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FDA grants drug priority review as FL therapy
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively. 
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
Breast cancer drug may also work in MCL, myeloma
showing multiple myeloma
NEW YORK—Targeting the cell cycle with cyclin-dependent kinase (CDK) inhibitors may be an effective strategy to treat lymphoma and myeloma, according to a presentation at Lymphoma & Myeloma 2015.
Palbociclib, an inhibitor of CDK4 and CDK6, received accelerated approval from the US Food and Drug Administration to treat advanced breast cancer.
Now, it is showing promise in mantle cell lymphoma (MCL) and multiple myeloma (MM) as well.
CDK family members are important regulators of cell-cycle progression. Dysregulation of CDK4 and CDK6 is one of the most common genomic aberrations in human cancer, including myeloma, lymphoma, leukemia, breast cancer, metastatic lung adenocarcinoma, and glioblastoma.
MCL, which accounts for 6% of non-Hodgkin lymphomas, has an overall poor prognosis, with most patients eventually becoming resistant to drugs. MCL expresses cyclin D1 as a consequence of the t(11;14) translocation and overexpresses CDK4.
“So this is a perfect disease for the development of targeting CDK4,” said Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, New York, who presented this information at the meeting.
CDK4 and CDK6 signaling occur at the beginning of the cell cycle and bring the cell from the resting state into early G2.
“If we could control that,” Dr Chen-Kiang explained, “we reasoned that we could control the DNA replication and cell division” and increase tumor-specific cell death.
Palbociclib (PD0332991; Ibrance), an orally bioavailable, selective CDK4/CDK6 inhibitor, induces early G1 arrest. It is reversible and low in toxicity, according to Dr Chen-Kiang.
Currently, it’s being tested in phase 1 trials in MCL with ibrutinib and in MM with lenalidomide-dexamethasone. Phase 1 trials have also been completed at Cornell with palbociclib as a single agent in MCL, with bortezomib in MCL, and with bortezomib-dexamethasone in MM.
Palbociclib in MCL
Investigators conducted a phase 1, single-agent study of palbociclib to determine whether it could be tolerated in humans.
“CDK4/CDK6 is expressed in every cell,” Dr Chen-Kiang noted, “and you are targeting 2 proteins that are needed for every cell.”
Seventeen patients received 125 mg of palbociclib per day for 21 of 28 days.
“And surprisingly,” Dr Chen-Kiang said, “it’s very well tolerated.”
The most common adverse events were neutropenia, fatigue, and diarrhea.
“And even more surprising,” she added “is that we actually had a complete response (CR) [and] 2 partial responses, in addition to 5 stable diseases.”
The investigators hypothesized that blocking the cell cycle in G1 creates an imbalance in gene expression.
They then conducted a trial of palbociclib plus bortezomib in 17 patients with recurrent MCL. Patients received palbociclib on days 1–12 and low-dose bortezomib on days 8, 11, 15, and 18.
The palbociclib dose ranged from 75 mg to 125 mg, and the bortezomib dose ranged from 1.0 mg/m2 to 1.3 mg/m2.
Eleven patients experienced a reduction in tumor volume, the majority at the 125-mg dose.
Using whole-exome and whole-transcriptome sequencing of serial biopsies, investigators determined that CDK4/CDK6 inhibition induces early G1 arrest in MCL cells in both responders and non-responders initially.
This may occur because the cell cycle is perfectly controlled, and there’s no mutation in CDK4 in any of the patients.
Investigators attempted to identify genes that could differentiate sensitivity from resistance to CDK4 targeting. They found that a very small number of genes display opposite regulation in prolonged early G1 arrest in responding versus non-responding patients.
These genes are involved in metabolism and redox homeostasis and include a gene called PIK3IP1, an inhibitor of PI3 kinase.
In earlier analyses, the investigators had discovered a relapse-specific C481S mutation at the ibrutinib binding site of Bruton’s tyrosine kinase (BTK) in MCL cells. The mutation occurred at progression following a durable response to ibrutinib.
The mutation is absent, however, in patients with transient ibrutinib responses or in primary resistance.
The team observed that early cell-cycle arrest by CDK4 inhibition reprograms MCL cells for killing by ibrutinib. This occurs through inhibition of BTK and AKT (protein kinase B).
So the investigators undertook to study palbociclib in combination with ibrutinib, “with extraordinary results,” Dr Chen-Kiang said.
The trial is ongoing and, at the moment, has a 60% CR rate with durable responses.
“We’re very happy with this,” Dr Chen-Kiang said.
Palbociclib in MM
In addition to the phase 1/2 study of palbociclib with bortezomib and dexamethasone, investigators are also pursuing palbociclib in combination with lenalidomide and dexamethasone, which Dr Chen-Kiang briefly elaborated upon.
Lenalidomide rarely produces a complete remission on its own, she explained, so the team decided to study palbociclib in combination with immunomodulatory drugs in MM (NCT02030483).
The strategy is to prime the cell cycle with palbociclib and then use lenalidomide and dexamethasone to increase efficacy.
Twenty patients have received this combination thus far, and investigators found that palbociclib enhances the activity of lenalidomide in the killing of primary bone marrow myeloma cells.
Lenalidomide reduces the MEIS2/CRBN ratio in these cells. The drug changes the ratio, reduces the blocker, and allows the CRBN to work.
“The whole principle here is to control the gene coupling to the cell cycle and induce imbalance in gene expression,” Dr Chen-Kiang said. “And this weakens the tumor cells.”
Two-thirds of the samples respond to palboclib, she said, and those patients go on to be treated with lenalidomide or pomalidomide.
One third will not respond, but their in vivo clinical response and the ex vivo responders’ purified cells mimic one another.
“Now, this is very exciting to us,” she said.
The combination study with lenalidomide and dexamethasone is currently underway.
Palbociclib is being developed by Pfizer.
showing multiple myeloma
NEW YORK—Targeting the cell cycle with cyclin-dependent kinase (CDK) inhibitors may be an effective strategy to treat lymphoma and myeloma, according to a presentation at Lymphoma & Myeloma 2015.
Palbociclib, an inhibitor of CDK4 and CDK6, received accelerated approval from the US Food and Drug Administration to treat advanced breast cancer.
Now, it is showing promise in mantle cell lymphoma (MCL) and multiple myeloma (MM) as well.
CDK family members are important regulators of cell-cycle progression. Dysregulation of CDK4 and CDK6 is one of the most common genomic aberrations in human cancer, including myeloma, lymphoma, leukemia, breast cancer, metastatic lung adenocarcinoma, and glioblastoma.
MCL, which accounts for 6% of non-Hodgkin lymphomas, has an overall poor prognosis, with most patients eventually becoming resistant to drugs. MCL expresses cyclin D1 as a consequence of the t(11;14) translocation and overexpresses CDK4.
“So this is a perfect disease for the development of targeting CDK4,” said Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, New York, who presented this information at the meeting.
CDK4 and CDK6 signaling occur at the beginning of the cell cycle and bring the cell from the resting state into early G2.
“If we could control that,” Dr Chen-Kiang explained, “we reasoned that we could control the DNA replication and cell division” and increase tumor-specific cell death.
Palbociclib (PD0332991; Ibrance), an orally bioavailable, selective CDK4/CDK6 inhibitor, induces early G1 arrest. It is reversible and low in toxicity, according to Dr Chen-Kiang.
Currently, it’s being tested in phase 1 trials in MCL with ibrutinib and in MM with lenalidomide-dexamethasone. Phase 1 trials have also been completed at Cornell with palbociclib as a single agent in MCL, with bortezomib in MCL, and with bortezomib-dexamethasone in MM.
Palbociclib in MCL
Investigators conducted a phase 1, single-agent study of palbociclib to determine whether it could be tolerated in humans.
“CDK4/CDK6 is expressed in every cell,” Dr Chen-Kiang noted, “and you are targeting 2 proteins that are needed for every cell.”
Seventeen patients received 125 mg of palbociclib per day for 21 of 28 days.
“And surprisingly,” Dr Chen-Kiang said, “it’s very well tolerated.”
The most common adverse events were neutropenia, fatigue, and diarrhea.
“And even more surprising,” she added “is that we actually had a complete response (CR) [and] 2 partial responses, in addition to 5 stable diseases.”
The investigators hypothesized that blocking the cell cycle in G1 creates an imbalance in gene expression.
They then conducted a trial of palbociclib plus bortezomib in 17 patients with recurrent MCL. Patients received palbociclib on days 1–12 and low-dose bortezomib on days 8, 11, 15, and 18.
The palbociclib dose ranged from 75 mg to 125 mg, and the bortezomib dose ranged from 1.0 mg/m2 to 1.3 mg/m2.
Eleven patients experienced a reduction in tumor volume, the majority at the 125-mg dose.
Using whole-exome and whole-transcriptome sequencing of serial biopsies, investigators determined that CDK4/CDK6 inhibition induces early G1 arrest in MCL cells in both responders and non-responders initially.
This may occur because the cell cycle is perfectly controlled, and there’s no mutation in CDK4 in any of the patients.
Investigators attempted to identify genes that could differentiate sensitivity from resistance to CDK4 targeting. They found that a very small number of genes display opposite regulation in prolonged early G1 arrest in responding versus non-responding patients.
These genes are involved in metabolism and redox homeostasis and include a gene called PIK3IP1, an inhibitor of PI3 kinase.
In earlier analyses, the investigators had discovered a relapse-specific C481S mutation at the ibrutinib binding site of Bruton’s tyrosine kinase (BTK) in MCL cells. The mutation occurred at progression following a durable response to ibrutinib.
The mutation is absent, however, in patients with transient ibrutinib responses or in primary resistance.
The team observed that early cell-cycle arrest by CDK4 inhibition reprograms MCL cells for killing by ibrutinib. This occurs through inhibition of BTK and AKT (protein kinase B).
So the investigators undertook to study palbociclib in combination with ibrutinib, “with extraordinary results,” Dr Chen-Kiang said.
The trial is ongoing and, at the moment, has a 60% CR rate with durable responses.
“We’re very happy with this,” Dr Chen-Kiang said.
Palbociclib in MM
In addition to the phase 1/2 study of palbociclib with bortezomib and dexamethasone, investigators are also pursuing palbociclib in combination with lenalidomide and dexamethasone, which Dr Chen-Kiang briefly elaborated upon.
Lenalidomide rarely produces a complete remission on its own, she explained, so the team decided to study palbociclib in combination with immunomodulatory drugs in MM (NCT02030483).
The strategy is to prime the cell cycle with palbociclib and then use lenalidomide and dexamethasone to increase efficacy.
Twenty patients have received this combination thus far, and investigators found that palbociclib enhances the activity of lenalidomide in the killing of primary bone marrow myeloma cells.
Lenalidomide reduces the MEIS2/CRBN ratio in these cells. The drug changes the ratio, reduces the blocker, and allows the CRBN to work.
“The whole principle here is to control the gene coupling to the cell cycle and induce imbalance in gene expression,” Dr Chen-Kiang said. “And this weakens the tumor cells.”
Two-thirds of the samples respond to palboclib, she said, and those patients go on to be treated with lenalidomide or pomalidomide.
One third will not respond, but their in vivo clinical response and the ex vivo responders’ purified cells mimic one another.
“Now, this is very exciting to us,” she said.
The combination study with lenalidomide and dexamethasone is currently underway.
Palbociclib is being developed by Pfizer.
showing multiple myeloma
NEW YORK—Targeting the cell cycle with cyclin-dependent kinase (CDK) inhibitors may be an effective strategy to treat lymphoma and myeloma, according to a presentation at Lymphoma & Myeloma 2015.
Palbociclib, an inhibitor of CDK4 and CDK6, received accelerated approval from the US Food and Drug Administration to treat advanced breast cancer.
Now, it is showing promise in mantle cell lymphoma (MCL) and multiple myeloma (MM) as well.
CDK family members are important regulators of cell-cycle progression. Dysregulation of CDK4 and CDK6 is one of the most common genomic aberrations in human cancer, including myeloma, lymphoma, leukemia, breast cancer, metastatic lung adenocarcinoma, and glioblastoma.
MCL, which accounts for 6% of non-Hodgkin lymphomas, has an overall poor prognosis, with most patients eventually becoming resistant to drugs. MCL expresses cyclin D1 as a consequence of the t(11;14) translocation and overexpresses CDK4.
“So this is a perfect disease for the development of targeting CDK4,” said Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, New York, who presented this information at the meeting.
CDK4 and CDK6 signaling occur at the beginning of the cell cycle and bring the cell from the resting state into early G2.
“If we could control that,” Dr Chen-Kiang explained, “we reasoned that we could control the DNA replication and cell division” and increase tumor-specific cell death.
Palbociclib (PD0332991; Ibrance), an orally bioavailable, selective CDK4/CDK6 inhibitor, induces early G1 arrest. It is reversible and low in toxicity, according to Dr Chen-Kiang.
Currently, it’s being tested in phase 1 trials in MCL with ibrutinib and in MM with lenalidomide-dexamethasone. Phase 1 trials have also been completed at Cornell with palbociclib as a single agent in MCL, with bortezomib in MCL, and with bortezomib-dexamethasone in MM.
Palbociclib in MCL
Investigators conducted a phase 1, single-agent study of palbociclib to determine whether it could be tolerated in humans.
“CDK4/CDK6 is expressed in every cell,” Dr Chen-Kiang noted, “and you are targeting 2 proteins that are needed for every cell.”
Seventeen patients received 125 mg of palbociclib per day for 21 of 28 days.
“And surprisingly,” Dr Chen-Kiang said, “it’s very well tolerated.”
The most common adverse events were neutropenia, fatigue, and diarrhea.
“And even more surprising,” she added “is that we actually had a complete response (CR) [and] 2 partial responses, in addition to 5 stable diseases.”
The investigators hypothesized that blocking the cell cycle in G1 creates an imbalance in gene expression.
They then conducted a trial of palbociclib plus bortezomib in 17 patients with recurrent MCL. Patients received palbociclib on days 1–12 and low-dose bortezomib on days 8, 11, 15, and 18.
The palbociclib dose ranged from 75 mg to 125 mg, and the bortezomib dose ranged from 1.0 mg/m2 to 1.3 mg/m2.
Eleven patients experienced a reduction in tumor volume, the majority at the 125-mg dose.
Using whole-exome and whole-transcriptome sequencing of serial biopsies, investigators determined that CDK4/CDK6 inhibition induces early G1 arrest in MCL cells in both responders and non-responders initially.
This may occur because the cell cycle is perfectly controlled, and there’s no mutation in CDK4 in any of the patients.
Investigators attempted to identify genes that could differentiate sensitivity from resistance to CDK4 targeting. They found that a very small number of genes display opposite regulation in prolonged early G1 arrest in responding versus non-responding patients.
These genes are involved in metabolism and redox homeostasis and include a gene called PIK3IP1, an inhibitor of PI3 kinase.
In earlier analyses, the investigators had discovered a relapse-specific C481S mutation at the ibrutinib binding site of Bruton’s tyrosine kinase (BTK) in MCL cells. The mutation occurred at progression following a durable response to ibrutinib.
The mutation is absent, however, in patients with transient ibrutinib responses or in primary resistance.
The team observed that early cell-cycle arrest by CDK4 inhibition reprograms MCL cells for killing by ibrutinib. This occurs through inhibition of BTK and AKT (protein kinase B).
So the investigators undertook to study palbociclib in combination with ibrutinib, “with extraordinary results,” Dr Chen-Kiang said.
The trial is ongoing and, at the moment, has a 60% CR rate with durable responses.
“We’re very happy with this,” Dr Chen-Kiang said.
Palbociclib in MM
In addition to the phase 1/2 study of palbociclib with bortezomib and dexamethasone, investigators are also pursuing palbociclib in combination with lenalidomide and dexamethasone, which Dr Chen-Kiang briefly elaborated upon.
Lenalidomide rarely produces a complete remission on its own, she explained, so the team decided to study palbociclib in combination with immunomodulatory drugs in MM (NCT02030483).
The strategy is to prime the cell cycle with palbociclib and then use lenalidomide and dexamethasone to increase efficacy.
Twenty patients have received this combination thus far, and investigators found that palbociclib enhances the activity of lenalidomide in the killing of primary bone marrow myeloma cells.
Lenalidomide reduces the MEIS2/CRBN ratio in these cells. The drug changes the ratio, reduces the blocker, and allows the CRBN to work.
“The whole principle here is to control the gene coupling to the cell cycle and induce imbalance in gene expression,” Dr Chen-Kiang said. “And this weakens the tumor cells.”
Two-thirds of the samples respond to palboclib, she said, and those patients go on to be treated with lenalidomide or pomalidomide.
One third will not respond, but their in vivo clinical response and the ex vivo responders’ purified cells mimic one another.
“Now, this is very exciting to us,” she said.
The combination study with lenalidomide and dexamethasone is currently underway.
Palbociclib is being developed by Pfizer.
RIC can improve HSCT outcomes in older AML patients
Photo by Chad McNeeley
Results of a phase 2 study suggest that reduced-intensity conditioning (RIC) may allow older patients with acute myeloid leukemia (AML) to remain in long-term remission after allogeneic hematopoietic stem cell transplant (HSCT).
The study included patients age 60 and older who were in their first complete remission (CR1) at transplant.
Two years later, the probability of overall survival was 48%, and the probability of disease-free survival was 42%.
“This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” said Steven Devine, MD, of The Ohio State University in Columbus.
He and his colleagues shared the data in the Journal of Clinical Oncology.
The researchers wanted to determine whether RIC could improve long-term remission rates after HSCT for older patients with AML.
So the team studied 114 patients with a median age of 65 (range, 60-74) who were treated at 21 US hospitals between November 2004 and November 2011. Most patients were male (62%), and most had intermediate cytogenetics (70%).
All of the patients were in CR1 according to International Working Group criteria. The CR had to be achieved after no more than 2 cycles of induction chemotherapy, and patients were required to undergo HSCT within 6 months of the initial documentation of morphologic CR.
The median time from CR1 documentation to HSCT was 85 days (range, 9-184), and the median time from AML diagnosis to HSCT was 138 days (range, 61-265).
All patients received RIC (fludarabine followed by busulfan) prior to HSCT, which essentially cut treatment strength by half compared to traditional high-dose conditioning. The patients received tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis.
Forty-eight percent of patients underwent HSCT from a matched, related donor, and 52% had a matched, unrelated donor.
At 2 years, disease-free survival was 42%, and overall survival was 48%. Among patients with unrelated donors, disease-free survival was 40%, and overall survival was 50%.
The cumulative incidence of relapse was 44%, and non-relapse mortality was 15%. Twenty-eight percent of patients had chronic GVHD, and 9.6% had grade 2-4 acute GVHD.
“Close to half of the patients treated in this study achieved long-term, cancer-free survival after 2 years,” Dr Devine noted. “These outcomes are similar to what we would expect to see in younger patients and appear to be better results than those that can be achieved with conventional chemotherapy-based approaches typically used in AML patients over 60.”
Photo by Chad McNeeley
Results of a phase 2 study suggest that reduced-intensity conditioning (RIC) may allow older patients with acute myeloid leukemia (AML) to remain in long-term remission after allogeneic hematopoietic stem cell transplant (HSCT).
The study included patients age 60 and older who were in their first complete remission (CR1) at transplant.
Two years later, the probability of overall survival was 48%, and the probability of disease-free survival was 42%.
“This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” said Steven Devine, MD, of The Ohio State University in Columbus.
He and his colleagues shared the data in the Journal of Clinical Oncology.
The researchers wanted to determine whether RIC could improve long-term remission rates after HSCT for older patients with AML.
So the team studied 114 patients with a median age of 65 (range, 60-74) who were treated at 21 US hospitals between November 2004 and November 2011. Most patients were male (62%), and most had intermediate cytogenetics (70%).
All of the patients were in CR1 according to International Working Group criteria. The CR had to be achieved after no more than 2 cycles of induction chemotherapy, and patients were required to undergo HSCT within 6 months of the initial documentation of morphologic CR.
The median time from CR1 documentation to HSCT was 85 days (range, 9-184), and the median time from AML diagnosis to HSCT was 138 days (range, 61-265).
All patients received RIC (fludarabine followed by busulfan) prior to HSCT, which essentially cut treatment strength by half compared to traditional high-dose conditioning. The patients received tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis.
Forty-eight percent of patients underwent HSCT from a matched, related donor, and 52% had a matched, unrelated donor.
At 2 years, disease-free survival was 42%, and overall survival was 48%. Among patients with unrelated donors, disease-free survival was 40%, and overall survival was 50%.
The cumulative incidence of relapse was 44%, and non-relapse mortality was 15%. Twenty-eight percent of patients had chronic GVHD, and 9.6% had grade 2-4 acute GVHD.
“Close to half of the patients treated in this study achieved long-term, cancer-free survival after 2 years,” Dr Devine noted. “These outcomes are similar to what we would expect to see in younger patients and appear to be better results than those that can be achieved with conventional chemotherapy-based approaches typically used in AML patients over 60.”
Photo by Chad McNeeley
Results of a phase 2 study suggest that reduced-intensity conditioning (RIC) may allow older patients with acute myeloid leukemia (AML) to remain in long-term remission after allogeneic hematopoietic stem cell transplant (HSCT).
The study included patients age 60 and older who were in their first complete remission (CR1) at transplant.
Two years later, the probability of overall survival was 48%, and the probability of disease-free survival was 42%.
“This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” said Steven Devine, MD, of The Ohio State University in Columbus.
He and his colleagues shared the data in the Journal of Clinical Oncology.
The researchers wanted to determine whether RIC could improve long-term remission rates after HSCT for older patients with AML.
So the team studied 114 patients with a median age of 65 (range, 60-74) who were treated at 21 US hospitals between November 2004 and November 2011. Most patients were male (62%), and most had intermediate cytogenetics (70%).
All of the patients were in CR1 according to International Working Group criteria. The CR had to be achieved after no more than 2 cycles of induction chemotherapy, and patients were required to undergo HSCT within 6 months of the initial documentation of morphologic CR.
The median time from CR1 documentation to HSCT was 85 days (range, 9-184), and the median time from AML diagnosis to HSCT was 138 days (range, 61-265).
All patients received RIC (fludarabine followed by busulfan) prior to HSCT, which essentially cut treatment strength by half compared to traditional high-dose conditioning. The patients received tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis.
Forty-eight percent of patients underwent HSCT from a matched, related donor, and 52% had a matched, unrelated donor.
At 2 years, disease-free survival was 42%, and overall survival was 48%. Among patients with unrelated donors, disease-free survival was 40%, and overall survival was 50%.
The cumulative incidence of relapse was 44%, and non-relapse mortality was 15%. Twenty-eight percent of patients had chronic GVHD, and 9.6% had grade 2-4 acute GVHD.
“Close to half of the patients treated in this study achieved long-term, cancer-free survival after 2 years,” Dr Devine noted. “These outcomes are similar to what we would expect to see in younger patients and appear to be better results than those that can be achieved with conventional chemotherapy-based approaches typically used in AML patients over 60.”
SDEF: Improved responses with newer topical onychomycosis treatments
LAS VEGAS – Better penetration through the nail is a key driver behind the increased efficacy of newer topical treatments for onychomycosis, affording a better chance for a clinical and mycologic cure without the potential for toxicity that comes with systemic treatments, according to Dr. David M. Pariser.
At the Skin Disease Education Foundation’s annual Las Vegas dermatology seminar, Dr. Pariser, professor in the department of dermatology at Eastern Virginia Medical School, Norfolk, reviewed clinical trial data for 10% topical efinaconazole solution and 5% tavaborole topical solution, newer treatment options for the old problem of nail fungus. “New topical antifungals have improved the challenge of nail penetration,” which had been a key obstacle to efficacy with earlier topical treatments, he said.
Though topical treatments for onychomycosis avoid the risk of systemic side effects and the need for periodic blood tests to check liver function, historically, these treatments have not been very effective, he commented.
Ciclopirox (Penlac), one of the more efficacious treatments, achieves a cure rate of 5.5%-8.5%, and the buildup of the lacquer vehicle requires frequent nail debridement. Because of real or perceived risks, patients may be reluctant to take oral antifungals for onychomycosis, he said, noting that in addition to the potential for liver injury, use of these medications may also be limited by multiple drug-drug interactions.
The two new topical formulations he reviewed have a low molecular weight to allow better penetration through the dense, keratin-rich nail plate, Dr. Pariser said.
One of the topicals, 10% topical efinaconazole solution (Jublia), uses a formulation with low surface tension for good penetration with no surface buildup of vehicle material, achieving better nail penetration than do lacquer-based products, he noted.
A key efinaconazole study assessed clinical improvement in nail appearance in combination with mycologic cure, defined as negative findings on KOH prep exam and negative fungal culture. A complete cure was defined as a “totally clear target toenail and negative KOH/negative fungal culture,” and an “almost complete cure” was defined as mycologic cure, combined with no more than 5% clinically apparent involvement of the target toenail.
After double-blinded randomization into two parallel studies, patients applied either efinaconazole or the vehicle alone once daily at bedtime to the target toenail for 48 weeks. In the studies, 18% and 15% of those in the efinaconazole arm had achieved complete cure 52 weeks after beginning treatment, compared with 3% and 6% of the vehicle arm patients, respectively. However, for a pooled intent-to-treat population, the treatment arm saw a 28% cured or almost-cured rate, compared with 7% of the pooled vehicle-treated patients (P less than .001). Mycologic cure was achieved by 55% and 53% of the patients in the two efinaconazole arms, compared with 17% of the vehicle-only patients in each arm, according to Dr. Pariser.
Adverse events, similar between treatment arms, were mostly mild to moderate and localized, with dermatitis, vesicles, pain, and ingrown toenails the most commonly reported effects.
Tavaborole topical solution, 5% (Kerydin), is a boron-based compound that is highly water soluble, with broad antifungal activity that persists in the presence of keratin. As with efinaconazole, there is no product buildup, so nail debridement is not needed during treatment, Dr. Pariser said.
Two multicenter tavaborole trials compared the active tavaborole solution with a vehicle-only arm in a randomized, double-blind fashion, with product application daily for 48 weeks. The primary efficacy outcome for the trials was complete cure of the target great toenail at week 52. Secondary endpoints were a completely clear or almost clear (10% or less involvement of the target nail) target great toenail, as well as mycologic cure of the nail. Safety was measured by tracking adverse events, and local tolerability, as well as monitoring labs and ECG parameters.
A complete cure for the tavaborole trials required a completely clear nail on clinical exam, as well as negative mycology (negative KOH and negative fungal culture). At 52 weeks, 6.5% and 9.1% of the tavaborole-treated patients saw a complete cure, compared with 0.5% and 1.5% of vehicle-only patients in the two studies. Of those treated with tavaborole, 31.1% and 35.9% achieved mycologic cure, compared with 7.2% and 12.2% of those in the vehicle arm.
The rates of complete or almost complete clearing of the target great toenail for those in the tavaborole arms were 26.1% and 27.5%, compared with 9.3% and 14.6% in the vehicle arms. Predefined treatment success – a combination of mycologic cure and clear or almost clear target great toenail – was seen in 15.3% and 17.9% of the tavaborole-treated patients, compared with 1.5% and 3.9% of the vehicle-only patients (P less than or equal to .001 for all endpoints in both studies).
Treatment-related adverse events were generally mild and similar between the vehicle and treatment arms, with application site exfoliation, erythema, dermatitis, as well as ingrown toenails, the most commonly reported events for both arms.
Dr. Pariser noted that comparing efficacy of the newer agents directly is difficult, since the pivotal clinical trials for each had different designs, entry criteria, clinical assessments, and endpoints.
He disclosed that he is an investigator and consultant for Valeant, which manufactures the 10% topical efinaconazole solution, and an investigator for Anacor Pharmaceuticals, which markets tavaborole.
SDEF and this news organization are owned by the same parent company.
On Twitter @karioakes
LAS VEGAS – Better penetration through the nail is a key driver behind the increased efficacy of newer topical treatments for onychomycosis, affording a better chance for a clinical and mycologic cure without the potential for toxicity that comes with systemic treatments, according to Dr. David M. Pariser.
At the Skin Disease Education Foundation’s annual Las Vegas dermatology seminar, Dr. Pariser, professor in the department of dermatology at Eastern Virginia Medical School, Norfolk, reviewed clinical trial data for 10% topical efinaconazole solution and 5% tavaborole topical solution, newer treatment options for the old problem of nail fungus. “New topical antifungals have improved the challenge of nail penetration,” which had been a key obstacle to efficacy with earlier topical treatments, he said.
Though topical treatments for onychomycosis avoid the risk of systemic side effects and the need for periodic blood tests to check liver function, historically, these treatments have not been very effective, he commented.
Ciclopirox (Penlac), one of the more efficacious treatments, achieves a cure rate of 5.5%-8.5%, and the buildup of the lacquer vehicle requires frequent nail debridement. Because of real or perceived risks, patients may be reluctant to take oral antifungals for onychomycosis, he said, noting that in addition to the potential for liver injury, use of these medications may also be limited by multiple drug-drug interactions.
The two new topical formulations he reviewed have a low molecular weight to allow better penetration through the dense, keratin-rich nail plate, Dr. Pariser said.
One of the topicals, 10% topical efinaconazole solution (Jublia), uses a formulation with low surface tension for good penetration with no surface buildup of vehicle material, achieving better nail penetration than do lacquer-based products, he noted.
A key efinaconazole study assessed clinical improvement in nail appearance in combination with mycologic cure, defined as negative findings on KOH prep exam and negative fungal culture. A complete cure was defined as a “totally clear target toenail and negative KOH/negative fungal culture,” and an “almost complete cure” was defined as mycologic cure, combined with no more than 5% clinically apparent involvement of the target toenail.
After double-blinded randomization into two parallel studies, patients applied either efinaconazole or the vehicle alone once daily at bedtime to the target toenail for 48 weeks. In the studies, 18% and 15% of those in the efinaconazole arm had achieved complete cure 52 weeks after beginning treatment, compared with 3% and 6% of the vehicle arm patients, respectively. However, for a pooled intent-to-treat population, the treatment arm saw a 28% cured or almost-cured rate, compared with 7% of the pooled vehicle-treated patients (P less than .001). Mycologic cure was achieved by 55% and 53% of the patients in the two efinaconazole arms, compared with 17% of the vehicle-only patients in each arm, according to Dr. Pariser.
Adverse events, similar between treatment arms, were mostly mild to moderate and localized, with dermatitis, vesicles, pain, and ingrown toenails the most commonly reported effects.
Tavaborole topical solution, 5% (Kerydin), is a boron-based compound that is highly water soluble, with broad antifungal activity that persists in the presence of keratin. As with efinaconazole, there is no product buildup, so nail debridement is not needed during treatment, Dr. Pariser said.
Two multicenter tavaborole trials compared the active tavaborole solution with a vehicle-only arm in a randomized, double-blind fashion, with product application daily for 48 weeks. The primary efficacy outcome for the trials was complete cure of the target great toenail at week 52. Secondary endpoints were a completely clear or almost clear (10% or less involvement of the target nail) target great toenail, as well as mycologic cure of the nail. Safety was measured by tracking adverse events, and local tolerability, as well as monitoring labs and ECG parameters.
A complete cure for the tavaborole trials required a completely clear nail on clinical exam, as well as negative mycology (negative KOH and negative fungal culture). At 52 weeks, 6.5% and 9.1% of the tavaborole-treated patients saw a complete cure, compared with 0.5% and 1.5% of vehicle-only patients in the two studies. Of those treated with tavaborole, 31.1% and 35.9% achieved mycologic cure, compared with 7.2% and 12.2% of those in the vehicle arm.
The rates of complete or almost complete clearing of the target great toenail for those in the tavaborole arms were 26.1% and 27.5%, compared with 9.3% and 14.6% in the vehicle arms. Predefined treatment success – a combination of mycologic cure and clear or almost clear target great toenail – was seen in 15.3% and 17.9% of the tavaborole-treated patients, compared with 1.5% and 3.9% of the vehicle-only patients (P less than or equal to .001 for all endpoints in both studies).
Treatment-related adverse events were generally mild and similar between the vehicle and treatment arms, with application site exfoliation, erythema, dermatitis, as well as ingrown toenails, the most commonly reported events for both arms.
Dr. Pariser noted that comparing efficacy of the newer agents directly is difficult, since the pivotal clinical trials for each had different designs, entry criteria, clinical assessments, and endpoints.
He disclosed that he is an investigator and consultant for Valeant, which manufactures the 10% topical efinaconazole solution, and an investigator for Anacor Pharmaceuticals, which markets tavaborole.
SDEF and this news organization are owned by the same parent company.
On Twitter @karioakes
LAS VEGAS – Better penetration through the nail is a key driver behind the increased efficacy of newer topical treatments for onychomycosis, affording a better chance for a clinical and mycologic cure without the potential for toxicity that comes with systemic treatments, according to Dr. David M. Pariser.
At the Skin Disease Education Foundation’s annual Las Vegas dermatology seminar, Dr. Pariser, professor in the department of dermatology at Eastern Virginia Medical School, Norfolk, reviewed clinical trial data for 10% topical efinaconazole solution and 5% tavaborole topical solution, newer treatment options for the old problem of nail fungus. “New topical antifungals have improved the challenge of nail penetration,” which had been a key obstacle to efficacy with earlier topical treatments, he said.
Though topical treatments for onychomycosis avoid the risk of systemic side effects and the need for periodic blood tests to check liver function, historically, these treatments have not been very effective, he commented.
Ciclopirox (Penlac), one of the more efficacious treatments, achieves a cure rate of 5.5%-8.5%, and the buildup of the lacquer vehicle requires frequent nail debridement. Because of real or perceived risks, patients may be reluctant to take oral antifungals for onychomycosis, he said, noting that in addition to the potential for liver injury, use of these medications may also be limited by multiple drug-drug interactions.
The two new topical formulations he reviewed have a low molecular weight to allow better penetration through the dense, keratin-rich nail plate, Dr. Pariser said.
One of the topicals, 10% topical efinaconazole solution (Jublia), uses a formulation with low surface tension for good penetration with no surface buildup of vehicle material, achieving better nail penetration than do lacquer-based products, he noted.
A key efinaconazole study assessed clinical improvement in nail appearance in combination with mycologic cure, defined as negative findings on KOH prep exam and negative fungal culture. A complete cure was defined as a “totally clear target toenail and negative KOH/negative fungal culture,” and an “almost complete cure” was defined as mycologic cure, combined with no more than 5% clinically apparent involvement of the target toenail.
After double-blinded randomization into two parallel studies, patients applied either efinaconazole or the vehicle alone once daily at bedtime to the target toenail for 48 weeks. In the studies, 18% and 15% of those in the efinaconazole arm had achieved complete cure 52 weeks after beginning treatment, compared with 3% and 6% of the vehicle arm patients, respectively. However, for a pooled intent-to-treat population, the treatment arm saw a 28% cured or almost-cured rate, compared with 7% of the pooled vehicle-treated patients (P less than .001). Mycologic cure was achieved by 55% and 53% of the patients in the two efinaconazole arms, compared with 17% of the vehicle-only patients in each arm, according to Dr. Pariser.
Adverse events, similar between treatment arms, were mostly mild to moderate and localized, with dermatitis, vesicles, pain, and ingrown toenails the most commonly reported effects.
Tavaborole topical solution, 5% (Kerydin), is a boron-based compound that is highly water soluble, with broad antifungal activity that persists in the presence of keratin. As with efinaconazole, there is no product buildup, so nail debridement is not needed during treatment, Dr. Pariser said.
Two multicenter tavaborole trials compared the active tavaborole solution with a vehicle-only arm in a randomized, double-blind fashion, with product application daily for 48 weeks. The primary efficacy outcome for the trials was complete cure of the target great toenail at week 52. Secondary endpoints were a completely clear or almost clear (10% or less involvement of the target nail) target great toenail, as well as mycologic cure of the nail. Safety was measured by tracking adverse events, and local tolerability, as well as monitoring labs and ECG parameters.
A complete cure for the tavaborole trials required a completely clear nail on clinical exam, as well as negative mycology (negative KOH and negative fungal culture). At 52 weeks, 6.5% and 9.1% of the tavaborole-treated patients saw a complete cure, compared with 0.5% and 1.5% of vehicle-only patients in the two studies. Of those treated with tavaborole, 31.1% and 35.9% achieved mycologic cure, compared with 7.2% and 12.2% of those in the vehicle arm.
The rates of complete or almost complete clearing of the target great toenail for those in the tavaborole arms were 26.1% and 27.5%, compared with 9.3% and 14.6% in the vehicle arms. Predefined treatment success – a combination of mycologic cure and clear or almost clear target great toenail – was seen in 15.3% and 17.9% of the tavaborole-treated patients, compared with 1.5% and 3.9% of the vehicle-only patients (P less than or equal to .001 for all endpoints in both studies).
Treatment-related adverse events were generally mild and similar between the vehicle and treatment arms, with application site exfoliation, erythema, dermatitis, as well as ingrown toenails, the most commonly reported events for both arms.
Dr. Pariser noted that comparing efficacy of the newer agents directly is difficult, since the pivotal clinical trials for each had different designs, entry criteria, clinical assessments, and endpoints.
He disclosed that he is an investigator and consultant for Valeant, which manufactures the 10% topical efinaconazole solution, and an investigator for Anacor Pharmaceuticals, which markets tavaborole.
SDEF and this news organization are owned by the same parent company.
On Twitter @karioakes
EXPERT ANALYSIS FROM SDEF LAS VEGAS DERMATOLOGY SEMINAR
Providing ambivalent medical advice
When did some doctors become so wishy-washy?
A large part of what we do is guide people through an often-confusing maze of test results and treatment options. I respect patients’ right to make their own decisions, but it came as a surprise to me to find that some doctors are turning such things over to the patients. After all, doctors are the ones who went through over a decade of training to understand the risks, benefits, and goals of each step for them. Granted, I live in Arizona, where you don’t need a doctor’s order to have labs done. You can research whatever you want on Google, decide what work-up you need, and go get whatever labs you want done.
But back to my original point. Recently, one of my patients was admitted to the hospital, then followed up with me in the office. I looked through his test results and told him what I felt the next step should be, ordered a few things, and wrote an instruction sheet to start daily aspirin. I commented that it surprised me the last hadn’t been done as an inpatient.
His answer? “They said I could if I wanted to, but didn’t make a clear suggestion.” I figured this was a simple miscommunication, so I pulled up the hospital chart on my computer. There I found a note from the attending that said, “The patient was told he may or may not want to take a daily aspirin, and that doing so might or might not be to his benefit.” What on Earth?
I understand there are no guarantees in this job. There’s no crystal ball to know for sure that what we’re doing is right. Any drug can cause serious and unexpected complications. We take calculated risks and hope we come out ahead. But to phrase it like this? Where the patient isn’t given the guidance we’re supposed to provide? What’s the point of even being a doctor?
Since then, I’ve noticed similar phrasing in other charts: “We discussed doing a brain MRI, and she’ll let me know what she decides” and “I told her that starting Lamictal may or may not prevent seizures, and to consider it as something she should or shouldn’t do.”
I’m sure some of it is part of the hurried flight-of-ideas dictations we all do when we’re busy at the hospital. There’s also a component of legalese to make sure that we documented discussing risks with the patient.
But I still don’t get the ambivalence. In similar situations, I provide guidance and advice and tell people what I think they should do. I’m not going to force anyone to do anything they don’t want to. If they disagree, I note it and make whatever suggestions I think will help. In the end, it’s their decision. I get that.
When I take my car to get fixed, I don’t want the mechanic to tell me what may or may not need to be repaired, and I hope patients see me the same way.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
When did some doctors become so wishy-washy?
A large part of what we do is guide people through an often-confusing maze of test results and treatment options. I respect patients’ right to make their own decisions, but it came as a surprise to me to find that some doctors are turning such things over to the patients. After all, doctors are the ones who went through over a decade of training to understand the risks, benefits, and goals of each step for them. Granted, I live in Arizona, where you don’t need a doctor’s order to have labs done. You can research whatever you want on Google, decide what work-up you need, and go get whatever labs you want done.
But back to my original point. Recently, one of my patients was admitted to the hospital, then followed up with me in the office. I looked through his test results and told him what I felt the next step should be, ordered a few things, and wrote an instruction sheet to start daily aspirin. I commented that it surprised me the last hadn’t been done as an inpatient.
His answer? “They said I could if I wanted to, but didn’t make a clear suggestion.” I figured this was a simple miscommunication, so I pulled up the hospital chart on my computer. There I found a note from the attending that said, “The patient was told he may or may not want to take a daily aspirin, and that doing so might or might not be to his benefit.” What on Earth?
I understand there are no guarantees in this job. There’s no crystal ball to know for sure that what we’re doing is right. Any drug can cause serious and unexpected complications. We take calculated risks and hope we come out ahead. But to phrase it like this? Where the patient isn’t given the guidance we’re supposed to provide? What’s the point of even being a doctor?
Since then, I’ve noticed similar phrasing in other charts: “We discussed doing a brain MRI, and she’ll let me know what she decides” and “I told her that starting Lamictal may or may not prevent seizures, and to consider it as something she should or shouldn’t do.”
I’m sure some of it is part of the hurried flight-of-ideas dictations we all do when we’re busy at the hospital. There’s also a component of legalese to make sure that we documented discussing risks with the patient.
But I still don’t get the ambivalence. In similar situations, I provide guidance and advice and tell people what I think they should do. I’m not going to force anyone to do anything they don’t want to. If they disagree, I note it and make whatever suggestions I think will help. In the end, it’s their decision. I get that.
When I take my car to get fixed, I don’t want the mechanic to tell me what may or may not need to be repaired, and I hope patients see me the same way.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
When did some doctors become so wishy-washy?
A large part of what we do is guide people through an often-confusing maze of test results and treatment options. I respect patients’ right to make their own decisions, but it came as a surprise to me to find that some doctors are turning such things over to the patients. After all, doctors are the ones who went through over a decade of training to understand the risks, benefits, and goals of each step for them. Granted, I live in Arizona, where you don’t need a doctor’s order to have labs done. You can research whatever you want on Google, decide what work-up you need, and go get whatever labs you want done.
But back to my original point. Recently, one of my patients was admitted to the hospital, then followed up with me in the office. I looked through his test results and told him what I felt the next step should be, ordered a few things, and wrote an instruction sheet to start daily aspirin. I commented that it surprised me the last hadn’t been done as an inpatient.
His answer? “They said I could if I wanted to, but didn’t make a clear suggestion.” I figured this was a simple miscommunication, so I pulled up the hospital chart on my computer. There I found a note from the attending that said, “The patient was told he may or may not want to take a daily aspirin, and that doing so might or might not be to his benefit.” What on Earth?
I understand there are no guarantees in this job. There’s no crystal ball to know for sure that what we’re doing is right. Any drug can cause serious and unexpected complications. We take calculated risks and hope we come out ahead. But to phrase it like this? Where the patient isn’t given the guidance we’re supposed to provide? What’s the point of even being a doctor?
Since then, I’ve noticed similar phrasing in other charts: “We discussed doing a brain MRI, and she’ll let me know what she decides” and “I told her that starting Lamictal may or may not prevent seizures, and to consider it as something she should or shouldn’t do.”
I’m sure some of it is part of the hurried flight-of-ideas dictations we all do when we’re busy at the hospital. There’s also a component of legalese to make sure that we documented discussing risks with the patient.
But I still don’t get the ambivalence. In similar situations, I provide guidance and advice and tell people what I think they should do. I’m not going to force anyone to do anything they don’t want to. If they disagree, I note it and make whatever suggestions I think will help. In the end, it’s their decision. I get that.
When I take my car to get fixed, I don’t want the mechanic to tell me what may or may not need to be repaired, and I hope patients see me the same way.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
TCT: Lower MI, thrombosis, higher bleeding with extended DAPT in patients with everolimus-eluting stents
SAN FRANCISCO – Continued thienopyridine therapy beyond 1 year in patients treated with an everolimus-eluting stent was associated with significantly lower rates of myocardial infarction and thrombosis, but an increased risk of bleeding, study results have shown.
Dr. James B. Hermiller of St. Vincent´s Medical Group, Indianapolis, presented the data at the Transcatheter Cardiovascular Therapeutics annual meeting. The results were also published online (JACC: Cardiovasc Interv 2015. doi: 10.1016/j.jcin.2015.10.001).
In a post hoc analysis of a subset of patients from the DAPT (Dual Antiplatelet Therapy) study, Dr. James B. Hermiller Jr. and his colleagues evaluated major adverse cardiac and cerebrovascular event (MACCE) and bleeding events in 4,703 patients who’d been treated with an everolimus-eluting stent and 1 year of therapy with thienopyridine and aspirin before being randomly assigned to 18 additional months of the same DAPT, or an additional 18 months of aspirin plus placebo.
The original DAPT Study, a multisite, international, double-blinded, trial of 25,682 coronary stent patients was done to evaluate the efficacy and safety of various combinations of types of drug-eluting stents plus DAPT.
Results from the subanalysis of the everolimus-eluting stent group were that at 12-30 months post percutaneous intervention, those given additional DAPT had significantly reduced thrombosis (P =.04) and MI (P =.01), compared with aspirin-only controls, but the DAPT test cohort had more moderate to severe bleeding complications (P = .01). Composite death, MI, or stroke rates were also better in the placebo group (P = .42), Dr. Hermiller said at the meeting sponsored by the Cardiovascular Research Foundation.
The continuous-DAPT group had a stent thrombosis rate of 0.3%, compared with 0.7% of the 12-month–only group (hazard ratio, 0.38). The rate of MI in the test group was 2.11% vs. 3.2% in controls (HR, 0.63). The DAPT test group had a 2.5% rate of increased bleeding vs. 1.3% in the placebo group (HR, 1.79).
Patients in the subanalysis were typically older than across all original study groups – typically, men in their early 60s who were more likely to have been treated with clopidogrel (84.4% vs. 48.2%), and to have a slightly lower body mass index, although they were still obese (30.3 vs. 30.8 kg/m2).
The subanalysis group also had a slightly higher rate of history of cancer (P less than .001), a data point that Dr. Hermiller and his coauthors noted in the study accounted for the DAPT continuation group’s significantly increased all-cause mortality, compared with the placebo group (2.2% vs. 1.1%, P =.02).
In an interview, Dr. Spencer B. King, president of the Heart and Vascular Institute of St. Joseph’s Health System in Georgia, and comoderator of the session where the data were presented, also emphasized this finding’s importance, since “cancer increases bleeding risk and is one of the conditions in which prolonged DAPT should usually be avoided.”
The most frequent cause of noncardiovascular death in the DAPT-continuation group was cancer: 18 of the test group vs. 4 in the placebo group (P =.002); 3 of the study group’s cancer deaths involved bleeding. Overall, the second most common cause of death was bleeding, which occurred more in the DAPT test group than in placebo (P = .04).
Dr. Hermiller and his coauthors wrote that the therapeutic window for continued thienopyridine therapy “may be narrow” since the number needed to treat to benefit for stent thrombosis was 235 over 18 months. For MI it was 98. The number needed to treat to harm for moderate or severe bleeding was 84.
“Therefore, meticulous assessment of bleeding risk should always impact decisions regarding thienopyridine therapy duration.”
However, they also noted that current data suggest a net benefit to continuing therapy with absolute reductions in stent thrombosis or MI of about 0.2%, an effect that was exceeded in the everolimus-eluting stent patient subset.
Dr. Hermiller is a consultant for Abbott Vascular, Boston Scientific, Medtronic, and St. Jude Medical. The study also was sponsored by the Harvard Clinical Research Institute Harvard Clinical Research Institute and funded by Abbott, Boston Scientific Corporation, Cordis Corporation, Medtronic, Bristol-Myers Squibb Company/Sanofi Pharmaceuticals Partnership, Eli Lilly and Company, and Daiichi Sankyo Company Limited and the U.S. Department of Health & Human Services.
On Twitter @whitneymcknight
SAN FRANCISCO – Continued thienopyridine therapy beyond 1 year in patients treated with an everolimus-eluting stent was associated with significantly lower rates of myocardial infarction and thrombosis, but an increased risk of bleeding, study results have shown.
Dr. James B. Hermiller of St. Vincent´s Medical Group, Indianapolis, presented the data at the Transcatheter Cardiovascular Therapeutics annual meeting. The results were also published online (JACC: Cardiovasc Interv 2015. doi: 10.1016/j.jcin.2015.10.001).
In a post hoc analysis of a subset of patients from the DAPT (Dual Antiplatelet Therapy) study, Dr. James B. Hermiller Jr. and his colleagues evaluated major adverse cardiac and cerebrovascular event (MACCE) and bleeding events in 4,703 patients who’d been treated with an everolimus-eluting stent and 1 year of therapy with thienopyridine and aspirin before being randomly assigned to 18 additional months of the same DAPT, or an additional 18 months of aspirin plus placebo.
The original DAPT Study, a multisite, international, double-blinded, trial of 25,682 coronary stent patients was done to evaluate the efficacy and safety of various combinations of types of drug-eluting stents plus DAPT.
Results from the subanalysis of the everolimus-eluting stent group were that at 12-30 months post percutaneous intervention, those given additional DAPT had significantly reduced thrombosis (P =.04) and MI (P =.01), compared with aspirin-only controls, but the DAPT test cohort had more moderate to severe bleeding complications (P = .01). Composite death, MI, or stroke rates were also better in the placebo group (P = .42), Dr. Hermiller said at the meeting sponsored by the Cardiovascular Research Foundation.
The continuous-DAPT group had a stent thrombosis rate of 0.3%, compared with 0.7% of the 12-month–only group (hazard ratio, 0.38). The rate of MI in the test group was 2.11% vs. 3.2% in controls (HR, 0.63). The DAPT test group had a 2.5% rate of increased bleeding vs. 1.3% in the placebo group (HR, 1.79).
Patients in the subanalysis were typically older than across all original study groups – typically, men in their early 60s who were more likely to have been treated with clopidogrel (84.4% vs. 48.2%), and to have a slightly lower body mass index, although they were still obese (30.3 vs. 30.8 kg/m2).
The subanalysis group also had a slightly higher rate of history of cancer (P less than .001), a data point that Dr. Hermiller and his coauthors noted in the study accounted for the DAPT continuation group’s significantly increased all-cause mortality, compared with the placebo group (2.2% vs. 1.1%, P =.02).
In an interview, Dr. Spencer B. King, president of the Heart and Vascular Institute of St. Joseph’s Health System in Georgia, and comoderator of the session where the data were presented, also emphasized this finding’s importance, since “cancer increases bleeding risk and is one of the conditions in which prolonged DAPT should usually be avoided.”
The most frequent cause of noncardiovascular death in the DAPT-continuation group was cancer: 18 of the test group vs. 4 in the placebo group (P =.002); 3 of the study group’s cancer deaths involved bleeding. Overall, the second most common cause of death was bleeding, which occurred more in the DAPT test group than in placebo (P = .04).
Dr. Hermiller and his coauthors wrote that the therapeutic window for continued thienopyridine therapy “may be narrow” since the number needed to treat to benefit for stent thrombosis was 235 over 18 months. For MI it was 98. The number needed to treat to harm for moderate or severe bleeding was 84.
“Therefore, meticulous assessment of bleeding risk should always impact decisions regarding thienopyridine therapy duration.”
However, they also noted that current data suggest a net benefit to continuing therapy with absolute reductions in stent thrombosis or MI of about 0.2%, an effect that was exceeded in the everolimus-eluting stent patient subset.
Dr. Hermiller is a consultant for Abbott Vascular, Boston Scientific, Medtronic, and St. Jude Medical. The study also was sponsored by the Harvard Clinical Research Institute Harvard Clinical Research Institute and funded by Abbott, Boston Scientific Corporation, Cordis Corporation, Medtronic, Bristol-Myers Squibb Company/Sanofi Pharmaceuticals Partnership, Eli Lilly and Company, and Daiichi Sankyo Company Limited and the U.S. Department of Health & Human Services.
On Twitter @whitneymcknight
SAN FRANCISCO – Continued thienopyridine therapy beyond 1 year in patients treated with an everolimus-eluting stent was associated with significantly lower rates of myocardial infarction and thrombosis, but an increased risk of bleeding, study results have shown.
Dr. James B. Hermiller of St. Vincent´s Medical Group, Indianapolis, presented the data at the Transcatheter Cardiovascular Therapeutics annual meeting. The results were also published online (JACC: Cardiovasc Interv 2015. doi: 10.1016/j.jcin.2015.10.001).
In a post hoc analysis of a subset of patients from the DAPT (Dual Antiplatelet Therapy) study, Dr. James B. Hermiller Jr. and his colleagues evaluated major adverse cardiac and cerebrovascular event (MACCE) and bleeding events in 4,703 patients who’d been treated with an everolimus-eluting stent and 1 year of therapy with thienopyridine and aspirin before being randomly assigned to 18 additional months of the same DAPT, or an additional 18 months of aspirin plus placebo.
The original DAPT Study, a multisite, international, double-blinded, trial of 25,682 coronary stent patients was done to evaluate the efficacy and safety of various combinations of types of drug-eluting stents plus DAPT.
Results from the subanalysis of the everolimus-eluting stent group were that at 12-30 months post percutaneous intervention, those given additional DAPT had significantly reduced thrombosis (P =.04) and MI (P =.01), compared with aspirin-only controls, but the DAPT test cohort had more moderate to severe bleeding complications (P = .01). Composite death, MI, or stroke rates were also better in the placebo group (P = .42), Dr. Hermiller said at the meeting sponsored by the Cardiovascular Research Foundation.
The continuous-DAPT group had a stent thrombosis rate of 0.3%, compared with 0.7% of the 12-month–only group (hazard ratio, 0.38). The rate of MI in the test group was 2.11% vs. 3.2% in controls (HR, 0.63). The DAPT test group had a 2.5% rate of increased bleeding vs. 1.3% in the placebo group (HR, 1.79).
Patients in the subanalysis were typically older than across all original study groups – typically, men in their early 60s who were more likely to have been treated with clopidogrel (84.4% vs. 48.2%), and to have a slightly lower body mass index, although they were still obese (30.3 vs. 30.8 kg/m2).
The subanalysis group also had a slightly higher rate of history of cancer (P less than .001), a data point that Dr. Hermiller and his coauthors noted in the study accounted for the DAPT continuation group’s significantly increased all-cause mortality, compared with the placebo group (2.2% vs. 1.1%, P =.02).
In an interview, Dr. Spencer B. King, president of the Heart and Vascular Institute of St. Joseph’s Health System in Georgia, and comoderator of the session where the data were presented, also emphasized this finding’s importance, since “cancer increases bleeding risk and is one of the conditions in which prolonged DAPT should usually be avoided.”
The most frequent cause of noncardiovascular death in the DAPT-continuation group was cancer: 18 of the test group vs. 4 in the placebo group (P =.002); 3 of the study group’s cancer deaths involved bleeding. Overall, the second most common cause of death was bleeding, which occurred more in the DAPT test group than in placebo (P = .04).
Dr. Hermiller and his coauthors wrote that the therapeutic window for continued thienopyridine therapy “may be narrow” since the number needed to treat to benefit for stent thrombosis was 235 over 18 months. For MI it was 98. The number needed to treat to harm for moderate or severe bleeding was 84.
“Therefore, meticulous assessment of bleeding risk should always impact decisions regarding thienopyridine therapy duration.”
However, they also noted that current data suggest a net benefit to continuing therapy with absolute reductions in stent thrombosis or MI of about 0.2%, an effect that was exceeded in the everolimus-eluting stent patient subset.
Dr. Hermiller is a consultant for Abbott Vascular, Boston Scientific, Medtronic, and St. Jude Medical. The study also was sponsored by the Harvard Clinical Research Institute Harvard Clinical Research Institute and funded by Abbott, Boston Scientific Corporation, Cordis Corporation, Medtronic, Bristol-Myers Squibb Company/Sanofi Pharmaceuticals Partnership, Eli Lilly and Company, and Daiichi Sankyo Company Limited and the U.S. Department of Health & Human Services.
On Twitter @whitneymcknight
AT TCT 2015
Key clinical point: The window of extended DAPT therapy may be narrow in patients stented with an everolimus-eluting stent.
Major finding: Patients randomly assigned to 18 months of thienopyridine plus aspirin after 1 year of DAPT had significantly reduced thrombosis (P = .04) and MI (P = .01) vs. placebo plus aspirin but more bleeding (P = .01).
Data source: Subanalysis of 4,703 patients from a double-blind, international, multisite, randomized, controlled trial of 25,682 patients.
Disclosures: Dr. Hermiller is a consultant for Abbott Vascular, Boston Scientific, Medtronic, and St. Jude Medical. The study also was sponsored by the Harvard Clinical Research Institute Harvard Clinical Research Institute and funded by Abbott, Boston Scientific Corporation, Cordis Corporation, Medtronic, Bristol-Myers Squibb Company/Sanofi Pharmaceuticals Partnership, Eli Lilly and Company, and Daiichi Sankyo Company Limited and the U.S. Department of Health & Human Services.
New therapies finding their place in management of follicular lymphoma
SAN FRANCISCO – A variety of emerging therapies are being incorporated into the management of follicular lymphoma, which is typically a long-term endeavor requiring strategic use of multiple treatments, Dr. Andrew D. Zelenetz said at the National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies.
“Follicular lymphoma is a disease of paradox. The reality is that overall survival is excellent, but patients are not going to be able to do that with one treatment; they are going to get a series of treatments,” he said. “Survival is the sum of your exposures to treatment, time on active therapy, time in remission, and actually time with relapse not needing treatment.”
Risk stratification
Overall survival for patients with follicular lymphoma diagnosed today and treated with modern therapy is only slightly inferior to that for age-matched controls, noted Dr. Zelenetz of the department of medicine at Memorial Sloan-Kettering Cancer Center and professor of medicine at Cornell University, both in New York.
But patients who are faring poorly at 12 months (American Society of Hematology [ASH] 2014, Abstract 1664) or at 24 months (J Clin Oncol. 2015;33[23]:2516-22) into care have a much worse prognosis. “This shows the importance of identifying those patients with poor biology, and [the question of] whether we can identify them without treating them first and having them progress,” he said.
Hematologists have historically looked to the Follicular Lymphoma International Prognostic Index (FLIPI) to estimate outcome. “The FLIPI clearly works; it’s an important clinical tool. But the FLIPI high-risk patients are still identifying more than those very high-risk patients,” he said.
Therefore, a clinicogenomic risk model was developed that incorporates seven mutations having poor prognostic impact, the m7-FLIPI (Lancet Oncol. 2015;16[9]:1111-22). Adding the mutations split the previously defined high-risk patients into a group with a prognosis similar to that of low-risk patients and a small group with a very poor prognosis.
“This actually represents something very close to the 20% of patients that we think have bad biology,” Dr. Zelenetz noted. “There will be some additional data at ASH looking at this exact question, because the holy grail is to know when you diagnose someone if they are in that bad-risk group because those are the patients you want to do novel clinical trials on. If your overall survival is equivalent to the general population, it’s going to be hard to ever prove an overall survival advantage for an intervention in an unselected group of patients.”
Advanced-stage disease with low tumor bulk
For patients who have advanced-stage follicular lymphoma but with low tumor bulk, the NCCN endorses a modification of criteria developed by the Follicular Lymphoma Study Group (GELF) in deciding when to start treatment (J Clin Oncol. 1998;16[7]:2332-8).
Roughly a fifth of patients who are eligible for and managed with a watch-and-wait approach will not need chemotherapy or die of their disease in the next 10 years (Lancet. 2003;362[9383]:516-22). Furthermore, this strategy nets a median delay in the need for chemotherapy of 2.6 years.
Compared with observation, treatment with the anti-CD20 antibody rituximab (Rituxan) improves progression-free survival but not overall survival in this setting (ASH 2010, Abstract 6). “Though in selected patients, rituximab may be appropriate as initial treatment for the observable patient, I would argue for the observable patient with no survival disadvantage, the standard of care remains observation,” Dr. Zelenetz said.
Advanced-stage disease requiring treatment
A meta-analysis has shown a clear survival benefit from adding rituximab to chemotherapy (R-chemo) in patients with advanced follicular lymphoma who need treatment (J Natl Cancer Inst. 2007;99[9]:706-14). “Based on the results, it is the standard of care to add rituximab to a chemotherapy backbone, but the optimum R-chemo actually remains undefined and would be customized to the individual clinical situation,” he commented.
A variety of emerging agents are being tested in this setting. Among the subset of patients with untreated follicular lymphoma in a single-center trial, the combination of rituximab with the immunomodulator lenalidomide (Revlimid) yielded an overall response rate of 98% and a complete response rate of 87%, as well as excellent progression-free and overall survival (Lancet Oncol. 2014;15[12]:1311-8). The main grade 3 or 4 toxicity was neutropenia, seen in 35% of all patients studied. Efficacy results were much the same in a multicenter trial (International Conference on Malignant Lymphoma [ICML] 2013, Abstract 63).
This combination is now being tested as front-line therapy for follicular lymphoma in the RELEVANCE (Rituximab and Lenalidomide Versus Any Chemotherapy) phase III trial. “The trial is now done, but we don’t have results, and we won’t have results until 2019, so don’t hold your breath,” Dr. Zelenetz commented. “That’s because this was an unselected trial; we took all patients, all comers. And if you don’t try to identify bad-risk patients, you actually have to do very large trials, and the effect size is relatively small.”
Relapsed and refractory disease
“Many times when patients with follicular lymphoma relapse, they are immediately started on treatment. It’s not necessary and probably in most cases not appropriate. If patients are asymptomatic and have a low tumor burden, they can have a second and a third and even a fourth period of observation, where they don’t need active treatment,” he said. “So I would encourage you to …wait until they actually meet GELF criteria again.”
A key question in this setting is whether patients previously given rituximab can derive benefit from an alternative anti-CD20 antibody. Taking on this question, the GADOLIN trial tested the addition of obinutuzumab (induction plus maintenance) to bendamustine among patients with rituximab-refractory disease (American Society of Clinical Oncology [ASCO] 2015, Abstract LBA8502; ICML 2015, Abstract 123).
Toxicities were generally similar by arm, except for a higher rate of infusion-related reactions with obinutuzumab. The overall response rates were comparable for the two arms, but progression-free survival was better with the combination (median event-free survival, not reached, vs. 14.9 months; hazard ratio, 0.55), and there was a trend for overall survival.
“These curves start separating after 6 months, and 6 months is the time of chemotherapy,” Dr. Zelenetz noted. “So I would argue from these data that the obinutuzumab didn’t add very much to the bendamustine backbone, but actually the obinutuzumab maintenance was effective even in rituximab-refractory patients.”
The combination of lenalidomide and rituximab has been compared with lenalidomide alone in patients with relapsed follicular lymphoma (ASCO 2012, Abstract 8000). The results showed a trend toward better median event-free survival with the combination (2.0 vs. 1.2 years; hazard ratio, 1.9; P = .061) but not overall survival.
In a phase II trial, idelalisib (Zydelig) was tested among patients with indolent non-Hodgkin lymphomas (60% with follicular lymphoma) that were refractory to both rituximab and an alkylator (N Engl J Med. 2014;370:1008-18). Noteworthy grade 3 or worse toxicities included pneumonia and transaminase elevations. The overall response rate was 57%, and the complete response rate was 6%; median progression-free survival was 11 months.
“Idelalisib can be safely combined with other agents including rituximab and bendamustine,” Dr. Zelenetz added (ASH 2014, Abstract 3063). “Interestingly, the overall response seems to be a little higher when you combine it, but it doesn’t seem to matter which drug you combine it with – rituximab, bendamustine, or [both] – you get good overall responses,” ranging from 71% to 85%.
The BCL-2 inhibitor venetoclax (formerly ABT-199/GDC-199) has been tested in non-Hodgkin lymphomas, where it has not been associated with the life-threatening tumor lysis syndrome seen in some other hematologic malignancies (European Hematology Association [EHA] 2015, Davis et al). It yielded an overall response rate of 31% in patients with relatively refractory follicular lymphoma. “This will lead to additional studies in this area,” he predicted.
Finally, nivolumab (Opdivo), a PD-1 immune checkpoint inhibitor, has been evaluated in a phase I study in relapsed or refractory hematologic malignancies, where it was well tolerated (ASH 2014, Abstract 291). Among the small subset of patients with follicular lymphoma, the overall response rate was 40%, prompting initiation of more trials.
Although chimeric antigen receptor (CAR) T-cell therapy is showing promise in various malignancies, Dr. Zelenetz said that other options are probably better avenues for research in follicular lymphoma at present.
“I’m much more interested in the tools that we have now, between the checkpoint inhibitors, the T-cell activators, and the bispecific monoclonal antibodies. I think I can [apply these therapies] with less money for probably less toxicity without the complexity of having to make a customized drug for the patient,” he said. “So I’m not very enthusiastic about CAR T cells in follicular lymphoma.”
SAN FRANCISCO – A variety of emerging therapies are being incorporated into the management of follicular lymphoma, which is typically a long-term endeavor requiring strategic use of multiple treatments, Dr. Andrew D. Zelenetz said at the National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies.
“Follicular lymphoma is a disease of paradox. The reality is that overall survival is excellent, but patients are not going to be able to do that with one treatment; they are going to get a series of treatments,” he said. “Survival is the sum of your exposures to treatment, time on active therapy, time in remission, and actually time with relapse not needing treatment.”
Risk stratification
Overall survival for patients with follicular lymphoma diagnosed today and treated with modern therapy is only slightly inferior to that for age-matched controls, noted Dr. Zelenetz of the department of medicine at Memorial Sloan-Kettering Cancer Center and professor of medicine at Cornell University, both in New York.
But patients who are faring poorly at 12 months (American Society of Hematology [ASH] 2014, Abstract 1664) or at 24 months (J Clin Oncol. 2015;33[23]:2516-22) into care have a much worse prognosis. “This shows the importance of identifying those patients with poor biology, and [the question of] whether we can identify them without treating them first and having them progress,” he said.
Hematologists have historically looked to the Follicular Lymphoma International Prognostic Index (FLIPI) to estimate outcome. “The FLIPI clearly works; it’s an important clinical tool. But the FLIPI high-risk patients are still identifying more than those very high-risk patients,” he said.
Therefore, a clinicogenomic risk model was developed that incorporates seven mutations having poor prognostic impact, the m7-FLIPI (Lancet Oncol. 2015;16[9]:1111-22). Adding the mutations split the previously defined high-risk patients into a group with a prognosis similar to that of low-risk patients and a small group with a very poor prognosis.
“This actually represents something very close to the 20% of patients that we think have bad biology,” Dr. Zelenetz noted. “There will be some additional data at ASH looking at this exact question, because the holy grail is to know when you diagnose someone if they are in that bad-risk group because those are the patients you want to do novel clinical trials on. If your overall survival is equivalent to the general population, it’s going to be hard to ever prove an overall survival advantage for an intervention in an unselected group of patients.”
Advanced-stage disease with low tumor bulk
For patients who have advanced-stage follicular lymphoma but with low tumor bulk, the NCCN endorses a modification of criteria developed by the Follicular Lymphoma Study Group (GELF) in deciding when to start treatment (J Clin Oncol. 1998;16[7]:2332-8).
Roughly a fifth of patients who are eligible for and managed with a watch-and-wait approach will not need chemotherapy or die of their disease in the next 10 years (Lancet. 2003;362[9383]:516-22). Furthermore, this strategy nets a median delay in the need for chemotherapy of 2.6 years.
Compared with observation, treatment with the anti-CD20 antibody rituximab (Rituxan) improves progression-free survival but not overall survival in this setting (ASH 2010, Abstract 6). “Though in selected patients, rituximab may be appropriate as initial treatment for the observable patient, I would argue for the observable patient with no survival disadvantage, the standard of care remains observation,” Dr. Zelenetz said.
Advanced-stage disease requiring treatment
A meta-analysis has shown a clear survival benefit from adding rituximab to chemotherapy (R-chemo) in patients with advanced follicular lymphoma who need treatment (J Natl Cancer Inst. 2007;99[9]:706-14). “Based on the results, it is the standard of care to add rituximab to a chemotherapy backbone, but the optimum R-chemo actually remains undefined and would be customized to the individual clinical situation,” he commented.
A variety of emerging agents are being tested in this setting. Among the subset of patients with untreated follicular lymphoma in a single-center trial, the combination of rituximab with the immunomodulator lenalidomide (Revlimid) yielded an overall response rate of 98% and a complete response rate of 87%, as well as excellent progression-free and overall survival (Lancet Oncol. 2014;15[12]:1311-8). The main grade 3 or 4 toxicity was neutropenia, seen in 35% of all patients studied. Efficacy results were much the same in a multicenter trial (International Conference on Malignant Lymphoma [ICML] 2013, Abstract 63).
This combination is now being tested as front-line therapy for follicular lymphoma in the RELEVANCE (Rituximab and Lenalidomide Versus Any Chemotherapy) phase III trial. “The trial is now done, but we don’t have results, and we won’t have results until 2019, so don’t hold your breath,” Dr. Zelenetz commented. “That’s because this was an unselected trial; we took all patients, all comers. And if you don’t try to identify bad-risk patients, you actually have to do very large trials, and the effect size is relatively small.”
Relapsed and refractory disease
“Many times when patients with follicular lymphoma relapse, they are immediately started on treatment. It’s not necessary and probably in most cases not appropriate. If patients are asymptomatic and have a low tumor burden, they can have a second and a third and even a fourth period of observation, where they don’t need active treatment,” he said. “So I would encourage you to …wait until they actually meet GELF criteria again.”
A key question in this setting is whether patients previously given rituximab can derive benefit from an alternative anti-CD20 antibody. Taking on this question, the GADOLIN trial tested the addition of obinutuzumab (induction plus maintenance) to bendamustine among patients with rituximab-refractory disease (American Society of Clinical Oncology [ASCO] 2015, Abstract LBA8502; ICML 2015, Abstract 123).
Toxicities were generally similar by arm, except for a higher rate of infusion-related reactions with obinutuzumab. The overall response rates were comparable for the two arms, but progression-free survival was better with the combination (median event-free survival, not reached, vs. 14.9 months; hazard ratio, 0.55), and there was a trend for overall survival.
“These curves start separating after 6 months, and 6 months is the time of chemotherapy,” Dr. Zelenetz noted. “So I would argue from these data that the obinutuzumab didn’t add very much to the bendamustine backbone, but actually the obinutuzumab maintenance was effective even in rituximab-refractory patients.”
The combination of lenalidomide and rituximab has been compared with lenalidomide alone in patients with relapsed follicular lymphoma (ASCO 2012, Abstract 8000). The results showed a trend toward better median event-free survival with the combination (2.0 vs. 1.2 years; hazard ratio, 1.9; P = .061) but not overall survival.
In a phase II trial, idelalisib (Zydelig) was tested among patients with indolent non-Hodgkin lymphomas (60% with follicular lymphoma) that were refractory to both rituximab and an alkylator (N Engl J Med. 2014;370:1008-18). Noteworthy grade 3 or worse toxicities included pneumonia and transaminase elevations. The overall response rate was 57%, and the complete response rate was 6%; median progression-free survival was 11 months.
“Idelalisib can be safely combined with other agents including rituximab and bendamustine,” Dr. Zelenetz added (ASH 2014, Abstract 3063). “Interestingly, the overall response seems to be a little higher when you combine it, but it doesn’t seem to matter which drug you combine it with – rituximab, bendamustine, or [both] – you get good overall responses,” ranging from 71% to 85%.
The BCL-2 inhibitor venetoclax (formerly ABT-199/GDC-199) has been tested in non-Hodgkin lymphomas, where it has not been associated with the life-threatening tumor lysis syndrome seen in some other hematologic malignancies (European Hematology Association [EHA] 2015, Davis et al). It yielded an overall response rate of 31% in patients with relatively refractory follicular lymphoma. “This will lead to additional studies in this area,” he predicted.
Finally, nivolumab (Opdivo), a PD-1 immune checkpoint inhibitor, has been evaluated in a phase I study in relapsed or refractory hematologic malignancies, where it was well tolerated (ASH 2014, Abstract 291). Among the small subset of patients with follicular lymphoma, the overall response rate was 40%, prompting initiation of more trials.
Although chimeric antigen receptor (CAR) T-cell therapy is showing promise in various malignancies, Dr. Zelenetz said that other options are probably better avenues for research in follicular lymphoma at present.
“I’m much more interested in the tools that we have now, between the checkpoint inhibitors, the T-cell activators, and the bispecific monoclonal antibodies. I think I can [apply these therapies] with less money for probably less toxicity without the complexity of having to make a customized drug for the patient,” he said. “So I’m not very enthusiastic about CAR T cells in follicular lymphoma.”
SAN FRANCISCO – A variety of emerging therapies are being incorporated into the management of follicular lymphoma, which is typically a long-term endeavor requiring strategic use of multiple treatments, Dr. Andrew D. Zelenetz said at the National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies.
“Follicular lymphoma is a disease of paradox. The reality is that overall survival is excellent, but patients are not going to be able to do that with one treatment; they are going to get a series of treatments,” he said. “Survival is the sum of your exposures to treatment, time on active therapy, time in remission, and actually time with relapse not needing treatment.”
Risk stratification
Overall survival for patients with follicular lymphoma diagnosed today and treated with modern therapy is only slightly inferior to that for age-matched controls, noted Dr. Zelenetz of the department of medicine at Memorial Sloan-Kettering Cancer Center and professor of medicine at Cornell University, both in New York.
But patients who are faring poorly at 12 months (American Society of Hematology [ASH] 2014, Abstract 1664) or at 24 months (J Clin Oncol. 2015;33[23]:2516-22) into care have a much worse prognosis. “This shows the importance of identifying those patients with poor biology, and [the question of] whether we can identify them without treating them first and having them progress,” he said.
Hematologists have historically looked to the Follicular Lymphoma International Prognostic Index (FLIPI) to estimate outcome. “The FLIPI clearly works; it’s an important clinical tool. But the FLIPI high-risk patients are still identifying more than those very high-risk patients,” he said.
Therefore, a clinicogenomic risk model was developed that incorporates seven mutations having poor prognostic impact, the m7-FLIPI (Lancet Oncol. 2015;16[9]:1111-22). Adding the mutations split the previously defined high-risk patients into a group with a prognosis similar to that of low-risk patients and a small group with a very poor prognosis.
“This actually represents something very close to the 20% of patients that we think have bad biology,” Dr. Zelenetz noted. “There will be some additional data at ASH looking at this exact question, because the holy grail is to know when you diagnose someone if they are in that bad-risk group because those are the patients you want to do novel clinical trials on. If your overall survival is equivalent to the general population, it’s going to be hard to ever prove an overall survival advantage for an intervention in an unselected group of patients.”
Advanced-stage disease with low tumor bulk
For patients who have advanced-stage follicular lymphoma but with low tumor bulk, the NCCN endorses a modification of criteria developed by the Follicular Lymphoma Study Group (GELF) in deciding when to start treatment (J Clin Oncol. 1998;16[7]:2332-8).
Roughly a fifth of patients who are eligible for and managed with a watch-and-wait approach will not need chemotherapy or die of their disease in the next 10 years (Lancet. 2003;362[9383]:516-22). Furthermore, this strategy nets a median delay in the need for chemotherapy of 2.6 years.
Compared with observation, treatment with the anti-CD20 antibody rituximab (Rituxan) improves progression-free survival but not overall survival in this setting (ASH 2010, Abstract 6). “Though in selected patients, rituximab may be appropriate as initial treatment for the observable patient, I would argue for the observable patient with no survival disadvantage, the standard of care remains observation,” Dr. Zelenetz said.
Advanced-stage disease requiring treatment
A meta-analysis has shown a clear survival benefit from adding rituximab to chemotherapy (R-chemo) in patients with advanced follicular lymphoma who need treatment (J Natl Cancer Inst. 2007;99[9]:706-14). “Based on the results, it is the standard of care to add rituximab to a chemotherapy backbone, but the optimum R-chemo actually remains undefined and would be customized to the individual clinical situation,” he commented.
A variety of emerging agents are being tested in this setting. Among the subset of patients with untreated follicular lymphoma in a single-center trial, the combination of rituximab with the immunomodulator lenalidomide (Revlimid) yielded an overall response rate of 98% and a complete response rate of 87%, as well as excellent progression-free and overall survival (Lancet Oncol. 2014;15[12]:1311-8). The main grade 3 or 4 toxicity was neutropenia, seen in 35% of all patients studied. Efficacy results were much the same in a multicenter trial (International Conference on Malignant Lymphoma [ICML] 2013, Abstract 63).
This combination is now being tested as front-line therapy for follicular lymphoma in the RELEVANCE (Rituximab and Lenalidomide Versus Any Chemotherapy) phase III trial. “The trial is now done, but we don’t have results, and we won’t have results until 2019, so don’t hold your breath,” Dr. Zelenetz commented. “That’s because this was an unselected trial; we took all patients, all comers. And if you don’t try to identify bad-risk patients, you actually have to do very large trials, and the effect size is relatively small.”
Relapsed and refractory disease
“Many times when patients with follicular lymphoma relapse, they are immediately started on treatment. It’s not necessary and probably in most cases not appropriate. If patients are asymptomatic and have a low tumor burden, they can have a second and a third and even a fourth period of observation, where they don’t need active treatment,” he said. “So I would encourage you to …wait until they actually meet GELF criteria again.”
A key question in this setting is whether patients previously given rituximab can derive benefit from an alternative anti-CD20 antibody. Taking on this question, the GADOLIN trial tested the addition of obinutuzumab (induction plus maintenance) to bendamustine among patients with rituximab-refractory disease (American Society of Clinical Oncology [ASCO] 2015, Abstract LBA8502; ICML 2015, Abstract 123).
Toxicities were generally similar by arm, except for a higher rate of infusion-related reactions with obinutuzumab. The overall response rates were comparable for the two arms, but progression-free survival was better with the combination (median event-free survival, not reached, vs. 14.9 months; hazard ratio, 0.55), and there was a trend for overall survival.
“These curves start separating after 6 months, and 6 months is the time of chemotherapy,” Dr. Zelenetz noted. “So I would argue from these data that the obinutuzumab didn’t add very much to the bendamustine backbone, but actually the obinutuzumab maintenance was effective even in rituximab-refractory patients.”
The combination of lenalidomide and rituximab has been compared with lenalidomide alone in patients with relapsed follicular lymphoma (ASCO 2012, Abstract 8000). The results showed a trend toward better median event-free survival with the combination (2.0 vs. 1.2 years; hazard ratio, 1.9; P = .061) but not overall survival.
In a phase II trial, idelalisib (Zydelig) was tested among patients with indolent non-Hodgkin lymphomas (60% with follicular lymphoma) that were refractory to both rituximab and an alkylator (N Engl J Med. 2014;370:1008-18). Noteworthy grade 3 or worse toxicities included pneumonia and transaminase elevations. The overall response rate was 57%, and the complete response rate was 6%; median progression-free survival was 11 months.
“Idelalisib can be safely combined with other agents including rituximab and bendamustine,” Dr. Zelenetz added (ASH 2014, Abstract 3063). “Interestingly, the overall response seems to be a little higher when you combine it, but it doesn’t seem to matter which drug you combine it with – rituximab, bendamustine, or [both] – you get good overall responses,” ranging from 71% to 85%.
The BCL-2 inhibitor venetoclax (formerly ABT-199/GDC-199) has been tested in non-Hodgkin lymphomas, where it has not been associated with the life-threatening tumor lysis syndrome seen in some other hematologic malignancies (European Hematology Association [EHA] 2015, Davis et al). It yielded an overall response rate of 31% in patients with relatively refractory follicular lymphoma. “This will lead to additional studies in this area,” he predicted.
Finally, nivolumab (Opdivo), a PD-1 immune checkpoint inhibitor, has been evaluated in a phase I study in relapsed or refractory hematologic malignancies, where it was well tolerated (ASH 2014, Abstract 291). Among the small subset of patients with follicular lymphoma, the overall response rate was 40%, prompting initiation of more trials.
Although chimeric antigen receptor (CAR) T-cell therapy is showing promise in various malignancies, Dr. Zelenetz said that other options are probably better avenues for research in follicular lymphoma at present.
“I’m much more interested in the tools that we have now, between the checkpoint inhibitors, the T-cell activators, and the bispecific monoclonal antibodies. I think I can [apply these therapies] with less money for probably less toxicity without the complexity of having to make a customized drug for the patient,” he said. “So I’m not very enthusiastic about CAR T cells in follicular lymphoma.”
AT NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
CHEST: Catheter-directed thrombolysis shows pulmonary embolism efficacy
MONTREAL – Catheter-directed thrombolysis surpassed systemic thrombolysis for minimizing in-hospital mortality of patients with an acute pulmonary embolism in a review of more than 1,500 U.S. patients.
The review also found evidence that U.S. pulmonary embolism (PE) patients increasingly undergo catheter-directed thrombolysis, with usage jumping by more than 50% from 2010 to 2012, although in 2012 U.S. clinicians performed catheter-directed thrombolysis on 160 patients with an acute pulmonary embolism (PE) who were included in a national U.S. registry of hospitalized patients, Dr. Amina Saqib said at the annual meeting of the American College of Chest Physicians.
Catheter-directed thrombolysis resulted in a 9% in-hospital mortality rate and a 10% combined rate of in-hospital mortality plus intracerebral hemorrhages, rates significantly below those tallied in propensity score–matched patients who underwent systemic thrombolysis of their acute PE. The matched group with systemic thrombolysis had a 17% in-hospital mortality rate and a 17% combined mortality plus intracerebral hemorrhage rate, said Dr. Saqib, a researcher at Staten Island (N.Y.) University Hospital.
“To the best of our knowledge, this is the first, large, nationwide, observational study that compared safety and efficacy outcomes between systemic thrombolysis and catheter-directed thrombolysis in acute PE,” Dr. Saqib said.
The U.S. data, collected during 2010-2012, also showed that, after adjustment for clinical and demographic variables, each acute PE treatment by catheter-directed thrombolysis cost an average $9,428 above the cost for systemic thrombolysis, she said.
“We need to more systematically identify the patients with an acute PE who could benefit from catheter-directed thrombolysis, especially patients with a massive PE,” commented Dr. Muthiah P. Muthiah, a critical-care medicine physician at the University of Tennessee Health Science Center in Memphis. “This may be something to offer to patients who have an absolute contraindication for systemic thrombolysis, such as recent surgery, but it is not available everywhere,” Dr. Muthiah said in an interview.
Dr. Saqib and her associates used data collected by the Federal National Inpatient Sample. Among U.S. patients hospitalized during 2010-2012 and entered into this database, they identified 1,169 adult acute PE patients who underwent systemic thrombolysis and 352 patients who received catheter-directed thrombolysis. The patients averaged about 58 years old and just under half were men.
The propensity score–adjusted analysis also showed no statistically significant difference between the two treatment approaches for the incidence of intracerebral hemorrhage, any hemorrhages requiring a transfusion, new-onset acute renal failure, or hospital length of stay. Among the patients treated by catheter-directed thrombolysis, all the intracerebral hemorrhages occurred during 2010; during 2011 and 2012 none of the patients treated this way had an intracerebral hemorrhage, Dr. Saqib noted.
Although the findings were consistent with results from prior analyses, the propensity-score adjustment used in the current study cannot fully account for all unmeasured confounding factors. The best way to compare catheter-directed thrombolysis and systemic thrombolysis for treating acute PE would be in a prospective, randomized study, Dr. Saqib said.
Dr. Saqib and Dr. Muthiah had no disclosures.
On Twitter @mitchelzoler
MONTREAL – Catheter-directed thrombolysis surpassed systemic thrombolysis for minimizing in-hospital mortality of patients with an acute pulmonary embolism in a review of more than 1,500 U.S. patients.
The review also found evidence that U.S. pulmonary embolism (PE) patients increasingly undergo catheter-directed thrombolysis, with usage jumping by more than 50% from 2010 to 2012, although in 2012 U.S. clinicians performed catheter-directed thrombolysis on 160 patients with an acute pulmonary embolism (PE) who were included in a national U.S. registry of hospitalized patients, Dr. Amina Saqib said at the annual meeting of the American College of Chest Physicians.
Catheter-directed thrombolysis resulted in a 9% in-hospital mortality rate and a 10% combined rate of in-hospital mortality plus intracerebral hemorrhages, rates significantly below those tallied in propensity score–matched patients who underwent systemic thrombolysis of their acute PE. The matched group with systemic thrombolysis had a 17% in-hospital mortality rate and a 17% combined mortality plus intracerebral hemorrhage rate, said Dr. Saqib, a researcher at Staten Island (N.Y.) University Hospital.
“To the best of our knowledge, this is the first, large, nationwide, observational study that compared safety and efficacy outcomes between systemic thrombolysis and catheter-directed thrombolysis in acute PE,” Dr. Saqib said.
The U.S. data, collected during 2010-2012, also showed that, after adjustment for clinical and demographic variables, each acute PE treatment by catheter-directed thrombolysis cost an average $9,428 above the cost for systemic thrombolysis, she said.
“We need to more systematically identify the patients with an acute PE who could benefit from catheter-directed thrombolysis, especially patients with a massive PE,” commented Dr. Muthiah P. Muthiah, a critical-care medicine physician at the University of Tennessee Health Science Center in Memphis. “This may be something to offer to patients who have an absolute contraindication for systemic thrombolysis, such as recent surgery, but it is not available everywhere,” Dr. Muthiah said in an interview.
Dr. Saqib and her associates used data collected by the Federal National Inpatient Sample. Among U.S. patients hospitalized during 2010-2012 and entered into this database, they identified 1,169 adult acute PE patients who underwent systemic thrombolysis and 352 patients who received catheter-directed thrombolysis. The patients averaged about 58 years old and just under half were men.
The propensity score–adjusted analysis also showed no statistically significant difference between the two treatment approaches for the incidence of intracerebral hemorrhage, any hemorrhages requiring a transfusion, new-onset acute renal failure, or hospital length of stay. Among the patients treated by catheter-directed thrombolysis, all the intracerebral hemorrhages occurred during 2010; during 2011 and 2012 none of the patients treated this way had an intracerebral hemorrhage, Dr. Saqib noted.
Although the findings were consistent with results from prior analyses, the propensity-score adjustment used in the current study cannot fully account for all unmeasured confounding factors. The best way to compare catheter-directed thrombolysis and systemic thrombolysis for treating acute PE would be in a prospective, randomized study, Dr. Saqib said.
Dr. Saqib and Dr. Muthiah had no disclosures.
On Twitter @mitchelzoler
MONTREAL – Catheter-directed thrombolysis surpassed systemic thrombolysis for minimizing in-hospital mortality of patients with an acute pulmonary embolism in a review of more than 1,500 U.S. patients.
The review also found evidence that U.S. pulmonary embolism (PE) patients increasingly undergo catheter-directed thrombolysis, with usage jumping by more than 50% from 2010 to 2012, although in 2012 U.S. clinicians performed catheter-directed thrombolysis on 160 patients with an acute pulmonary embolism (PE) who were included in a national U.S. registry of hospitalized patients, Dr. Amina Saqib said at the annual meeting of the American College of Chest Physicians.
Catheter-directed thrombolysis resulted in a 9% in-hospital mortality rate and a 10% combined rate of in-hospital mortality plus intracerebral hemorrhages, rates significantly below those tallied in propensity score–matched patients who underwent systemic thrombolysis of their acute PE. The matched group with systemic thrombolysis had a 17% in-hospital mortality rate and a 17% combined mortality plus intracerebral hemorrhage rate, said Dr. Saqib, a researcher at Staten Island (N.Y.) University Hospital.
“To the best of our knowledge, this is the first, large, nationwide, observational study that compared safety and efficacy outcomes between systemic thrombolysis and catheter-directed thrombolysis in acute PE,” Dr. Saqib said.
The U.S. data, collected during 2010-2012, also showed that, after adjustment for clinical and demographic variables, each acute PE treatment by catheter-directed thrombolysis cost an average $9,428 above the cost for systemic thrombolysis, she said.
“We need to more systematically identify the patients with an acute PE who could benefit from catheter-directed thrombolysis, especially patients with a massive PE,” commented Dr. Muthiah P. Muthiah, a critical-care medicine physician at the University of Tennessee Health Science Center in Memphis. “This may be something to offer to patients who have an absolute contraindication for systemic thrombolysis, such as recent surgery, but it is not available everywhere,” Dr. Muthiah said in an interview.
Dr. Saqib and her associates used data collected by the Federal National Inpatient Sample. Among U.S. patients hospitalized during 2010-2012 and entered into this database, they identified 1,169 adult acute PE patients who underwent systemic thrombolysis and 352 patients who received catheter-directed thrombolysis. The patients averaged about 58 years old and just under half were men.
The propensity score–adjusted analysis also showed no statistically significant difference between the two treatment approaches for the incidence of intracerebral hemorrhage, any hemorrhages requiring a transfusion, new-onset acute renal failure, or hospital length of stay. Among the patients treated by catheter-directed thrombolysis, all the intracerebral hemorrhages occurred during 2010; during 2011 and 2012 none of the patients treated this way had an intracerebral hemorrhage, Dr. Saqib noted.
Although the findings were consistent with results from prior analyses, the propensity-score adjustment used in the current study cannot fully account for all unmeasured confounding factors. The best way to compare catheter-directed thrombolysis and systemic thrombolysis for treating acute PE would be in a prospective, randomized study, Dr. Saqib said.
Dr. Saqib and Dr. Muthiah had no disclosures.
On Twitter @mitchelzoler
AT CHEST 2015
Key clinical point: Catheter-directed thrombolysis was linked to reduced mortality, compared with systemic thrombolysis in patients with an acute pulmonary embolism.
Major finding: In-hospital mortality in acute pulmonary embolism patients ran 10% with catheter-directed thrombolysis and 17% with systemic thrombolysis.
Data source: Review of 1,521 U.S. patients treated for acute pulmonary embolism during 2010-2012 in the National Inpatient Sample.
Disclosures: Dr. Saqib and Dr. Muthiah had no disclosures.
Storytelling that heals: Movies and families
Movies are storytelling in high definition. Have you ever used movies to teach your students or residents? Have you ever prescribed therapeutic movie watching to your patients, families, or couples? Movie watching helps us to understand and process the challenges we face. Movie watching helps us to imagine new stories for ourselves.
Stories connect us to our own families. The experiences of our elders and other family members are the story of our family and give coherence to our own life story. We may identify with a family member whose life experience resonates with our life experience; maybe it is the relative who perseveres, or the black sheep, or the one with depression, or the pioneer, or the one who settles for happiness or the alcoholic or workaholic. Maybe we cherish stories that connect us to our generation rather than our family, such as stories about a generational war experience or the stories and camaraderie of Alcoholics Anonymous meetings.
Stories help us understand ourselves. Stories give us scripts, maps, mental models, metaphors, and narratives to help us navigate through our lives. Stories are how we explain our lives to others, reach decisions, understand our place in the world, create our identities, and define and teach social and moral values. Many children come to understand the morals of the world by reading about the lives of animals in Aesop’s Fables. How often do parents have to read the same story over and over to their child? Familiar stories give our lives a narrative structure that is familiar, predictable, and comforting.
Storytelling is fundamental to all cultures. Stories live in our imagination. We can rehearse imagined experiences and imagine our life story in many different ways. Stories help us step out, step forward, see the world and ourselves. Story reading and movie watching help us imagine. Psychotherapy is a therapeutic way to help patients relinquish old stories and begin to construct a new story about themselves.
Movie watching can be used in therapy and has been studied as a therapeutic tool. Cinema therapy, or movie therapy, is considered a form of supplemental therapy and a form of self-help. Cinema therapy was popularized by Gary Solomon, Ph.D., the first to write on using movies as therapy (“The Motion Picture Prescription: Watch This Movie and Call Me in the Morning.” Santa Rosa, Calif.: Aslan Publishing,1995).
Watching movies was used in one arm of the first long-term investigation to compare different types of early marriage intervention programs. In this study, 174 couples in their first 3 years of marriage were enrolled in one of three treatment arms: conflict management, compassion and acceptance training, or relationship awareness through film. Each arm was equally effective in reducing the 3-year divorce/separation rate for newlyweds from 24% to 11%.
The first arm
The conflict management group learned “active listening” or the “speaker-listener technique.” This technique slows down communication and helps individuals focus on what their partner is saying. The practice requires one spouse to listen and then paraphrase back to the partner what the spouse heard to ensure the message has been properly understood. This technique has been shown to be effective at promoting happier and more satisfying relationships for 3-5 years (see the Prevention and Relationship Enhancement Program). This model provides couples with training in communication and problem-solving skills, as well as relationship expectations, friendship, and commitment.
The second arm
The compassion and acceptance training cohort focused on couples working as a team. Through a series of lectures and exercises, couples were taught to approach their relationships with more compassion and empathy by doing things like listening as a friend, practicing random acts of kindness and affection, and using the language of acceptance. Both programs involved weekly lectures, supervised practice sessions, and homework assignments over the course of a month, for a total investment of roughly 20 hours, with 18 hours of therapy time.
The third arm
The movie-and-talk group attended a 10-minute lecture on the importance of relationship awareness and how watching couples in movies could help spouses pay attention to their own behavior, both constructive and destructive. They spent 10 hours on “movie and talk” with 4 hours outside of the home. After each movie, the couple discussed a list of 12 questions about the screen couple’s interactions. Questions included: “How did the movie partners handle arguments? Were they able to open up and tell each other how they really felt, or did they tend to just snap at each other with anger? Did they try using humor to keep things from getting nasty?” The couple was asked to consider in what way the movie relationship was “similar to or different from your own relationship in this area.”
All couples in the third arm met with a therapist to watch “Two for the Road,” a 1967 romantic comedy about the joys and strains of young love, infidelity, and professional pressures across 10 years of a marriage. They were then led by the therapist in a guided discussion. They went home with a list of 47 movies with intimate relationships as a major plot focus, and were asked to watch 1 a week for the next month, followed by a guided discussion for about 45 minutes. For couples interested in trying the film discussions for themselves, the website ofRonald D. Rogge, Ph.D., offers interactive tools to help with the process, including lists of movies and the discussion questions used.
What happened?
The couples invested in their relationship and began to examine their own behavior. Watching a movie together and having a discussion was therapeutic but did not pathologize their relationship, nor did the partners seek to blame each other. The therapist-led marriage intervention programs available usually require trained therapists, and are expensive and intensive. Can couples work on their relationships on their own? The assumption has been that you need to teach couples skills to manage conflict; this might not be true. This study indicates that relationship storytelling can be a step that couples and families can take, on their own.
Movies also can be used in teaching
Family medicine teachers Catherine M. Weber, Ph.D., and Dr. Hugh J. Silk (Fam Med. 2007;39[5]:317-9) developed a movie-watching curriculum to deepen trainees’ understanding of patients and their families. The curriculum was divided into sections. The family and illness section focused on how family members find a will to help their loved ones, even in the midst of a lack of resources or medical futility. They watched “Lorenzo’s Oil” (1992), “The Straight Story” (2006), and “A River Runs Through It” (1992). The family and loss section examined how families become dysfunctional in the presence of the loss of a loved one and what it takes to heal. They watched “Ordinary People” (1980), “The Barbarian Invasions” (2003), and “The Trip to Bountiful” (1985). The section on family and caregiving identifies the strain of illness on family members who provide direct care to ill patients. They watched “Marvin’s Room” (1996) and “Iris” (2001). The section on the family and substance abuse identified how family members got caught in roles and included “When a Man Loves a Woman” (1994) and “The Days of Wine and Roses” (1962). The section on the extended family and illness illustrated how illness brings people together. They watched “Flawless” (1999), “My House in Umbria” (2003), “Beaches” (1988), and “The Barbarian Invasions (2003).
A more specific look at family systems is provided by the curriculum of Dr. Robin O. Winter and Bruce A. Birnberg (Fam Med. 2005;37[2]:96-8) in a series called “Family Systems at the Movies.” Their overarching objective was to promote an understanding of multigenerational issues, the impact of family secrets and family dynamics, the effect of stress on family life, and the attributes of a functional family. Concepts such as homeostasis, boundaries, coalitions, and scapegoating were then applied to the clinical setting. Selected scenes were chosen from three works: “The Joy Luck Club” (1993), “Shine” (1996), and a TV series called “Secrets and Lies” (2015-).
Regarding early marriage, Dr. Salman Ahktar and Dr. Zoe Billinkoff (Am J Psychoanal. 2011; 71[2]:110-20) used movies to discuss how identity, the development of mutuality, and the synthesis of affection and sensuality develop in early marriage. Their goal was to help therapists develop greater empathy with newly married individuals. They focused on three movies: “Barefoot in the Park” (1967), “Raising Arizona” (1987), and “The Quiet Man” (1952). Regarding divorce, Toni Mandelbaum(Am J Psychoanal. 2011;71[2]:121-33) used movies to illustrate the interplay between dependence and independence using “Eat Pray Love” (2010) and “Kramer vs. Kramer” (1979).
Many psychiatry residency programs have journal clubs and film clubs that use movies as a jumping-off point to deepen trainees’ understanding of psychopathology. Implementing these curricula is a simple way of beginning family training in residency, especially when the use of family videos are curtailed by strict confidentiality rules.
Future ‘family and film’ events
Dr. Francis G. Lu, (www.francislumd.com), a regular presenter at many conferences, including the American Psychiatric Association annual meetings, uses film to promote a deeper understanding of the world around us and within us. In 2007, he and Brother David Steindl-Rast, Ph.D., a Benedictine monk, co-led a 7-day seminar entitled, “Families in Film, Now and Forever” at Esalen Institute (go to www.gratefulness.org, then search “films”). From July 10-17, 2016, Dr. Lu and Dr. Steindl-Rast will co-lead “The Resilience of the Family in Film: Epics of Love, Loss, and Recovery” and from July 17-24, 2016, “Through Compassion to Serenity in the Mindful Viewing of Japanese and Western Films.” Registration opens in January 2016 at www.esalen.org. If you have ever attended one of Dr. Lu’s seminars at the APA, then you know you will be in for a rich experience at Esalen.
Dr. Heru is with the department of psychiatry at the University of Colorado Denver, Aurora. She is editor of “Working With Families in Medical Settings: A Multidisciplinary Guide for Psychiatrists and Other Health Professionals” (New York: Routledge, 2013).
Movies are storytelling in high definition. Have you ever used movies to teach your students or residents? Have you ever prescribed therapeutic movie watching to your patients, families, or couples? Movie watching helps us to understand and process the challenges we face. Movie watching helps us to imagine new stories for ourselves.
Stories connect us to our own families. The experiences of our elders and other family members are the story of our family and give coherence to our own life story. We may identify with a family member whose life experience resonates with our life experience; maybe it is the relative who perseveres, or the black sheep, or the one with depression, or the pioneer, or the one who settles for happiness or the alcoholic or workaholic. Maybe we cherish stories that connect us to our generation rather than our family, such as stories about a generational war experience or the stories and camaraderie of Alcoholics Anonymous meetings.
Stories help us understand ourselves. Stories give us scripts, maps, mental models, metaphors, and narratives to help us navigate through our lives. Stories are how we explain our lives to others, reach decisions, understand our place in the world, create our identities, and define and teach social and moral values. Many children come to understand the morals of the world by reading about the lives of animals in Aesop’s Fables. How often do parents have to read the same story over and over to their child? Familiar stories give our lives a narrative structure that is familiar, predictable, and comforting.
Storytelling is fundamental to all cultures. Stories live in our imagination. We can rehearse imagined experiences and imagine our life story in many different ways. Stories help us step out, step forward, see the world and ourselves. Story reading and movie watching help us imagine. Psychotherapy is a therapeutic way to help patients relinquish old stories and begin to construct a new story about themselves.
Movie watching can be used in therapy and has been studied as a therapeutic tool. Cinema therapy, or movie therapy, is considered a form of supplemental therapy and a form of self-help. Cinema therapy was popularized by Gary Solomon, Ph.D., the first to write on using movies as therapy (“The Motion Picture Prescription: Watch This Movie and Call Me in the Morning.” Santa Rosa, Calif.: Aslan Publishing,1995).
Watching movies was used in one arm of the first long-term investigation to compare different types of early marriage intervention programs. In this study, 174 couples in their first 3 years of marriage were enrolled in one of three treatment arms: conflict management, compassion and acceptance training, or relationship awareness through film. Each arm was equally effective in reducing the 3-year divorce/separation rate for newlyweds from 24% to 11%.
The first arm
The conflict management group learned “active listening” or the “speaker-listener technique.” This technique slows down communication and helps individuals focus on what their partner is saying. The practice requires one spouse to listen and then paraphrase back to the partner what the spouse heard to ensure the message has been properly understood. This technique has been shown to be effective at promoting happier and more satisfying relationships for 3-5 years (see the Prevention and Relationship Enhancement Program). This model provides couples with training in communication and problem-solving skills, as well as relationship expectations, friendship, and commitment.
The second arm
The compassion and acceptance training cohort focused on couples working as a team. Through a series of lectures and exercises, couples were taught to approach their relationships with more compassion and empathy by doing things like listening as a friend, practicing random acts of kindness and affection, and using the language of acceptance. Both programs involved weekly lectures, supervised practice sessions, and homework assignments over the course of a month, for a total investment of roughly 20 hours, with 18 hours of therapy time.
The third arm
The movie-and-talk group attended a 10-minute lecture on the importance of relationship awareness and how watching couples in movies could help spouses pay attention to their own behavior, both constructive and destructive. They spent 10 hours on “movie and talk” with 4 hours outside of the home. After each movie, the couple discussed a list of 12 questions about the screen couple’s interactions. Questions included: “How did the movie partners handle arguments? Were they able to open up and tell each other how they really felt, or did they tend to just snap at each other with anger? Did they try using humor to keep things from getting nasty?” The couple was asked to consider in what way the movie relationship was “similar to or different from your own relationship in this area.”
All couples in the third arm met with a therapist to watch “Two for the Road,” a 1967 romantic comedy about the joys and strains of young love, infidelity, and professional pressures across 10 years of a marriage. They were then led by the therapist in a guided discussion. They went home with a list of 47 movies with intimate relationships as a major plot focus, and were asked to watch 1 a week for the next month, followed by a guided discussion for about 45 minutes. For couples interested in trying the film discussions for themselves, the website ofRonald D. Rogge, Ph.D., offers interactive tools to help with the process, including lists of movies and the discussion questions used.
What happened?
The couples invested in their relationship and began to examine their own behavior. Watching a movie together and having a discussion was therapeutic but did not pathologize their relationship, nor did the partners seek to blame each other. The therapist-led marriage intervention programs available usually require trained therapists, and are expensive and intensive. Can couples work on their relationships on their own? The assumption has been that you need to teach couples skills to manage conflict; this might not be true. This study indicates that relationship storytelling can be a step that couples and families can take, on their own.
Movies also can be used in teaching
Family medicine teachers Catherine M. Weber, Ph.D., and Dr. Hugh J. Silk (Fam Med. 2007;39[5]:317-9) developed a movie-watching curriculum to deepen trainees’ understanding of patients and their families. The curriculum was divided into sections. The family and illness section focused on how family members find a will to help their loved ones, even in the midst of a lack of resources or medical futility. They watched “Lorenzo’s Oil” (1992), “The Straight Story” (2006), and “A River Runs Through It” (1992). The family and loss section examined how families become dysfunctional in the presence of the loss of a loved one and what it takes to heal. They watched “Ordinary People” (1980), “The Barbarian Invasions” (2003), and “The Trip to Bountiful” (1985). The section on family and caregiving identifies the strain of illness on family members who provide direct care to ill patients. They watched “Marvin’s Room” (1996) and “Iris” (2001). The section on the family and substance abuse identified how family members got caught in roles and included “When a Man Loves a Woman” (1994) and “The Days of Wine and Roses” (1962). The section on the extended family and illness illustrated how illness brings people together. They watched “Flawless” (1999), “My House in Umbria” (2003), “Beaches” (1988), and “The Barbarian Invasions (2003).
A more specific look at family systems is provided by the curriculum of Dr. Robin O. Winter and Bruce A. Birnberg (Fam Med. 2005;37[2]:96-8) in a series called “Family Systems at the Movies.” Their overarching objective was to promote an understanding of multigenerational issues, the impact of family secrets and family dynamics, the effect of stress on family life, and the attributes of a functional family. Concepts such as homeostasis, boundaries, coalitions, and scapegoating were then applied to the clinical setting. Selected scenes were chosen from three works: “The Joy Luck Club” (1993), “Shine” (1996), and a TV series called “Secrets and Lies” (2015-).
Regarding early marriage, Dr. Salman Ahktar and Dr. Zoe Billinkoff (Am J Psychoanal. 2011; 71[2]:110-20) used movies to discuss how identity, the development of mutuality, and the synthesis of affection and sensuality develop in early marriage. Their goal was to help therapists develop greater empathy with newly married individuals. They focused on three movies: “Barefoot in the Park” (1967), “Raising Arizona” (1987), and “The Quiet Man” (1952). Regarding divorce, Toni Mandelbaum(Am J Psychoanal. 2011;71[2]:121-33) used movies to illustrate the interplay between dependence and independence using “Eat Pray Love” (2010) and “Kramer vs. Kramer” (1979).
Many psychiatry residency programs have journal clubs and film clubs that use movies as a jumping-off point to deepen trainees’ understanding of psychopathology. Implementing these curricula is a simple way of beginning family training in residency, especially when the use of family videos are curtailed by strict confidentiality rules.
Future ‘family and film’ events
Dr. Francis G. Lu, (www.francislumd.com), a regular presenter at many conferences, including the American Psychiatric Association annual meetings, uses film to promote a deeper understanding of the world around us and within us. In 2007, he and Brother David Steindl-Rast, Ph.D., a Benedictine monk, co-led a 7-day seminar entitled, “Families in Film, Now and Forever” at Esalen Institute (go to www.gratefulness.org, then search “films”). From July 10-17, 2016, Dr. Lu and Dr. Steindl-Rast will co-lead “The Resilience of the Family in Film: Epics of Love, Loss, and Recovery” and from July 17-24, 2016, “Through Compassion to Serenity in the Mindful Viewing of Japanese and Western Films.” Registration opens in January 2016 at www.esalen.org. If you have ever attended one of Dr. Lu’s seminars at the APA, then you know you will be in for a rich experience at Esalen.
Dr. Heru is with the department of psychiatry at the University of Colorado Denver, Aurora. She is editor of “Working With Families in Medical Settings: A Multidisciplinary Guide for Psychiatrists and Other Health Professionals” (New York: Routledge, 2013).
Movies are storytelling in high definition. Have you ever used movies to teach your students or residents? Have you ever prescribed therapeutic movie watching to your patients, families, or couples? Movie watching helps us to understand and process the challenges we face. Movie watching helps us to imagine new stories for ourselves.
Stories connect us to our own families. The experiences of our elders and other family members are the story of our family and give coherence to our own life story. We may identify with a family member whose life experience resonates with our life experience; maybe it is the relative who perseveres, or the black sheep, or the one with depression, or the pioneer, or the one who settles for happiness or the alcoholic or workaholic. Maybe we cherish stories that connect us to our generation rather than our family, such as stories about a generational war experience or the stories and camaraderie of Alcoholics Anonymous meetings.
Stories help us understand ourselves. Stories give us scripts, maps, mental models, metaphors, and narratives to help us navigate through our lives. Stories are how we explain our lives to others, reach decisions, understand our place in the world, create our identities, and define and teach social and moral values. Many children come to understand the morals of the world by reading about the lives of animals in Aesop’s Fables. How often do parents have to read the same story over and over to their child? Familiar stories give our lives a narrative structure that is familiar, predictable, and comforting.
Storytelling is fundamental to all cultures. Stories live in our imagination. We can rehearse imagined experiences and imagine our life story in many different ways. Stories help us step out, step forward, see the world and ourselves. Story reading and movie watching help us imagine. Psychotherapy is a therapeutic way to help patients relinquish old stories and begin to construct a new story about themselves.
Movie watching can be used in therapy and has been studied as a therapeutic tool. Cinema therapy, or movie therapy, is considered a form of supplemental therapy and a form of self-help. Cinema therapy was popularized by Gary Solomon, Ph.D., the first to write on using movies as therapy (“The Motion Picture Prescription: Watch This Movie and Call Me in the Morning.” Santa Rosa, Calif.: Aslan Publishing,1995).
Watching movies was used in one arm of the first long-term investigation to compare different types of early marriage intervention programs. In this study, 174 couples in their first 3 years of marriage were enrolled in one of three treatment arms: conflict management, compassion and acceptance training, or relationship awareness through film. Each arm was equally effective in reducing the 3-year divorce/separation rate for newlyweds from 24% to 11%.
The first arm
The conflict management group learned “active listening” or the “speaker-listener technique.” This technique slows down communication and helps individuals focus on what their partner is saying. The practice requires one spouse to listen and then paraphrase back to the partner what the spouse heard to ensure the message has been properly understood. This technique has been shown to be effective at promoting happier and more satisfying relationships for 3-5 years (see the Prevention and Relationship Enhancement Program). This model provides couples with training in communication and problem-solving skills, as well as relationship expectations, friendship, and commitment.
The second arm
The compassion and acceptance training cohort focused on couples working as a team. Through a series of lectures and exercises, couples were taught to approach their relationships with more compassion and empathy by doing things like listening as a friend, practicing random acts of kindness and affection, and using the language of acceptance. Both programs involved weekly lectures, supervised practice sessions, and homework assignments over the course of a month, for a total investment of roughly 20 hours, with 18 hours of therapy time.
The third arm
The movie-and-talk group attended a 10-minute lecture on the importance of relationship awareness and how watching couples in movies could help spouses pay attention to their own behavior, both constructive and destructive. They spent 10 hours on “movie and talk” with 4 hours outside of the home. After each movie, the couple discussed a list of 12 questions about the screen couple’s interactions. Questions included: “How did the movie partners handle arguments? Were they able to open up and tell each other how they really felt, or did they tend to just snap at each other with anger? Did they try using humor to keep things from getting nasty?” The couple was asked to consider in what way the movie relationship was “similar to or different from your own relationship in this area.”
All couples in the third arm met with a therapist to watch “Two for the Road,” a 1967 romantic comedy about the joys and strains of young love, infidelity, and professional pressures across 10 years of a marriage. They were then led by the therapist in a guided discussion. They went home with a list of 47 movies with intimate relationships as a major plot focus, and were asked to watch 1 a week for the next month, followed by a guided discussion for about 45 minutes. For couples interested in trying the film discussions for themselves, the website ofRonald D. Rogge, Ph.D., offers interactive tools to help with the process, including lists of movies and the discussion questions used.
What happened?
The couples invested in their relationship and began to examine their own behavior. Watching a movie together and having a discussion was therapeutic but did not pathologize their relationship, nor did the partners seek to blame each other. The therapist-led marriage intervention programs available usually require trained therapists, and are expensive and intensive. Can couples work on their relationships on their own? The assumption has been that you need to teach couples skills to manage conflict; this might not be true. This study indicates that relationship storytelling can be a step that couples and families can take, on their own.
Movies also can be used in teaching
Family medicine teachers Catherine M. Weber, Ph.D., and Dr. Hugh J. Silk (Fam Med. 2007;39[5]:317-9) developed a movie-watching curriculum to deepen trainees’ understanding of patients and their families. The curriculum was divided into sections. The family and illness section focused on how family members find a will to help their loved ones, even in the midst of a lack of resources or medical futility. They watched “Lorenzo’s Oil” (1992), “The Straight Story” (2006), and “A River Runs Through It” (1992). The family and loss section examined how families become dysfunctional in the presence of the loss of a loved one and what it takes to heal. They watched “Ordinary People” (1980), “The Barbarian Invasions” (2003), and “The Trip to Bountiful” (1985). The section on family and caregiving identifies the strain of illness on family members who provide direct care to ill patients. They watched “Marvin’s Room” (1996) and “Iris” (2001). The section on the family and substance abuse identified how family members got caught in roles and included “When a Man Loves a Woman” (1994) and “The Days of Wine and Roses” (1962). The section on the extended family and illness illustrated how illness brings people together. They watched “Flawless” (1999), “My House in Umbria” (2003), “Beaches” (1988), and “The Barbarian Invasions (2003).
A more specific look at family systems is provided by the curriculum of Dr. Robin O. Winter and Bruce A. Birnberg (Fam Med. 2005;37[2]:96-8) in a series called “Family Systems at the Movies.” Their overarching objective was to promote an understanding of multigenerational issues, the impact of family secrets and family dynamics, the effect of stress on family life, and the attributes of a functional family. Concepts such as homeostasis, boundaries, coalitions, and scapegoating were then applied to the clinical setting. Selected scenes were chosen from three works: “The Joy Luck Club” (1993), “Shine” (1996), and a TV series called “Secrets and Lies” (2015-).
Regarding early marriage, Dr. Salman Ahktar and Dr. Zoe Billinkoff (Am J Psychoanal. 2011; 71[2]:110-20) used movies to discuss how identity, the development of mutuality, and the synthesis of affection and sensuality develop in early marriage. Their goal was to help therapists develop greater empathy with newly married individuals. They focused on three movies: “Barefoot in the Park” (1967), “Raising Arizona” (1987), and “The Quiet Man” (1952). Regarding divorce, Toni Mandelbaum(Am J Psychoanal. 2011;71[2]:121-33) used movies to illustrate the interplay between dependence and independence using “Eat Pray Love” (2010) and “Kramer vs. Kramer” (1979).
Many psychiatry residency programs have journal clubs and film clubs that use movies as a jumping-off point to deepen trainees’ understanding of psychopathology. Implementing these curricula is a simple way of beginning family training in residency, especially when the use of family videos are curtailed by strict confidentiality rules.
Future ‘family and film’ events
Dr. Francis G. Lu, (www.francislumd.com), a regular presenter at many conferences, including the American Psychiatric Association annual meetings, uses film to promote a deeper understanding of the world around us and within us. In 2007, he and Brother David Steindl-Rast, Ph.D., a Benedictine monk, co-led a 7-day seminar entitled, “Families in Film, Now and Forever” at Esalen Institute (go to www.gratefulness.org, then search “films”). From July 10-17, 2016, Dr. Lu and Dr. Steindl-Rast will co-lead “The Resilience of the Family in Film: Epics of Love, Loss, and Recovery” and from July 17-24, 2016, “Through Compassion to Serenity in the Mindful Viewing of Japanese and Western Films.” Registration opens in January 2016 at www.esalen.org. If you have ever attended one of Dr. Lu’s seminars at the APA, then you know you will be in for a rich experience at Esalen.
Dr. Heru is with the department of psychiatry at the University of Colorado Denver, Aurora. She is editor of “Working With Families in Medical Settings: A Multidisciplinary Guide for Psychiatrists and Other Health Professionals” (New York: Routledge, 2013).
Beta-Blockers Increase Mortality in Hypertensive Patients
NEW YORK - Perioperative beta-blocker use in patients with hypertension is associated with increased cardiovascular complications and mortality after noncardiac surgery, researchers from Denmark report.
"The consistency of the findings of increased risks associated with beta-blockers across numerous subgroups was an important finding," Dr. Mads Emil Jorgensen from Gentofte Hospital in Hellerup said by email. "It supports our concern that in a low-risk population, beta-blocker-associated risks may outweigh the advantages of the treatment, in a wide range of low-risk patients."
Several studies have shown that perioperative beta-blocker use may benefit patients at high cardiac risk, but may increase mortality in others. Guidelines from the United States and Europe support continuing beta-blocker use perioperatively in patients already using being treated with them, but literature support for these recommendations is sparse.
Dr. Jorgensen's team used data from Statistics Denmark to investigate whether perioperative beta-blocker use is associated with an increased risk of major adverse cardiovascular events (MACEs) and all-cause mortality in the 30 days after noncardiac surgery in hypertensive patients free of cardiac, renal, and liver disease.
Among 14,644 patients treated with beta-blockers and 40,676 patients treated with other antihypertensives, the incidence of 30-day MACEs was significantly higher among those taking beta-blockers than among those taking other antihypertensives (1.32% vs. 0.84%, p<0.001).
Thirty-day all-cause mortality was also significantly higher in the beta-blocker group than in the other antihypertensives group (1.93% vs. 1.32%, p<0.001), the researchers report in JAMA Internal Medicine, online Oct. 5.
With the exception of combinations that included beta-blockers and two other antihypertensive drugs, all regimens that included a beta-blocker were associated with significantly increased risks of MACE and all-cause mortality, compared with regimens of renin-angiotensin system inhibitors and thiazides.
Results were comparable in subgroup analyses of diabetics versus nondiabetics and patients with low risk versus elevated risk.
The elevated risks were especially notable among patients at least 70 years old (number needed to harm, NNH, 140), men (NNH, 142), and patients undergoing acute surgery (NNH, 97).
"This study, among others, presents the case that the beneficial effects of beta-blockers might be subgroup dependent and that beta-blockers may not be the safe haven that previous perioperative guidelines have suggested," Dr. Jorgensen concluded. "More studies are needed to further the understanding of patient subgroups at risk, preferably in the setting of a randomized trial."
"The use of beta-blockers in 1 out of 4 patients with uncomplicated hypertension was higher than expected, as beta-blockers are no longer first-line drugs for treating hypertension," Dr. Jorgensen noted. "The high prevalence of beta-blocker use in this patient group underlines the clinical importance of these findings."
"Although we cannot conclude on whether the therapy should be changed prior to surgery, clinicians might want to pay special attention to these otherwise low-risk patients in the perioperative setting," he said.
"It is important to keep in mind that our population consisted of hypertensive patients without cardiac, renal or liver disease; thus not all patients with hypertension receiving a beta-blocker are expected to be at increased risk," Dr. Jorgensen cautioned. "Several conditions may necessitate and fully justify the use of beta-blockers, such as congestive heart failure or recent myocardial infarction, as demonstrated in a previous study from our research group."
Dr. Mark L. Friedell from the University of Missouri Kansas City School of Medicine in Kansas City coauthored one of the earlier reports that called into question the safety of perioperative beta-blocker use in low-risk patients. He said by email, "I was surprised at the higher mortality of patients with no cardiac risk factors. But, when taking the POISE trial into consideration, it makes sense that patients with no risk factors might be the ones most harmed by hypotension/stroke since there was no counter balance of cardiac protection such as that given to the patients with 3-4 cardiac risk factors."
His conclusion: "Patients with no or 1-2 cardiac risk factors do not need to be started on a beta-blocker perioperatively to try to mitigate cardiac risk."
"I think patients with perioperative hypertension and tachycardia could probably still be treated with short-acting beta-blockers," Dr. Friedell said. "If starting a beta-blocker in preparation for surgery (3-4 cardiac risk factors), do it at least a week in advance."
Dr. Elisabetta Patorno from Harvard Medical School in Boston recently coauthored a report of patterns of beta-blocker initiation in patients undergoing noncardiac surgery.
"These findings are just one piece of information and it is important not to overreact to only one study," she cautioned in an email. "These findings should be considered in addition to other available research, recommendations from professional societies like the American Heart Association, and patient specific considerations, when deciding regarding the perioperative management of patients with hypertension."
"Doctors should also balance these findings in light of the possible problems associated with this study," Dr. Patorno said. "Beta-blockers are not typically a first-line treatment for hypertension, so it is conceivable that the study participants treated with beta-blockers may have had a longer history and greater severity of hypertension compared with the patients treated with other antihypertensive therapy (the comparison group used in this study). This suggests the groups may be inherently different, with the implication that the underlying differential severity of hypertension and not the specific treatment may be responsible for the post-surgical increased risk of cardiovascular events and mortality observed among patients treated with beta-blocker therapy."
"Finally," she said, "as this study focuses on chronic antihypertensive users only, the question of whether there is real benefit or harm associated with initiating beta-blocker therapy prior to surgery remains unanswered."
Dr. Hermann Blessberger from Johannes Kepler University Linz School of Medicine, Linz, Austria, who has coauthored several papers regarding perioperative beta-blocker use, offered similar comments.
"We learned from our meta-analysis that dosage of beta-blockers (heart rate titrated), time point of start of beta-blockers before surgery (at least 2 weeks prior to surgery to allow the circulatory system to accommodate) as well as type of beta-blocker (issue with metoprolol metabolism - blood level may be heavily increased in poor metabolizers) are crucial," he said. "Except for the type of beta-blocker (mainly metoprolol and atenolol) this information could not be provided in this article as we can read in the discussion section but may be important."
"If a patient suffers from arterial hypertension, do not use a beta-blocker for initial treatment unless a beta-blocker seems desirable for another condition (rhythm disturbances, coronary heart disease, hyperthyroidism, etc.)," he advised.
NEW YORK - Perioperative beta-blocker use in patients with hypertension is associated with increased cardiovascular complications and mortality after noncardiac surgery, researchers from Denmark report.
"The consistency of the findings of increased risks associated with beta-blockers across numerous subgroups was an important finding," Dr. Mads Emil Jorgensen from Gentofte Hospital in Hellerup said by email. "It supports our concern that in a low-risk population, beta-blocker-associated risks may outweigh the advantages of the treatment, in a wide range of low-risk patients."
Several studies have shown that perioperative beta-blocker use may benefit patients at high cardiac risk, but may increase mortality in others. Guidelines from the United States and Europe support continuing beta-blocker use perioperatively in patients already using being treated with them, but literature support for these recommendations is sparse.
Dr. Jorgensen's team used data from Statistics Denmark to investigate whether perioperative beta-blocker use is associated with an increased risk of major adverse cardiovascular events (MACEs) and all-cause mortality in the 30 days after noncardiac surgery in hypertensive patients free of cardiac, renal, and liver disease.
Among 14,644 patients treated with beta-blockers and 40,676 patients treated with other antihypertensives, the incidence of 30-day MACEs was significantly higher among those taking beta-blockers than among those taking other antihypertensives (1.32% vs. 0.84%, p<0.001).
Thirty-day all-cause mortality was also significantly higher in the beta-blocker group than in the other antihypertensives group (1.93% vs. 1.32%, p<0.001), the researchers report in JAMA Internal Medicine, online Oct. 5.
With the exception of combinations that included beta-blockers and two other antihypertensive drugs, all regimens that included a beta-blocker were associated with significantly increased risks of MACE and all-cause mortality, compared with regimens of renin-angiotensin system inhibitors and thiazides.
Results were comparable in subgroup analyses of diabetics versus nondiabetics and patients with low risk versus elevated risk.
The elevated risks were especially notable among patients at least 70 years old (number needed to harm, NNH, 140), men (NNH, 142), and patients undergoing acute surgery (NNH, 97).
"This study, among others, presents the case that the beneficial effects of beta-blockers might be subgroup dependent and that beta-blockers may not be the safe haven that previous perioperative guidelines have suggested," Dr. Jorgensen concluded. "More studies are needed to further the understanding of patient subgroups at risk, preferably in the setting of a randomized trial."
"The use of beta-blockers in 1 out of 4 patients with uncomplicated hypertension was higher than expected, as beta-blockers are no longer first-line drugs for treating hypertension," Dr. Jorgensen noted. "The high prevalence of beta-blocker use in this patient group underlines the clinical importance of these findings."
"Although we cannot conclude on whether the therapy should be changed prior to surgery, clinicians might want to pay special attention to these otherwise low-risk patients in the perioperative setting," he said.
"It is important to keep in mind that our population consisted of hypertensive patients without cardiac, renal or liver disease; thus not all patients with hypertension receiving a beta-blocker are expected to be at increased risk," Dr. Jorgensen cautioned. "Several conditions may necessitate and fully justify the use of beta-blockers, such as congestive heart failure or recent myocardial infarction, as demonstrated in a previous study from our research group."
Dr. Mark L. Friedell from the University of Missouri Kansas City School of Medicine in Kansas City coauthored one of the earlier reports that called into question the safety of perioperative beta-blocker use in low-risk patients. He said by email, "I was surprised at the higher mortality of patients with no cardiac risk factors. But, when taking the POISE trial into consideration, it makes sense that patients with no risk factors might be the ones most harmed by hypotension/stroke since there was no counter balance of cardiac protection such as that given to the patients with 3-4 cardiac risk factors."
His conclusion: "Patients with no or 1-2 cardiac risk factors do not need to be started on a beta-blocker perioperatively to try to mitigate cardiac risk."
"I think patients with perioperative hypertension and tachycardia could probably still be treated with short-acting beta-blockers," Dr. Friedell said. "If starting a beta-blocker in preparation for surgery (3-4 cardiac risk factors), do it at least a week in advance."
Dr. Elisabetta Patorno from Harvard Medical School in Boston recently coauthored a report of patterns of beta-blocker initiation in patients undergoing noncardiac surgery.
"These findings are just one piece of information and it is important not to overreact to only one study," she cautioned in an email. "These findings should be considered in addition to other available research, recommendations from professional societies like the American Heart Association, and patient specific considerations, when deciding regarding the perioperative management of patients with hypertension."
"Doctors should also balance these findings in light of the possible problems associated with this study," Dr. Patorno said. "Beta-blockers are not typically a first-line treatment for hypertension, so it is conceivable that the study participants treated with beta-blockers may have had a longer history and greater severity of hypertension compared with the patients treated with other antihypertensive therapy (the comparison group used in this study). This suggests the groups may be inherently different, with the implication that the underlying differential severity of hypertension and not the specific treatment may be responsible for the post-surgical increased risk of cardiovascular events and mortality observed among patients treated with beta-blocker therapy."
"Finally," she said, "as this study focuses on chronic antihypertensive users only, the question of whether there is real benefit or harm associated with initiating beta-blocker therapy prior to surgery remains unanswered."
Dr. Hermann Blessberger from Johannes Kepler University Linz School of Medicine, Linz, Austria, who has coauthored several papers regarding perioperative beta-blocker use, offered similar comments.
"We learned from our meta-analysis that dosage of beta-blockers (heart rate titrated), time point of start of beta-blockers before surgery (at least 2 weeks prior to surgery to allow the circulatory system to accommodate) as well as type of beta-blocker (issue with metoprolol metabolism - blood level may be heavily increased in poor metabolizers) are crucial," he said. "Except for the type of beta-blocker (mainly metoprolol and atenolol) this information could not be provided in this article as we can read in the discussion section but may be important."
"If a patient suffers from arterial hypertension, do not use a beta-blocker for initial treatment unless a beta-blocker seems desirable for another condition (rhythm disturbances, coronary heart disease, hyperthyroidism, etc.)," he advised.
NEW YORK - Perioperative beta-blocker use in patients with hypertension is associated with increased cardiovascular complications and mortality after noncardiac surgery, researchers from Denmark report.
"The consistency of the findings of increased risks associated with beta-blockers across numerous subgroups was an important finding," Dr. Mads Emil Jorgensen from Gentofte Hospital in Hellerup said by email. "It supports our concern that in a low-risk population, beta-blocker-associated risks may outweigh the advantages of the treatment, in a wide range of low-risk patients."
Several studies have shown that perioperative beta-blocker use may benefit patients at high cardiac risk, but may increase mortality in others. Guidelines from the United States and Europe support continuing beta-blocker use perioperatively in patients already using being treated with them, but literature support for these recommendations is sparse.
Dr. Jorgensen's team used data from Statistics Denmark to investigate whether perioperative beta-blocker use is associated with an increased risk of major adverse cardiovascular events (MACEs) and all-cause mortality in the 30 days after noncardiac surgery in hypertensive patients free of cardiac, renal, and liver disease.
Among 14,644 patients treated with beta-blockers and 40,676 patients treated with other antihypertensives, the incidence of 30-day MACEs was significantly higher among those taking beta-blockers than among those taking other antihypertensives (1.32% vs. 0.84%, p<0.001).
Thirty-day all-cause mortality was also significantly higher in the beta-blocker group than in the other antihypertensives group (1.93% vs. 1.32%, p<0.001), the researchers report in JAMA Internal Medicine, online Oct. 5.
With the exception of combinations that included beta-blockers and two other antihypertensive drugs, all regimens that included a beta-blocker were associated with significantly increased risks of MACE and all-cause mortality, compared with regimens of renin-angiotensin system inhibitors and thiazides.
Results were comparable in subgroup analyses of diabetics versus nondiabetics and patients with low risk versus elevated risk.
The elevated risks were especially notable among patients at least 70 years old (number needed to harm, NNH, 140), men (NNH, 142), and patients undergoing acute surgery (NNH, 97).
"This study, among others, presents the case that the beneficial effects of beta-blockers might be subgroup dependent and that beta-blockers may not be the safe haven that previous perioperative guidelines have suggested," Dr. Jorgensen concluded. "More studies are needed to further the understanding of patient subgroups at risk, preferably in the setting of a randomized trial."
"The use of beta-blockers in 1 out of 4 patients with uncomplicated hypertension was higher than expected, as beta-blockers are no longer first-line drugs for treating hypertension," Dr. Jorgensen noted. "The high prevalence of beta-blocker use in this patient group underlines the clinical importance of these findings."
"Although we cannot conclude on whether the therapy should be changed prior to surgery, clinicians might want to pay special attention to these otherwise low-risk patients in the perioperative setting," he said.
"It is important to keep in mind that our population consisted of hypertensive patients without cardiac, renal or liver disease; thus not all patients with hypertension receiving a beta-blocker are expected to be at increased risk," Dr. Jorgensen cautioned. "Several conditions may necessitate and fully justify the use of beta-blockers, such as congestive heart failure or recent myocardial infarction, as demonstrated in a previous study from our research group."
Dr. Mark L. Friedell from the University of Missouri Kansas City School of Medicine in Kansas City coauthored one of the earlier reports that called into question the safety of perioperative beta-blocker use in low-risk patients. He said by email, "I was surprised at the higher mortality of patients with no cardiac risk factors. But, when taking the POISE trial into consideration, it makes sense that patients with no risk factors might be the ones most harmed by hypotension/stroke since there was no counter balance of cardiac protection such as that given to the patients with 3-4 cardiac risk factors."
His conclusion: "Patients with no or 1-2 cardiac risk factors do not need to be started on a beta-blocker perioperatively to try to mitigate cardiac risk."
"I think patients with perioperative hypertension and tachycardia could probably still be treated with short-acting beta-blockers," Dr. Friedell said. "If starting a beta-blocker in preparation for surgery (3-4 cardiac risk factors), do it at least a week in advance."
Dr. Elisabetta Patorno from Harvard Medical School in Boston recently coauthored a report of patterns of beta-blocker initiation in patients undergoing noncardiac surgery.
"These findings are just one piece of information and it is important not to overreact to only one study," she cautioned in an email. "These findings should be considered in addition to other available research, recommendations from professional societies like the American Heart Association, and patient specific considerations, when deciding regarding the perioperative management of patients with hypertension."
"Doctors should also balance these findings in light of the possible problems associated with this study," Dr. Patorno said. "Beta-blockers are not typically a first-line treatment for hypertension, so it is conceivable that the study participants treated with beta-blockers may have had a longer history and greater severity of hypertension compared with the patients treated with other antihypertensive therapy (the comparison group used in this study). This suggests the groups may be inherently different, with the implication that the underlying differential severity of hypertension and not the specific treatment may be responsible for the post-surgical increased risk of cardiovascular events and mortality observed among patients treated with beta-blocker therapy."
"Finally," she said, "as this study focuses on chronic antihypertensive users only, the question of whether there is real benefit or harm associated with initiating beta-blocker therapy prior to surgery remains unanswered."
Dr. Hermann Blessberger from Johannes Kepler University Linz School of Medicine, Linz, Austria, who has coauthored several papers regarding perioperative beta-blocker use, offered similar comments.
"We learned from our meta-analysis that dosage of beta-blockers (heart rate titrated), time point of start of beta-blockers before surgery (at least 2 weeks prior to surgery to allow the circulatory system to accommodate) as well as type of beta-blocker (issue with metoprolol metabolism - blood level may be heavily increased in poor metabolizers) are crucial," he said. "Except for the type of beta-blocker (mainly metoprolol and atenolol) this information could not be provided in this article as we can read in the discussion section but may be important."
"If a patient suffers from arterial hypertension, do not use a beta-blocker for initial treatment unless a beta-blocker seems desirable for another condition (rhythm disturbances, coronary heart disease, hyperthyroidism, etc.)," he advised.