymphoma in the US and the European Union (EU).
KTE-C19 also has COMP positive opinions for orphan designation in the EU for primary mediastinal B-cell lymphoma and mantle cell lymphoma.
About orphan designation
The COMP adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.
In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
KTE-C19 research
Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.
The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of the CAR T-cell therapy. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.
KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.
All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.
All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.
Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.
KTE-C19 is currently under investigation in a phase 1/2 trial (ZUMA-1) of patients with refractory, aggressive non-Hodgkin lymphomas. Kite Pharma, Inc., the company developing KTE-C19, plans to present top-line phase 1 data at the 2015 ASH Annual Meeting.
The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has adopted positive opinions recommending orphan designation for KTE-C19 to treat acute lymphoblastic leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma.
KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the surface of B cells.
The CAR T-cell therapy already has orphan designation for the treatment of diffuse large B-cell lymphoma in the US and the European Union (EU).
KTE-C19 also has COMP positive opinions for orphan designation in the EU for primary mediastinal B-cell lymphoma and mantle cell lymphoma.
About orphan designation
The COMP adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.
In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
KTE-C19 research
Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.
The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of the CAR T-cell therapy. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.
KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.
All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.
All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.
Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.
KTE-C19 is currently under investigation in a phase 1/2 trial (ZUMA-1) of patients with refractory, aggressive non-Hodgkin lymphomas. Kite Pharma, Inc., the company developing KTE-C19, plans to present top-line phase 1 data at the 2015 ASH Annual Meeting.
The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has adopted positive opinions recommending orphan designation for KTE-C19 to treat acute lymphoblastic leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma.
KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the surface of B cells.
The CAR T-cell therapy already has orphan designation for the treatment of diffuse large B-cell lymphoma in the US and the European Union (EU).
KTE-C19 also has COMP positive opinions for orphan designation in the EU for primary mediastinal B-cell lymphoma and mantle cell lymphoma.
About orphan designation
The COMP adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.
In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
KTE-C19 research
Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.
The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of the CAR T-cell therapy. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.
KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.
All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.
All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.
Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.
KTE-C19 is currently under investigation in a phase 1/2 trial (ZUMA-1) of patients with refractory, aggressive non-Hodgkin lymphomas. Kite Pharma, Inc., the company developing KTE-C19, plans to present top-line phase 1 data at the 2015 ASH Annual Meeting.
Watchdog condemns FDA oversight of dabigatran
The US Food and Drug Administration’s (FDA’s) oversight of the oral anticoagulant dabigatran (Pradaxa) raises questions about the agency’s reliability, according to a report by the Project On Government Oversight (POGO).
POGO’s report describes a series of “questionable” calls the FDA has made in its oversight of dabigatran.
The report calls attention to issues with the clinical trial used to support dabigatran’s approval.
It also details concerns regarding FDA advisory committee members, the distribution of potentially misleading information about dabigatran, the possibility that patients receiving dabigatran may actually need to be monitored, and other issues.
“The deeply disturbing part is that the public has to trust the FDA to keep it safe, and the way the agency handled Pradaxa doesn’t inspire confidence,” said Daniel Brian, POGO’s executive director.
This is not the first time the safety of dabigatran and results of dabigatran trials have been called into question.
Following post-marketing reports of adverse events and deaths related to dabigatran, the FDA conducted its own studies investigating the drug’s safety. The agency ultimately concluded that dabigatran’s benefits outweigh any detriments.
Still, a paper published in JAMA in 2012 suggested the FDA may have approved dabigatran too soon.
And several papers published in The BMJ last year indicated that Boehringer Ingelheim, the company developing dabigatran, underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.
The company has denied these allegations, but POGO’s report appears to support these claims, in addition to raising other concerns.
Trial issues
Dabigatran was initially approved by the FDA in 2010 on the basis of the RE-LY trial, in which researchers compared dabigatran and warfarin.
POGO’s report notes that this was an unblinded trial and suggests that investigators treated patients in the dabigatran arm differently than those in the warfarin arm. An FDA review showed that, when study subjects showed “signs of trouble,” those in the dabigatran arm were more likely to stop receiving treatment. This may have prevented adverse events such as hemorrhagic strokes.
FDA inspections also revealed that RE-LY investigators mismanaged parts of the trial. For example, they enrolled patients who were supposed to be excluded and failed to promptly inform Boehringer Ingelheim about possible adverse effects of dabigatran, among other infractions.
POGO’s report also cites FDA documents showing that the agency allowed Boehringer Ingelheim to finalize the scoring system for the RE-LY trial after it was over and the data had been gathered. A subsequent FDA review suggested that this allowance worked in dabigatran’s favor.
Advisory committee concerns
POGO’s report points out that members of the committee that advised the FDA on dabigatran’s approval have financial ties to the drug’s maker.
According to public databases, 2 of the advisory committee members who voted to approve dabigatran went on to receive tens of thousands of dollars from Boehringer Ingelheim.
POGO also found that when Boehringer Ingelheim held a practice session to prepare for questioning by the FDA advisory committee, a former member and a former chairman of that committee were paid to play roles in the rehearsal.
‘Misleading’ information
Another of POGO’s concerns is that the FDA redacted information from a public memo announcing and explaining its decision to approve dabigatran. The deleted section said that patients who were well-treated using warfarin had no reason to switch to dabigatran.
POGO’s report also points out that the FDA initially refused to allow Boehringer Ingelheim to claim that dabigatran was superior to warfarin but later changed its mind without providing much explanation.
In addition, the FDA allowed Boehringer Ingelheim to advertise that, in a clinical trial, dabigatran “reduced stroke risk 35% more than warfarin.” But after dabigatran had been on the market for more than 2.5 years, the FDA decided this claim was misleading.
The agency told Boehringer Ingelheim to add the following clarification: “That means that, in a large clinical study, 3.4% of patients taking warfarin had a stroke, compared to 2.2% of patients taking Pradaxa.” So, in absolute terms, the difference between the drugs was 1.2%.
Potential need for monitoring
According to POGO, Boehringer Ingelheim has been the target of thousands of lawsuits regarding adverse events and deaths thought to be related to dabigatran. In 2013, Boehringer Ingelheim was fined by a federal judge for withholding or failing to preserve records.
Some of these documents suggested that patients taking dabigatran may require monitoring to ensure they remain within a therapeutic range. A scientist at Boehringer Ingelheim, Thorsten Lehr, drafted a paper concluding that there is a therapeutic range for dabigatran.
But company emails indicated that other employees were against publishing this paper. An email from Boehringer Ingelheim’s Jutta Heinrich-Nols said publishing the paper would “make any defense of no monitoring . . . extremely difficult . . . and undermine our efforts to compete” with other new anticoagulants.
For more details, see POGO’s full report. POGO is a nonpartisan, independent watchdog that champions government reform.
The US Food and Drug Administration’s (FDA’s) oversight of the oral anticoagulant dabigatran (Pradaxa) raises questions about the agency’s reliability, according to a report by the Project On Government Oversight (POGO).
POGO’s report describes a series of “questionable” calls the FDA has made in its oversight of dabigatran.
The report calls attention to issues with the clinical trial used to support dabigatran’s approval.
It also details concerns regarding FDA advisory committee members, the distribution of potentially misleading information about dabigatran, the possibility that patients receiving dabigatran may actually need to be monitored, and other issues.
“The deeply disturbing part is that the public has to trust the FDA to keep it safe, and the way the agency handled Pradaxa doesn’t inspire confidence,” said Daniel Brian, POGO’s executive director.
This is not the first time the safety of dabigatran and results of dabigatran trials have been called into question.
Following post-marketing reports of adverse events and deaths related to dabigatran, the FDA conducted its own studies investigating the drug’s safety. The agency ultimately concluded that dabigatran’s benefits outweigh any detriments.
Still, a paper published in JAMA in 2012 suggested the FDA may have approved dabigatran too soon.
And several papers published in The BMJ last year indicated that Boehringer Ingelheim, the company developing dabigatran, underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.
The company has denied these allegations, but POGO’s report appears to support these claims, in addition to raising other concerns.
Trial issues
Dabigatran was initially approved by the FDA in 2010 on the basis of the RE-LY trial, in which researchers compared dabigatran and warfarin.
POGO’s report notes that this was an unblinded trial and suggests that investigators treated patients in the dabigatran arm differently than those in the warfarin arm. An FDA review showed that, when study subjects showed “signs of trouble,” those in the dabigatran arm were more likely to stop receiving treatment. This may have prevented adverse events such as hemorrhagic strokes.
FDA inspections also revealed that RE-LY investigators mismanaged parts of the trial. For example, they enrolled patients who were supposed to be excluded and failed to promptly inform Boehringer Ingelheim about possible adverse effects of dabigatran, among other infractions.
POGO’s report also cites FDA documents showing that the agency allowed Boehringer Ingelheim to finalize the scoring system for the RE-LY trial after it was over and the data had been gathered. A subsequent FDA review suggested that this allowance worked in dabigatran’s favor.
Advisory committee concerns
POGO’s report points out that members of the committee that advised the FDA on dabigatran’s approval have financial ties to the drug’s maker.
According to public databases, 2 of the advisory committee members who voted to approve dabigatran went on to receive tens of thousands of dollars from Boehringer Ingelheim.
POGO also found that when Boehringer Ingelheim held a practice session to prepare for questioning by the FDA advisory committee, a former member and a former chairman of that committee were paid to play roles in the rehearsal.
‘Misleading’ information
Another of POGO’s concerns is that the FDA redacted information from a public memo announcing and explaining its decision to approve dabigatran. The deleted section said that patients who were well-treated using warfarin had no reason to switch to dabigatran.
POGO’s report also points out that the FDA initially refused to allow Boehringer Ingelheim to claim that dabigatran was superior to warfarin but later changed its mind without providing much explanation.
In addition, the FDA allowed Boehringer Ingelheim to advertise that, in a clinical trial, dabigatran “reduced stroke risk 35% more than warfarin.” But after dabigatran had been on the market for more than 2.5 years, the FDA decided this claim was misleading.
The agency told Boehringer Ingelheim to add the following clarification: “That means that, in a large clinical study, 3.4% of patients taking warfarin had a stroke, compared to 2.2% of patients taking Pradaxa.” So, in absolute terms, the difference between the drugs was 1.2%.
Potential need for monitoring
According to POGO, Boehringer Ingelheim has been the target of thousands of lawsuits regarding adverse events and deaths thought to be related to dabigatran. In 2013, Boehringer Ingelheim was fined by a federal judge for withholding or failing to preserve records.
Some of these documents suggested that patients taking dabigatran may require monitoring to ensure they remain within a therapeutic range. A scientist at Boehringer Ingelheim, Thorsten Lehr, drafted a paper concluding that there is a therapeutic range for dabigatran.
But company emails indicated that other employees were against publishing this paper. An email from Boehringer Ingelheim’s Jutta Heinrich-Nols said publishing the paper would “make any defense of no monitoring . . . extremely difficult . . . and undermine our efforts to compete” with other new anticoagulants.
For more details, see POGO’s full report. POGO is a nonpartisan, independent watchdog that champions government reform.
The US Food and Drug Administration’s (FDA’s) oversight of the oral anticoagulant dabigatran (Pradaxa) raises questions about the agency’s reliability, according to a report by the Project On Government Oversight (POGO).
POGO’s report describes a series of “questionable” calls the FDA has made in its oversight of dabigatran.
The report calls attention to issues with the clinical trial used to support dabigatran’s approval.
It also details concerns regarding FDA advisory committee members, the distribution of potentially misleading information about dabigatran, the possibility that patients receiving dabigatran may actually need to be monitored, and other issues.
“The deeply disturbing part is that the public has to trust the FDA to keep it safe, and the way the agency handled Pradaxa doesn’t inspire confidence,” said Daniel Brian, POGO’s executive director.
This is not the first time the safety of dabigatran and results of dabigatran trials have been called into question.
Following post-marketing reports of adverse events and deaths related to dabigatran, the FDA conducted its own studies investigating the drug’s safety. The agency ultimately concluded that dabigatran’s benefits outweigh any detriments.
Still, a paper published in JAMA in 2012 suggested the FDA may have approved dabigatran too soon.
And several papers published in The BMJ last year indicated that Boehringer Ingelheim, the company developing dabigatran, underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.
The company has denied these allegations, but POGO’s report appears to support these claims, in addition to raising other concerns.
Trial issues
Dabigatran was initially approved by the FDA in 2010 on the basis of the RE-LY trial, in which researchers compared dabigatran and warfarin.
POGO’s report notes that this was an unblinded trial and suggests that investigators treated patients in the dabigatran arm differently than those in the warfarin arm. An FDA review showed that, when study subjects showed “signs of trouble,” those in the dabigatran arm were more likely to stop receiving treatment. This may have prevented adverse events such as hemorrhagic strokes.
FDA inspections also revealed that RE-LY investigators mismanaged parts of the trial. For example, they enrolled patients who were supposed to be excluded and failed to promptly inform Boehringer Ingelheim about possible adverse effects of dabigatran, among other infractions.
POGO’s report also cites FDA documents showing that the agency allowed Boehringer Ingelheim to finalize the scoring system for the RE-LY trial after it was over and the data had been gathered. A subsequent FDA review suggested that this allowance worked in dabigatran’s favor.
Advisory committee concerns
POGO’s report points out that members of the committee that advised the FDA on dabigatran’s approval have financial ties to the drug’s maker.
According to public databases, 2 of the advisory committee members who voted to approve dabigatran went on to receive tens of thousands of dollars from Boehringer Ingelheim.
POGO also found that when Boehringer Ingelheim held a practice session to prepare for questioning by the FDA advisory committee, a former member and a former chairman of that committee were paid to play roles in the rehearsal.
‘Misleading’ information
Another of POGO’s concerns is that the FDA redacted information from a public memo announcing and explaining its decision to approve dabigatran. The deleted section said that patients who were well-treated using warfarin had no reason to switch to dabigatran.
POGO’s report also points out that the FDA initially refused to allow Boehringer Ingelheim to claim that dabigatran was superior to warfarin but later changed its mind without providing much explanation.
In addition, the FDA allowed Boehringer Ingelheim to advertise that, in a clinical trial, dabigatran “reduced stroke risk 35% more than warfarin.” But after dabigatran had been on the market for more than 2.5 years, the FDA decided this claim was misleading.
The agency told Boehringer Ingelheim to add the following clarification: “That means that, in a large clinical study, 3.4% of patients taking warfarin had a stroke, compared to 2.2% of patients taking Pradaxa.” So, in absolute terms, the difference between the drugs was 1.2%.
Potential need for monitoring
According to POGO, Boehringer Ingelheim has been the target of thousands of lawsuits regarding adverse events and deaths thought to be related to dabigatran. In 2013, Boehringer Ingelheim was fined by a federal judge for withholding or failing to preserve records.
Some of these documents suggested that patients taking dabigatran may require monitoring to ensure they remain within a therapeutic range. A scientist at Boehringer Ingelheim, Thorsten Lehr, drafted a paper concluding that there is a therapeutic range for dabigatran.
But company emails indicated that other employees were against publishing this paper. An email from Boehringer Ingelheim’s Jutta Heinrich-Nols said publishing the paper would “make any defense of no monitoring . . . extremely difficult . . . and undermine our efforts to compete” with other new anticoagulants.
For more details, see POGO’s full report. POGO is a nonpartisan, independent watchdog that champions government reform.
MMF may increase risk of CNS lymphoma
A new study has linked the immunosuppressive drug mycophenolate mofetil (MMF) to an increased risk of central nervous system (CNS) lymphoma in solid organ transplant recipients.
However, the research also suggests that calcineurin inhibitors (CNIs), when given alone or in combination with MMF, may protect transplant recipients from CNS lymphoma.
Researchers reported these findings in Oncotarget.
“MMF remains one of the best current medications for immunosuppression that we have,” said study author Amy Duffield, MD, PhD, of The Johns Hopkins Medical Institutions in Baltimore, Maryland.
“But a better understanding of its association with CNS lymphoproliferative disease will be crucial to further improving patients’ transplant regimens based on all of the risks these patients face.”
Dr Duffield and her colleagues noted that lymphomas and leukemias are known to be complications of solid organ transplants, but these malignancies rarely start in the CNS.
Still, in recent years, clinicians have begun to notice a rise in primary CNS lymphoproliferative disorders among transplant recipients. The current study is thought to be the first large enough to identify a link between MMF and these tumors.
For this work, Dr Duffield and her colleagues analyzed information on 177 patients with post-transplant lymphoproliferative disorder (PTLD) who were seen at Johns Hopkins Hospital between 1986 and 2014.
In that group, 29 patients—mostly kidney transplant recipients—were diagnosed with primary CNS lymphoproliferative disorders. The researchers said these were predominantly classified as monomorphic PTLD (72%), and most of the classifiable lymphomas were large B-cell lymphomas.
There were no cases of primary CNS PTLD diagnosed between 1986 and 1997, but the diagnosis increased markedly in the next decades.
The proportion of primary CNS PTLD cases compared to other PTLDs was 4.4-fold higher in the period from 2005 to 2014 than in the period from 1995 to 2004 (P<0.0001), even though the total number of PTLD cases remained relatively stable over time.
The researchers had prescription records on 16 of the patients who developed primary CNS lymphoproliferative disease.
Fifteen of the 16 patients had been taking MMF in the year prior to, or at the time of, their PTLD diagnosis. On the other hand, 37 of the 102 patients with PTLD outside the CNS had taken MMF (P<0.001).
The researchers also found that patients who took CNIs, either alone or in combination with MMF, seemed to be protected from developing primary CNS disease.
Primary CNS lymphoproliferative disease accounted for 66.7% of PTLDs among patients who took MMF but not a CNI (n=6), 23.9% of PTLDs among patients who took both an MMF and a CNI (n=46), and 1.7% of PTLDs among patients who took just a CNI (n=60).
The researchers found similar trends in a set of 6966 patients with PTLD. Those patients’ records were gleaned from an organ transplant database managed by the Organ Procurement and Transplantation Network and the United Network for Organ Sharing.
“More research needs to be done to confirm our results,” said Genevieve Crane, MD, PhD, of The Johns Hopkins Medical Institutions.
“But our work suggests that, at least in some patients, the combination of MMF and CNIs may be protective against CNS lymphoproliferative disease in a way that had not previously been appreciated.”
A new study has linked the immunosuppressive drug mycophenolate mofetil (MMF) to an increased risk of central nervous system (CNS) lymphoma in solid organ transplant recipients.
However, the research also suggests that calcineurin inhibitors (CNIs), when given alone or in combination with MMF, may protect transplant recipients from CNS lymphoma.
Researchers reported these findings in Oncotarget.
“MMF remains one of the best current medications for immunosuppression that we have,” said study author Amy Duffield, MD, PhD, of The Johns Hopkins Medical Institutions in Baltimore, Maryland.
“But a better understanding of its association with CNS lymphoproliferative disease will be crucial to further improving patients’ transplant regimens based on all of the risks these patients face.”
Dr Duffield and her colleagues noted that lymphomas and leukemias are known to be complications of solid organ transplants, but these malignancies rarely start in the CNS.
Still, in recent years, clinicians have begun to notice a rise in primary CNS lymphoproliferative disorders among transplant recipients. The current study is thought to be the first large enough to identify a link between MMF and these tumors.
For this work, Dr Duffield and her colleagues analyzed information on 177 patients with post-transplant lymphoproliferative disorder (PTLD) who were seen at Johns Hopkins Hospital between 1986 and 2014.
In that group, 29 patients—mostly kidney transplant recipients—were diagnosed with primary CNS lymphoproliferative disorders. The researchers said these were predominantly classified as monomorphic PTLD (72%), and most of the classifiable lymphomas were large B-cell lymphomas.
There were no cases of primary CNS PTLD diagnosed between 1986 and 1997, but the diagnosis increased markedly in the next decades.
The proportion of primary CNS PTLD cases compared to other PTLDs was 4.4-fold higher in the period from 2005 to 2014 than in the period from 1995 to 2004 (P<0.0001), even though the total number of PTLD cases remained relatively stable over time.
The researchers had prescription records on 16 of the patients who developed primary CNS lymphoproliferative disease.
Fifteen of the 16 patients had been taking MMF in the year prior to, or at the time of, their PTLD diagnosis. On the other hand, 37 of the 102 patients with PTLD outside the CNS had taken MMF (P<0.001).
The researchers also found that patients who took CNIs, either alone or in combination with MMF, seemed to be protected from developing primary CNS disease.
Primary CNS lymphoproliferative disease accounted for 66.7% of PTLDs among patients who took MMF but not a CNI (n=6), 23.9% of PTLDs among patients who took both an MMF and a CNI (n=46), and 1.7% of PTLDs among patients who took just a CNI (n=60).
The researchers found similar trends in a set of 6966 patients with PTLD. Those patients’ records were gleaned from an organ transplant database managed by the Organ Procurement and Transplantation Network and the United Network for Organ Sharing.
“More research needs to be done to confirm our results,” said Genevieve Crane, MD, PhD, of The Johns Hopkins Medical Institutions.
“But our work suggests that, at least in some patients, the combination of MMF and CNIs may be protective against CNS lymphoproliferative disease in a way that had not previously been appreciated.”
A new study has linked the immunosuppressive drug mycophenolate mofetil (MMF) to an increased risk of central nervous system (CNS) lymphoma in solid organ transplant recipients.
However, the research also suggests that calcineurin inhibitors (CNIs), when given alone or in combination with MMF, may protect transplant recipients from CNS lymphoma.
Researchers reported these findings in Oncotarget.
“MMF remains one of the best current medications for immunosuppression that we have,” said study author Amy Duffield, MD, PhD, of The Johns Hopkins Medical Institutions in Baltimore, Maryland.
“But a better understanding of its association with CNS lymphoproliferative disease will be crucial to further improving patients’ transplant regimens based on all of the risks these patients face.”
Dr Duffield and her colleagues noted that lymphomas and leukemias are known to be complications of solid organ transplants, but these malignancies rarely start in the CNS.
Still, in recent years, clinicians have begun to notice a rise in primary CNS lymphoproliferative disorders among transplant recipients. The current study is thought to be the first large enough to identify a link between MMF and these tumors.
For this work, Dr Duffield and her colleagues analyzed information on 177 patients with post-transplant lymphoproliferative disorder (PTLD) who were seen at Johns Hopkins Hospital between 1986 and 2014.
In that group, 29 patients—mostly kidney transplant recipients—were diagnosed with primary CNS lymphoproliferative disorders. The researchers said these were predominantly classified as monomorphic PTLD (72%), and most of the classifiable lymphomas were large B-cell lymphomas.
There were no cases of primary CNS PTLD diagnosed between 1986 and 1997, but the diagnosis increased markedly in the next decades.
The proportion of primary CNS PTLD cases compared to other PTLDs was 4.4-fold higher in the period from 2005 to 2014 than in the period from 1995 to 2004 (P<0.0001), even though the total number of PTLD cases remained relatively stable over time.
The researchers had prescription records on 16 of the patients who developed primary CNS lymphoproliferative disease.
Fifteen of the 16 patients had been taking MMF in the year prior to, or at the time of, their PTLD diagnosis. On the other hand, 37 of the 102 patients with PTLD outside the CNS had taken MMF (P<0.001).
The researchers also found that patients who took CNIs, either alone or in combination with MMF, seemed to be protected from developing primary CNS disease.
Primary CNS lymphoproliferative disease accounted for 66.7% of PTLDs among patients who took MMF but not a CNI (n=6), 23.9% of PTLDs among patients who took both an MMF and a CNI (n=46), and 1.7% of PTLDs among patients who took just a CNI (n=60).
The researchers found similar trends in a set of 6966 patients with PTLD. Those patients’ records were gleaned from an organ transplant database managed by the Organ Procurement and Transplantation Network and the United Network for Organ Sharing.
“More research needs to be done to confirm our results,” said Genevieve Crane, MD, PhD, of The Johns Hopkins Medical Institutions.
“But our work suggests that, at least in some patients, the combination of MMF and CNIs may be protective against CNS lymphoproliferative disease in a way that had not previously been appreciated.”