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Some MCL patients can safely stop venetoclax-ibrutinib, study suggests
ORLANDO – Updated trial results have revealed durable responses with venetoclax and ibrutinib in patients with mantle cell lymphoma (MCL), allowing some patients to stop treatment.
Five of 24 patients were able to stop treatment after achieving minimal residual disease (MRD)-negative complete responses (CRs). Four of these patients remain in CR at up to 18 months off treatment, although one patient ultimately progressed and died.
“Treatment cessation was feasible for patients in MRD-negative complete responses, raising the prospect of limited-duration, targeted-agent therapy in the management of relapsed/refractory mantle cell lymphoma,” said Sasanka M. Handunnetti, MBBS, of Peter MacCallum Cancer Centre in Melbourne. Dr. Handunnetti presented these results, from the AIM trial, at the annual meeting of the American Society of Hematology.
The phase 2 trial enrolled 24 patients. At baseline, patients had a median age of 68 years (range, 47-81 years), and 88% were men. One patient was treatment-naive, but the rest had relapsed/refractory MCL. These patients had received a median of two prior therapies (range, 1-6).
The patients received venetoclax at 400 mg daily and ibrutinib at 560 mg daily.
In the primary analysis, the CR rate was 62% at week 16 and 71% overall, according to positron-emission tomography/computed tomography. MRD negativity was achieved by 67% of patients according to flow cytometry and 38% according to allele-specific oligonucleotide polymerase chain reaction (N Engl J Med. 2018 Mar 29;378[13]:1211-23).
Response and survival
For the current analysis, the median follow up was 37.5 months (range, 1.4-45.3 months). The median duration of response has not been reached, the median progression-free survival is 29 months, and the median overall survival is 32 months.
Thirteen patients have died, 8 of them due to progressive disease. The remaining 11 patients are still alive, and 9 of them are still in CR. One patient is still in partial response, and one has not responded but remains on ibrutinib and venetoclax.
Dr. Handunnetti pointed out that 12 patients had TP53 aberrations, and 8 of them died, but 4 remain alive and in CR. All four patients with SMARCA4 aberrations died.
Treatment status
Five patients are still receiving treatment with ibrutinib and venetoclax, and one patient is receiving only venetoclax. One patient went off study treatment due to a diagnosis of myelodysplastic syndrome, but that patient’s MCL is still in CR.
Five patients were able to stop treatment after achieving MRD-negative CR and were placed under “stringent surveillance,” Dr. Handunnetti said.
One of the five patients who stopped treatment progressed at 7 months and died. The remaining four patients are still alive and in CR at 6 months, 13 months, 17 months, and 18 months off treatment.
Safety update
Within the first 56 weeks of treatment, 15 patients required dose adjustments. Twelve patients required an adjustment to ibrutinib, seven to venetoclax, and four to both drugs. After 56 weeks, there were no dose adjustments.
Two patients developed therapy-related myelodysplastic syndrome. One patient had previously received FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The other patient had received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
This investigator-initiated trial was funded by Janssen and Abbvie. Dr. Handunnetti reported relationships with Abbvie and Gilead.
SOURCE: Handunnetti S et al. ASH 2019. Abstract 756.
ORLANDO – Updated trial results have revealed durable responses with venetoclax and ibrutinib in patients with mantle cell lymphoma (MCL), allowing some patients to stop treatment.
Five of 24 patients were able to stop treatment after achieving minimal residual disease (MRD)-negative complete responses (CRs). Four of these patients remain in CR at up to 18 months off treatment, although one patient ultimately progressed and died.
“Treatment cessation was feasible for patients in MRD-negative complete responses, raising the prospect of limited-duration, targeted-agent therapy in the management of relapsed/refractory mantle cell lymphoma,” said Sasanka M. Handunnetti, MBBS, of Peter MacCallum Cancer Centre in Melbourne. Dr. Handunnetti presented these results, from the AIM trial, at the annual meeting of the American Society of Hematology.
The phase 2 trial enrolled 24 patients. At baseline, patients had a median age of 68 years (range, 47-81 years), and 88% were men. One patient was treatment-naive, but the rest had relapsed/refractory MCL. These patients had received a median of two prior therapies (range, 1-6).
The patients received venetoclax at 400 mg daily and ibrutinib at 560 mg daily.
In the primary analysis, the CR rate was 62% at week 16 and 71% overall, according to positron-emission tomography/computed tomography. MRD negativity was achieved by 67% of patients according to flow cytometry and 38% according to allele-specific oligonucleotide polymerase chain reaction (N Engl J Med. 2018 Mar 29;378[13]:1211-23).
Response and survival
For the current analysis, the median follow up was 37.5 months (range, 1.4-45.3 months). The median duration of response has not been reached, the median progression-free survival is 29 months, and the median overall survival is 32 months.
Thirteen patients have died, 8 of them due to progressive disease. The remaining 11 patients are still alive, and 9 of them are still in CR. One patient is still in partial response, and one has not responded but remains on ibrutinib and venetoclax.
Dr. Handunnetti pointed out that 12 patients had TP53 aberrations, and 8 of them died, but 4 remain alive and in CR. All four patients with SMARCA4 aberrations died.
Treatment status
Five patients are still receiving treatment with ibrutinib and venetoclax, and one patient is receiving only venetoclax. One patient went off study treatment due to a diagnosis of myelodysplastic syndrome, but that patient’s MCL is still in CR.
Five patients were able to stop treatment after achieving MRD-negative CR and were placed under “stringent surveillance,” Dr. Handunnetti said.
One of the five patients who stopped treatment progressed at 7 months and died. The remaining four patients are still alive and in CR at 6 months, 13 months, 17 months, and 18 months off treatment.
Safety update
Within the first 56 weeks of treatment, 15 patients required dose adjustments. Twelve patients required an adjustment to ibrutinib, seven to venetoclax, and four to both drugs. After 56 weeks, there were no dose adjustments.
Two patients developed therapy-related myelodysplastic syndrome. One patient had previously received FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The other patient had received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
This investigator-initiated trial was funded by Janssen and Abbvie. Dr. Handunnetti reported relationships with Abbvie and Gilead.
SOURCE: Handunnetti S et al. ASH 2019. Abstract 756.
ORLANDO – Updated trial results have revealed durable responses with venetoclax and ibrutinib in patients with mantle cell lymphoma (MCL), allowing some patients to stop treatment.
Five of 24 patients were able to stop treatment after achieving minimal residual disease (MRD)-negative complete responses (CRs). Four of these patients remain in CR at up to 18 months off treatment, although one patient ultimately progressed and died.
“Treatment cessation was feasible for patients in MRD-negative complete responses, raising the prospect of limited-duration, targeted-agent therapy in the management of relapsed/refractory mantle cell lymphoma,” said Sasanka M. Handunnetti, MBBS, of Peter MacCallum Cancer Centre in Melbourne. Dr. Handunnetti presented these results, from the AIM trial, at the annual meeting of the American Society of Hematology.
The phase 2 trial enrolled 24 patients. At baseline, patients had a median age of 68 years (range, 47-81 years), and 88% were men. One patient was treatment-naive, but the rest had relapsed/refractory MCL. These patients had received a median of two prior therapies (range, 1-6).
The patients received venetoclax at 400 mg daily and ibrutinib at 560 mg daily.
In the primary analysis, the CR rate was 62% at week 16 and 71% overall, according to positron-emission tomography/computed tomography. MRD negativity was achieved by 67% of patients according to flow cytometry and 38% according to allele-specific oligonucleotide polymerase chain reaction (N Engl J Med. 2018 Mar 29;378[13]:1211-23).
Response and survival
For the current analysis, the median follow up was 37.5 months (range, 1.4-45.3 months). The median duration of response has not been reached, the median progression-free survival is 29 months, and the median overall survival is 32 months.
Thirteen patients have died, 8 of them due to progressive disease. The remaining 11 patients are still alive, and 9 of them are still in CR. One patient is still in partial response, and one has not responded but remains on ibrutinib and venetoclax.
Dr. Handunnetti pointed out that 12 patients had TP53 aberrations, and 8 of them died, but 4 remain alive and in CR. All four patients with SMARCA4 aberrations died.
Treatment status
Five patients are still receiving treatment with ibrutinib and venetoclax, and one patient is receiving only venetoclax. One patient went off study treatment due to a diagnosis of myelodysplastic syndrome, but that patient’s MCL is still in CR.
Five patients were able to stop treatment after achieving MRD-negative CR and were placed under “stringent surveillance,” Dr. Handunnetti said.
One of the five patients who stopped treatment progressed at 7 months and died. The remaining four patients are still alive and in CR at 6 months, 13 months, 17 months, and 18 months off treatment.
Safety update
Within the first 56 weeks of treatment, 15 patients required dose adjustments. Twelve patients required an adjustment to ibrutinib, seven to venetoclax, and four to both drugs. After 56 weeks, there were no dose adjustments.
Two patients developed therapy-related myelodysplastic syndrome. One patient had previously received FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The other patient had received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
This investigator-initiated trial was funded by Janssen and Abbvie. Dr. Handunnetti reported relationships with Abbvie and Gilead.
SOURCE: Handunnetti S et al. ASH 2019. Abstract 756.
REPORTING FROM ASH 2019
BCL11A-directed gene therapy advances in sickle cell disease
ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.
Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.
The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.
BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.
Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.
The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.
“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.
Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.
“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.
The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.
Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.
Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.
Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.
“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.
Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.
SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.
ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.
Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.
The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.
BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.
Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.
The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.
“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.
Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.
“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.
The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.
Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.
Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.
Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.
“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.
Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.
SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.
ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.
Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.
The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.
BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.
Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.
The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.
“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.
Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.
“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.
The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.
Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.
Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.
Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.
“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.
Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.
SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.
REPORTING FROM ASH 2019
KTE-X19 produces highest response rate in MCL subgroup
ORLANDO – KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated unprecedented efficacy in the ZUMA-2 trial, according to an investigator involved in the study.
KTE-X19 produced a 93% overall response rate in patients with relapsed/refractory mantle cell lymphoma (MCL). This is the highest reported response rate in patients who have failed treatment with a Bruton’s tyrosine kinase (BTK) inhibitor, said Michael L. Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.
Dr. Wang presented results from ZUMA-2 at the annual meeting of the American Society of Hematology.
“Patients with relapsed/refractory MCL have very poor outcomes,” Dr. Wang noted. “In patients who progress after BTK inhibition therapy, the overall response rate is only between 25% and 42%, and the overall survival is only between 6 and 10 months. Few patients proceed to allogeneic transplantation.”
The phase 2 ZUMA-2 trial was designed to test KTE-X19 in these patients. KTE-X19 is an anti-CD19 CAR T-cell therapy containing a CD3-zeta T-cell activation domain and a CD28 signaling domain. KTE-X19 is distinct from axicabtagene ciloleucel (KTE-C19) because the manufacturing process for KTE-X19 removes circulating tumor cells.
The trial enrolled 74 patients, and 68 of them received KTE-X19. Manufacturing failed for three patients, two patients died of progressive disease before they could receive KTE-X19, and one patient was found to be ineligible for treatment.
The 68 patients had a median age of 65 years (range, 38-79 years), and 84% were men. A majority of patients (85%) had stage IV disease and classical (59%) or blastoid (25%) morphology. Most patients (69%) had a Ki-67 proliferation index of 50% or greater, and most (56%) were intermediate- or high-risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI).
Patients had received a median of three prior therapies (range, one to five). All had been treated with a BTK inhibitor, with 85% receiving ibrutinib, 24% receiving acalabrutinib, and 9% receiving both. Most patients (68%) were refractory to BTK inhibition, and 32% relapsed on or after BTK inhibitor therapy.
In this study, patients could receive bridging therapy to keep their disease stable while KTE-X19 was being manufactured. There were 25 patients who received bridging therapy, which consisted of ibrutinib (n = 14), acalabrutinib (n = 5), dexamethasone (n = 12), and/or methylprednisolone (n = 2). Six patients received both BTK inhibitors and steroids.
All patients received conditioning with fludarabine and cyclophosphamide, followed by a single infusion of KTE-X19 at 2x106.
Efficacy
Sixty patients were evaluable for efficacy, and the median follow-up was 12.3 months (range, 7.0-32.3 months).
The overall response rate was 93%, with 67% of patients achieving a complete response and 27% achieving a partial response. Three percent of patients had stable disease, and 3% had progressive disease.
“The overall response rate was consistent across key subgroups, without any statistical difference,” Dr. Wang said. “This includes Ki-67, MIPI, and prior use of either steroids or bridging therapy.”
The median time to response was 1.0 month, and the median time to complete response was 3.0 months. Responses deepened over time, with 35% of patients converting from a partial response to a complete response, and 5% converting from stable disease to complete response.
The median duration of response has not been reached. At last follow-up, 57% of all patients and 78% of complete responders were still in response.
The median progression-free and overall survival have not been reached. At 12 months, the progression-free survival rate was 61%, and the overall survival rate was 83%.
Safety
All 68 patients were evaluable for safety. The most common adverse events were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%).
Grade 3/4 adverse events included pyrexia (13%), neutropenia (85%), thrombocytopenia (51%), anemia (50%), hypotension (22%), hypoxia (21%), hypophosphatemia (22%), fatigue (1%), and headache (1%).
There were two grade 5 treatment-related adverse events – organizing pneumonia on day 37 and staphylococcal bacteremia on day 134.
Cytokine release syndrome (CRS) occurred in 91% of patients, with 15% experiencing grade 3 or higher CRS. Patients were treated with tocilizumab or corticosteroids, and all CRS events resolved.
Neurologic adverse events occurred in 63% of patients, with grade 3 or higher events occurring in 31%. Neurologic events were treated with tocilizumab or corticosteroids, and 86% of neurologic events resolved.
This trial was sponsored by Kite, a Gilead company. Dr. Wang reported financial relationships with Kite and other companies.
SOURCE: Wang M et al. ASH 2019. Abstract 754.
ORLANDO – KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated unprecedented efficacy in the ZUMA-2 trial, according to an investigator involved in the study.
KTE-X19 produced a 93% overall response rate in patients with relapsed/refractory mantle cell lymphoma (MCL). This is the highest reported response rate in patients who have failed treatment with a Bruton’s tyrosine kinase (BTK) inhibitor, said Michael L. Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.
Dr. Wang presented results from ZUMA-2 at the annual meeting of the American Society of Hematology.
“Patients with relapsed/refractory MCL have very poor outcomes,” Dr. Wang noted. “In patients who progress after BTK inhibition therapy, the overall response rate is only between 25% and 42%, and the overall survival is only between 6 and 10 months. Few patients proceed to allogeneic transplantation.”
The phase 2 ZUMA-2 trial was designed to test KTE-X19 in these patients. KTE-X19 is an anti-CD19 CAR T-cell therapy containing a CD3-zeta T-cell activation domain and a CD28 signaling domain. KTE-X19 is distinct from axicabtagene ciloleucel (KTE-C19) because the manufacturing process for KTE-X19 removes circulating tumor cells.
The trial enrolled 74 patients, and 68 of them received KTE-X19. Manufacturing failed for three patients, two patients died of progressive disease before they could receive KTE-X19, and one patient was found to be ineligible for treatment.
The 68 patients had a median age of 65 years (range, 38-79 years), and 84% were men. A majority of patients (85%) had stage IV disease and classical (59%) or blastoid (25%) morphology. Most patients (69%) had a Ki-67 proliferation index of 50% or greater, and most (56%) were intermediate- or high-risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI).
Patients had received a median of three prior therapies (range, one to five). All had been treated with a BTK inhibitor, with 85% receiving ibrutinib, 24% receiving acalabrutinib, and 9% receiving both. Most patients (68%) were refractory to BTK inhibition, and 32% relapsed on or after BTK inhibitor therapy.
In this study, patients could receive bridging therapy to keep their disease stable while KTE-X19 was being manufactured. There were 25 patients who received bridging therapy, which consisted of ibrutinib (n = 14), acalabrutinib (n = 5), dexamethasone (n = 12), and/or methylprednisolone (n = 2). Six patients received both BTK inhibitors and steroids.
All patients received conditioning with fludarabine and cyclophosphamide, followed by a single infusion of KTE-X19 at 2x106.
Efficacy
Sixty patients were evaluable for efficacy, and the median follow-up was 12.3 months (range, 7.0-32.3 months).
The overall response rate was 93%, with 67% of patients achieving a complete response and 27% achieving a partial response. Three percent of patients had stable disease, and 3% had progressive disease.
“The overall response rate was consistent across key subgroups, without any statistical difference,” Dr. Wang said. “This includes Ki-67, MIPI, and prior use of either steroids or bridging therapy.”
The median time to response was 1.0 month, and the median time to complete response was 3.0 months. Responses deepened over time, with 35% of patients converting from a partial response to a complete response, and 5% converting from stable disease to complete response.
The median duration of response has not been reached. At last follow-up, 57% of all patients and 78% of complete responders were still in response.
The median progression-free and overall survival have not been reached. At 12 months, the progression-free survival rate was 61%, and the overall survival rate was 83%.
Safety
All 68 patients were evaluable for safety. The most common adverse events were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%).
Grade 3/4 adverse events included pyrexia (13%), neutropenia (85%), thrombocytopenia (51%), anemia (50%), hypotension (22%), hypoxia (21%), hypophosphatemia (22%), fatigue (1%), and headache (1%).
There were two grade 5 treatment-related adverse events – organizing pneumonia on day 37 and staphylococcal bacteremia on day 134.
Cytokine release syndrome (CRS) occurred in 91% of patients, with 15% experiencing grade 3 or higher CRS. Patients were treated with tocilizumab or corticosteroids, and all CRS events resolved.
Neurologic adverse events occurred in 63% of patients, with grade 3 or higher events occurring in 31%. Neurologic events were treated with tocilizumab or corticosteroids, and 86% of neurologic events resolved.
This trial was sponsored by Kite, a Gilead company. Dr. Wang reported financial relationships with Kite and other companies.
SOURCE: Wang M et al. ASH 2019. Abstract 754.
ORLANDO – KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated unprecedented efficacy in the ZUMA-2 trial, according to an investigator involved in the study.
KTE-X19 produced a 93% overall response rate in patients with relapsed/refractory mantle cell lymphoma (MCL). This is the highest reported response rate in patients who have failed treatment with a Bruton’s tyrosine kinase (BTK) inhibitor, said Michael L. Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.
Dr. Wang presented results from ZUMA-2 at the annual meeting of the American Society of Hematology.
“Patients with relapsed/refractory MCL have very poor outcomes,” Dr. Wang noted. “In patients who progress after BTK inhibition therapy, the overall response rate is only between 25% and 42%, and the overall survival is only between 6 and 10 months. Few patients proceed to allogeneic transplantation.”
The phase 2 ZUMA-2 trial was designed to test KTE-X19 in these patients. KTE-X19 is an anti-CD19 CAR T-cell therapy containing a CD3-zeta T-cell activation domain and a CD28 signaling domain. KTE-X19 is distinct from axicabtagene ciloleucel (KTE-C19) because the manufacturing process for KTE-X19 removes circulating tumor cells.
The trial enrolled 74 patients, and 68 of them received KTE-X19. Manufacturing failed for three patients, two patients died of progressive disease before they could receive KTE-X19, and one patient was found to be ineligible for treatment.
The 68 patients had a median age of 65 years (range, 38-79 years), and 84% were men. A majority of patients (85%) had stage IV disease and classical (59%) or blastoid (25%) morphology. Most patients (69%) had a Ki-67 proliferation index of 50% or greater, and most (56%) were intermediate- or high-risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI).
Patients had received a median of three prior therapies (range, one to five). All had been treated with a BTK inhibitor, with 85% receiving ibrutinib, 24% receiving acalabrutinib, and 9% receiving both. Most patients (68%) were refractory to BTK inhibition, and 32% relapsed on or after BTK inhibitor therapy.
In this study, patients could receive bridging therapy to keep their disease stable while KTE-X19 was being manufactured. There were 25 patients who received bridging therapy, which consisted of ibrutinib (n = 14), acalabrutinib (n = 5), dexamethasone (n = 12), and/or methylprednisolone (n = 2). Six patients received both BTK inhibitors and steroids.
All patients received conditioning with fludarabine and cyclophosphamide, followed by a single infusion of KTE-X19 at 2x106.
Efficacy
Sixty patients were evaluable for efficacy, and the median follow-up was 12.3 months (range, 7.0-32.3 months).
The overall response rate was 93%, with 67% of patients achieving a complete response and 27% achieving a partial response. Three percent of patients had stable disease, and 3% had progressive disease.
“The overall response rate was consistent across key subgroups, without any statistical difference,” Dr. Wang said. “This includes Ki-67, MIPI, and prior use of either steroids or bridging therapy.”
The median time to response was 1.0 month, and the median time to complete response was 3.0 months. Responses deepened over time, with 35% of patients converting from a partial response to a complete response, and 5% converting from stable disease to complete response.
The median duration of response has not been reached. At last follow-up, 57% of all patients and 78% of complete responders were still in response.
The median progression-free and overall survival have not been reached. At 12 months, the progression-free survival rate was 61%, and the overall survival rate was 83%.
Safety
All 68 patients were evaluable for safety. The most common adverse events were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%).
Grade 3/4 adverse events included pyrexia (13%), neutropenia (85%), thrombocytopenia (51%), anemia (50%), hypotension (22%), hypoxia (21%), hypophosphatemia (22%), fatigue (1%), and headache (1%).
There were two grade 5 treatment-related adverse events – organizing pneumonia on day 37 and staphylococcal bacteremia on day 134.
Cytokine release syndrome (CRS) occurred in 91% of patients, with 15% experiencing grade 3 or higher CRS. Patients were treated with tocilizumab or corticosteroids, and all CRS events resolved.
Neurologic adverse events occurred in 63% of patients, with grade 3 or higher events occurring in 31%. Neurologic events were treated with tocilizumab or corticosteroids, and 86% of neurologic events resolved.
This trial was sponsored by Kite, a Gilead company. Dr. Wang reported financial relationships with Kite and other companies.
SOURCE: Wang M et al. ASH 2019. Abstract 754.
REPORTING FROM ASH 2019
Residual cancer burden linked to long-term survival
SAN ANTONIO – Residual cancer burden (RCB) is poised to alter American Joint Committee on Cancer (AJCC) staging standards in breast cancer, according to investigators.
A meta-analysis showed that RCB – which is calculated in the neoadjuvant setting through a combination of primary tumor bed cellularity, lymph node positivity, and size of largest metastasis – was significantly associated with long-term survival of more than 5,000 breast cancer patients, reported principal investigator W. Fraser Symmans, MD, of MD Anderson Cancer Center, Houston, who presented the findings at the San Antonio Breast Cancer Symposium.
Coinvestigator Laura J. Esserman, MD, of the University of California, San Francisco, who was in attendance at Dr. Symmans’ presentation, put the study in context.
“The reason we did this meta-analysis was to really change the joint commission – the AJCC staging – and we expect that will happen on the basis of these results,” Dr. Esserman said. “[RBC] is, moving forward, the standard of care.”
The investigators analyzed individual-level data from 5,160 patients treated at multiple institutions. For each patient, RCB, which is scored from 0 to III, from pathologic complete response (0) to high disease burden (III), was compared with event-free survival (EFS) and disease relapse-free survival (DRFS).
The results showed that both EFS and DRFS were strongly associated with RCB for the overall population and each subtype. For instance, for triple-negative breast cancer, patients with pathologic complete response had a 10-year EFS of 86%, a rate that decreased as RCB increased from RCB-I (75%) to RCB-II (61%), and finally, RCB-III (25%). This trend was similar for patients with HR-negative/HER2-positive or HR-positive/HER2-positive disease. Risk stratification for HR-positive/HER2-negative disease deviated slightly; pathologic complete response was associated with a 10-year EFS of 81%, compared with 86% for RCB-I.
Regarding this finding, Dr. Symmans noted that RCB is most prognostic when higher levels of residual disease are present. Still, reviewing long-term risk across subtypes, Dr. Fraser emphasized the reliability of RCB as a prognostic tool.
“The strong relationship [between RCB and] risk is very clear in each and every subtype of disease,” he said. “There are very tight confidence intervals around those risk estimates.”
Multivariate analysis provided further support for this conclusion, as RCB was independently prognostic for survival in each subtype of disease.
According to Dr. Esserman, the study findings should encourage implementation of RCB in daily practice.
“There has to be training and a commitment to using this in a consistent way so that we can all rely on the information,” Dr. Esserman said. “This is critical for our patients, and this is ... how we’re going to get people to the best outcome, and [it should be done] up front, when we still have the chance to cure people.”
Session moderator Virginia Kaklamani, MD, of Mays Cancer Center, San Antonio, agreed that clinicians should use RCB in practice; however, she also explained that RCB results for some patients are not yet actionable.
“I ask my pathologist to give me the RCB score,” Dr. Kaklamani said. “The question is, what do I do with the results? It’s a little limited. In triple-negative patients I may consider giving capecitabine in the adjuvant setting, or obviously enrolling them in clinical trials. In my HER2-positive patients, I will look at the results from the KATHERINE trial and the ExteNET trial to guide me. In my HR-positive patients, I’m still waiting for results from other trials to see how these results can be interpreted. What we’ve [found] is in many trials, achieving a pathologic complete response in HR-positive patients may not be as important, but as you can see here, it looks like RCB really is.”
The investigators disclosed relationships with Seattle Genetics, Almac, Syndax, and others.
SOURCE: Yau et al. SABCS. 2019 Dec 13. Abstract GS5-01.
SAN ANTONIO – Residual cancer burden (RCB) is poised to alter American Joint Committee on Cancer (AJCC) staging standards in breast cancer, according to investigators.
A meta-analysis showed that RCB – which is calculated in the neoadjuvant setting through a combination of primary tumor bed cellularity, lymph node positivity, and size of largest metastasis – was significantly associated with long-term survival of more than 5,000 breast cancer patients, reported principal investigator W. Fraser Symmans, MD, of MD Anderson Cancer Center, Houston, who presented the findings at the San Antonio Breast Cancer Symposium.
Coinvestigator Laura J. Esserman, MD, of the University of California, San Francisco, who was in attendance at Dr. Symmans’ presentation, put the study in context.
“The reason we did this meta-analysis was to really change the joint commission – the AJCC staging – and we expect that will happen on the basis of these results,” Dr. Esserman said. “[RBC] is, moving forward, the standard of care.”
The investigators analyzed individual-level data from 5,160 patients treated at multiple institutions. For each patient, RCB, which is scored from 0 to III, from pathologic complete response (0) to high disease burden (III), was compared with event-free survival (EFS) and disease relapse-free survival (DRFS).
The results showed that both EFS and DRFS were strongly associated with RCB for the overall population and each subtype. For instance, for triple-negative breast cancer, patients with pathologic complete response had a 10-year EFS of 86%, a rate that decreased as RCB increased from RCB-I (75%) to RCB-II (61%), and finally, RCB-III (25%). This trend was similar for patients with HR-negative/HER2-positive or HR-positive/HER2-positive disease. Risk stratification for HR-positive/HER2-negative disease deviated slightly; pathologic complete response was associated with a 10-year EFS of 81%, compared with 86% for RCB-I.
Regarding this finding, Dr. Symmans noted that RCB is most prognostic when higher levels of residual disease are present. Still, reviewing long-term risk across subtypes, Dr. Fraser emphasized the reliability of RCB as a prognostic tool.
“The strong relationship [between RCB and] risk is very clear in each and every subtype of disease,” he said. “There are very tight confidence intervals around those risk estimates.”
Multivariate analysis provided further support for this conclusion, as RCB was independently prognostic for survival in each subtype of disease.
According to Dr. Esserman, the study findings should encourage implementation of RCB in daily practice.
“There has to be training and a commitment to using this in a consistent way so that we can all rely on the information,” Dr. Esserman said. “This is critical for our patients, and this is ... how we’re going to get people to the best outcome, and [it should be done] up front, when we still have the chance to cure people.”
Session moderator Virginia Kaklamani, MD, of Mays Cancer Center, San Antonio, agreed that clinicians should use RCB in practice; however, she also explained that RCB results for some patients are not yet actionable.
“I ask my pathologist to give me the RCB score,” Dr. Kaklamani said. “The question is, what do I do with the results? It’s a little limited. In triple-negative patients I may consider giving capecitabine in the adjuvant setting, or obviously enrolling them in clinical trials. In my HER2-positive patients, I will look at the results from the KATHERINE trial and the ExteNET trial to guide me. In my HR-positive patients, I’m still waiting for results from other trials to see how these results can be interpreted. What we’ve [found] is in many trials, achieving a pathologic complete response in HR-positive patients may not be as important, but as you can see here, it looks like RCB really is.”
The investigators disclosed relationships with Seattle Genetics, Almac, Syndax, and others.
SOURCE: Yau et al. SABCS. 2019 Dec 13. Abstract GS5-01.
SAN ANTONIO – Residual cancer burden (RCB) is poised to alter American Joint Committee on Cancer (AJCC) staging standards in breast cancer, according to investigators.
A meta-analysis showed that RCB – which is calculated in the neoadjuvant setting through a combination of primary tumor bed cellularity, lymph node positivity, and size of largest metastasis – was significantly associated with long-term survival of more than 5,000 breast cancer patients, reported principal investigator W. Fraser Symmans, MD, of MD Anderson Cancer Center, Houston, who presented the findings at the San Antonio Breast Cancer Symposium.
Coinvestigator Laura J. Esserman, MD, of the University of California, San Francisco, who was in attendance at Dr. Symmans’ presentation, put the study in context.
“The reason we did this meta-analysis was to really change the joint commission – the AJCC staging – and we expect that will happen on the basis of these results,” Dr. Esserman said. “[RBC] is, moving forward, the standard of care.”
The investigators analyzed individual-level data from 5,160 patients treated at multiple institutions. For each patient, RCB, which is scored from 0 to III, from pathologic complete response (0) to high disease burden (III), was compared with event-free survival (EFS) and disease relapse-free survival (DRFS).
The results showed that both EFS and DRFS were strongly associated with RCB for the overall population and each subtype. For instance, for triple-negative breast cancer, patients with pathologic complete response had a 10-year EFS of 86%, a rate that decreased as RCB increased from RCB-I (75%) to RCB-II (61%), and finally, RCB-III (25%). This trend was similar for patients with HR-negative/HER2-positive or HR-positive/HER2-positive disease. Risk stratification for HR-positive/HER2-negative disease deviated slightly; pathologic complete response was associated with a 10-year EFS of 81%, compared with 86% for RCB-I.
Regarding this finding, Dr. Symmans noted that RCB is most prognostic when higher levels of residual disease are present. Still, reviewing long-term risk across subtypes, Dr. Fraser emphasized the reliability of RCB as a prognostic tool.
“The strong relationship [between RCB and] risk is very clear in each and every subtype of disease,” he said. “There are very tight confidence intervals around those risk estimates.”
Multivariate analysis provided further support for this conclusion, as RCB was independently prognostic for survival in each subtype of disease.
According to Dr. Esserman, the study findings should encourage implementation of RCB in daily practice.
“There has to be training and a commitment to using this in a consistent way so that we can all rely on the information,” Dr. Esserman said. “This is critical for our patients, and this is ... how we’re going to get people to the best outcome, and [it should be done] up front, when we still have the chance to cure people.”
Session moderator Virginia Kaklamani, MD, of Mays Cancer Center, San Antonio, agreed that clinicians should use RCB in practice; however, she also explained that RCB results for some patients are not yet actionable.
“I ask my pathologist to give me the RCB score,” Dr. Kaklamani said. “The question is, what do I do with the results? It’s a little limited. In triple-negative patients I may consider giving capecitabine in the adjuvant setting, or obviously enrolling them in clinical trials. In my HER2-positive patients, I will look at the results from the KATHERINE trial and the ExteNET trial to guide me. In my HR-positive patients, I’m still waiting for results from other trials to see how these results can be interpreted. What we’ve [found] is in many trials, achieving a pathologic complete response in HR-positive patients may not be as important, but as you can see here, it looks like RCB really is.”
The investigators disclosed relationships with Seattle Genetics, Almac, Syndax, and others.
SOURCE: Yau et al. SABCS. 2019 Dec 13. Abstract GS5-01.
REPORTING FROM SABCS 2019
House passes drug pricing bill, likely ending its journey
The House of Representatives passed a partisan drug pricing bill, a move that likely ends its legislative journey as Senate Majority Leader Mitch McConnell (R-Ky.) has already signaled he will not bring it to the Senate floor.
The Elijah E. Cummings Lower Drug Costs Now Act (H.R. 3) passed Dec. 12 on a near party-line vote of 230-192, with two Republicans crossing the aisle to join the Democrats in support of the bill, and no Democrats voting against it. Four members from each party did not record votes.
“The American people are fed up with paying 3, 4, or 10 times more than people in other countries for the exact same drug,” House Energy and Commerce Committee Chairman Frank Pallone (D-N.J) said in a statement following the passage. “I’m proud that the House took decisive action today to finally level the playing field and provide real relief to the American people.”
H.R. 3 would give the secretary of Health and Human Services the ability to negotiate with drug manufacturers on the price of pharmaceuticals in Medicare Part D (and available in the commercial markets) using an international pricing benchmark and would penalize manufacturers who do not negotiate or fail to lower prices to be more in line with generally lower costs internationally.
Drug prices would need to be within 120% of the average price in a reference group of six nations: Australia, Canada, France, Germany, Japan, and the United Kingdom.
Savings from the lower costs that result from negotiations would be reinvested into medical research.
Passage of H.R. 3 would “lower ... medication by 65%” per year for women with breast cancer, Rep. Haley Stevens (D-Mich.) said during the floor debate.
The Congressional Budget Office estimated that the drug price negotiation provision would lower spending on pharmaceuticals by $465 billion over the next 10 years, offset partially by an increase in spending by $358 billion associated with provisions to provide dental, vision, and hearing coverage.
The bill also includes mandatory rebates to the federal government when a drug’s price rises faster than the rate of inflation. It includes an annual cap on out-of-pocket spending on pharmaceuticals of $2,000 for Medicare Part D participants.
The bill was contentious from its introduction, which erased bipartisan work across the committees of jurisdiction, including a number of individual bills that passed at the committee level with bipartisan support.
The price negotiation scheme, using the international benchmark, was a key point of objection, which some argued was more akin to price-setting.
“Government price setting will kill innovation in clinical areas where it is most needed,” Rep. George Holding (R-N.C.) said during the floor debate. “The pricing scheme outlined in H.R. 3 would disincentivize research and development for drugs that are first in their class, such as the future cure for Alzheimer’s.”
The CBO estimates that if the bill were enacted, “8 fewer drugs would be introduced to the U.S. market over the 2020-2029 period, and about 30 fewer drugs over the subsequent decade.”
An amendment offered by House Energy and Commerce Committee Ranking Member Greg Walden (R-Ore.) attempted to replace the language of H.R. 3 with substitute language that collected all the individual drug pricing–related bills that had previously passed with bipartisan support at the committee level, but that was voted down by 223-201 vote with 12 members not voting.
Rep. Walden noted that policies within his substitute “unanimously passed the Energy and Commerce Committee earlier this year. They would have unanimously passed on this House floor had a poison pill not been put in up in the Rules Committee.”
Rep. Katie Porter (D-Calif.) countered that Rep. Walden’s amendment “doesn’t tackle the fundamental problem, which is reducing drug prices. This amendment fails to solve the main problem of actually lowering drug prices.”
The House of Representatives passed a partisan drug pricing bill, a move that likely ends its legislative journey as Senate Majority Leader Mitch McConnell (R-Ky.) has already signaled he will not bring it to the Senate floor.
The Elijah E. Cummings Lower Drug Costs Now Act (H.R. 3) passed Dec. 12 on a near party-line vote of 230-192, with two Republicans crossing the aisle to join the Democrats in support of the bill, and no Democrats voting against it. Four members from each party did not record votes.
“The American people are fed up with paying 3, 4, or 10 times more than people in other countries for the exact same drug,” House Energy and Commerce Committee Chairman Frank Pallone (D-N.J) said in a statement following the passage. “I’m proud that the House took decisive action today to finally level the playing field and provide real relief to the American people.”
H.R. 3 would give the secretary of Health and Human Services the ability to negotiate with drug manufacturers on the price of pharmaceuticals in Medicare Part D (and available in the commercial markets) using an international pricing benchmark and would penalize manufacturers who do not negotiate or fail to lower prices to be more in line with generally lower costs internationally.
Drug prices would need to be within 120% of the average price in a reference group of six nations: Australia, Canada, France, Germany, Japan, and the United Kingdom.
Savings from the lower costs that result from negotiations would be reinvested into medical research.
Passage of H.R. 3 would “lower ... medication by 65%” per year for women with breast cancer, Rep. Haley Stevens (D-Mich.) said during the floor debate.
The Congressional Budget Office estimated that the drug price negotiation provision would lower spending on pharmaceuticals by $465 billion over the next 10 years, offset partially by an increase in spending by $358 billion associated with provisions to provide dental, vision, and hearing coverage.
The bill also includes mandatory rebates to the federal government when a drug’s price rises faster than the rate of inflation. It includes an annual cap on out-of-pocket spending on pharmaceuticals of $2,000 for Medicare Part D participants.
The bill was contentious from its introduction, which erased bipartisan work across the committees of jurisdiction, including a number of individual bills that passed at the committee level with bipartisan support.
The price negotiation scheme, using the international benchmark, was a key point of objection, which some argued was more akin to price-setting.
“Government price setting will kill innovation in clinical areas where it is most needed,” Rep. George Holding (R-N.C.) said during the floor debate. “The pricing scheme outlined in H.R. 3 would disincentivize research and development for drugs that are first in their class, such as the future cure for Alzheimer’s.”
The CBO estimates that if the bill were enacted, “8 fewer drugs would be introduced to the U.S. market over the 2020-2029 period, and about 30 fewer drugs over the subsequent decade.”
An amendment offered by House Energy and Commerce Committee Ranking Member Greg Walden (R-Ore.) attempted to replace the language of H.R. 3 with substitute language that collected all the individual drug pricing–related bills that had previously passed with bipartisan support at the committee level, but that was voted down by 223-201 vote with 12 members not voting.
Rep. Walden noted that policies within his substitute “unanimously passed the Energy and Commerce Committee earlier this year. They would have unanimously passed on this House floor had a poison pill not been put in up in the Rules Committee.”
Rep. Katie Porter (D-Calif.) countered that Rep. Walden’s amendment “doesn’t tackle the fundamental problem, which is reducing drug prices. This amendment fails to solve the main problem of actually lowering drug prices.”
The House of Representatives passed a partisan drug pricing bill, a move that likely ends its legislative journey as Senate Majority Leader Mitch McConnell (R-Ky.) has already signaled he will not bring it to the Senate floor.
The Elijah E. Cummings Lower Drug Costs Now Act (H.R. 3) passed Dec. 12 on a near party-line vote of 230-192, with two Republicans crossing the aisle to join the Democrats in support of the bill, and no Democrats voting against it. Four members from each party did not record votes.
“The American people are fed up with paying 3, 4, or 10 times more than people in other countries for the exact same drug,” House Energy and Commerce Committee Chairman Frank Pallone (D-N.J) said in a statement following the passage. “I’m proud that the House took decisive action today to finally level the playing field and provide real relief to the American people.”
H.R. 3 would give the secretary of Health and Human Services the ability to negotiate with drug manufacturers on the price of pharmaceuticals in Medicare Part D (and available in the commercial markets) using an international pricing benchmark and would penalize manufacturers who do not negotiate or fail to lower prices to be more in line with generally lower costs internationally.
Drug prices would need to be within 120% of the average price in a reference group of six nations: Australia, Canada, France, Germany, Japan, and the United Kingdom.
Savings from the lower costs that result from negotiations would be reinvested into medical research.
Passage of H.R. 3 would “lower ... medication by 65%” per year for women with breast cancer, Rep. Haley Stevens (D-Mich.) said during the floor debate.
The Congressional Budget Office estimated that the drug price negotiation provision would lower spending on pharmaceuticals by $465 billion over the next 10 years, offset partially by an increase in spending by $358 billion associated with provisions to provide dental, vision, and hearing coverage.
The bill also includes mandatory rebates to the federal government when a drug’s price rises faster than the rate of inflation. It includes an annual cap on out-of-pocket spending on pharmaceuticals of $2,000 for Medicare Part D participants.
The bill was contentious from its introduction, which erased bipartisan work across the committees of jurisdiction, including a number of individual bills that passed at the committee level with bipartisan support.
The price negotiation scheme, using the international benchmark, was a key point of objection, which some argued was more akin to price-setting.
“Government price setting will kill innovation in clinical areas where it is most needed,” Rep. George Holding (R-N.C.) said during the floor debate. “The pricing scheme outlined in H.R. 3 would disincentivize research and development for drugs that are first in their class, such as the future cure for Alzheimer’s.”
The CBO estimates that if the bill were enacted, “8 fewer drugs would be introduced to the U.S. market over the 2020-2029 period, and about 30 fewer drugs over the subsequent decade.”
An amendment offered by House Energy and Commerce Committee Ranking Member Greg Walden (R-Ore.) attempted to replace the language of H.R. 3 with substitute language that collected all the individual drug pricing–related bills that had previously passed with bipartisan support at the committee level, but that was voted down by 223-201 vote with 12 members not voting.
Rep. Walden noted that policies within his substitute “unanimously passed the Energy and Commerce Committee earlier this year. They would have unanimously passed on this House floor had a poison pill not been put in up in the Rules Committee.”
Rep. Katie Porter (D-Calif.) countered that Rep. Walden’s amendment “doesn’t tackle the fundamental problem, which is reducing drug prices. This amendment fails to solve the main problem of actually lowering drug prices.”
CPT® and ICD-10 Coding for Endobronchial Valves
The FDA recently approved endobronchial valves for the bronchoscopic treatment of adult patients with hyperinflation associated with severe emphysema in regions of the lung that have little to no collateral ventilation. There are CPT® and ICD 10 codes that are appropriate to report these new services. CPT® codes typically are not product or device specific and the codes below apply to current and future FDA approved endobronchial valves with similar clinical indications and intent for the treatment of emphysema.
To be a candidate for the currently approved service, patients must have little to no collateral ventilation between the target and adjacent lobes. In some patients, this can be determined by a quantitative CT analysis service to assess emphysematous destruction and fissure completeness.
If the bronchial blocking technique shows evidence of collateral ventilation, the patient would be discharged without valve placement. In that scenario the appropriate CPT® code would be 31634:
INSERT GRAPHIC HERE
If the patient is determined not to have collateral ventilation, the valve procedure would proceed, followed by a minimum three-day inpatient stay to monitor for possible side effects.
The appropriate CPT codes for placing, and removing FDA approved valves are:
INSERT GRAPHIC HERE
The table below identifies potential ICD-10-CM diagnosis codes for emphysema. Applicability and usage of these codes may vary per case. Hospitals and physicians also should check and verify current policies and requirements with the payer for any patient who will be treated with endobronchial valves.
INSERT GRAPHIC HERE
The CHEST/ATS Clinical Practice Committee provided information for this article.
The FDA recently approved endobronchial valves for the bronchoscopic treatment of adult patients with hyperinflation associated with severe emphysema in regions of the lung that have little to no collateral ventilation. There are CPT® and ICD 10 codes that are appropriate to report these new services. CPT® codes typically are not product or device specific and the codes below apply to current and future FDA approved endobronchial valves with similar clinical indications and intent for the treatment of emphysema.
To be a candidate for the currently approved service, patients must have little to no collateral ventilation between the target and adjacent lobes. In some patients, this can be determined by a quantitative CT analysis service to assess emphysematous destruction and fissure completeness.
If the bronchial blocking technique shows evidence of collateral ventilation, the patient would be discharged without valve placement. In that scenario the appropriate CPT® code would be 31634:
INSERT GRAPHIC HERE
If the patient is determined not to have collateral ventilation, the valve procedure would proceed, followed by a minimum three-day inpatient stay to monitor for possible side effects.
The appropriate CPT codes for placing, and removing FDA approved valves are:
INSERT GRAPHIC HERE
The table below identifies potential ICD-10-CM diagnosis codes for emphysema. Applicability and usage of these codes may vary per case. Hospitals and physicians also should check and verify current policies and requirements with the payer for any patient who will be treated with endobronchial valves.
INSERT GRAPHIC HERE
The CHEST/ATS Clinical Practice Committee provided information for this article.
The FDA recently approved endobronchial valves for the bronchoscopic treatment of adult patients with hyperinflation associated with severe emphysema in regions of the lung that have little to no collateral ventilation. There are CPT® and ICD 10 codes that are appropriate to report these new services. CPT® codes typically are not product or device specific and the codes below apply to current and future FDA approved endobronchial valves with similar clinical indications and intent for the treatment of emphysema.
To be a candidate for the currently approved service, patients must have little to no collateral ventilation between the target and adjacent lobes. In some patients, this can be determined by a quantitative CT analysis service to assess emphysematous destruction and fissure completeness.
If the bronchial blocking technique shows evidence of collateral ventilation, the patient would be discharged without valve placement. In that scenario the appropriate CPT® code would be 31634:
INSERT GRAPHIC HERE
If the patient is determined not to have collateral ventilation, the valve procedure would proceed, followed by a minimum three-day inpatient stay to monitor for possible side effects.
The appropriate CPT codes for placing, and removing FDA approved valves are:
INSERT GRAPHIC HERE
The table below identifies potential ICD-10-CM diagnosis codes for emphysema. Applicability and usage of these codes may vary per case. Hospitals and physicians also should check and verify current policies and requirements with the payer for any patient who will be treated with endobronchial valves.
INSERT GRAPHIC HERE
The CHEST/ATS Clinical Practice Committee provided information for this article.
Icosapent ethyl approved for cardiovascular risk reduction
Icosapent ethyl (Vascepa) has gained an indication from the Food and Drug Administration for reduction of cardiovascular events in patients with high triglycerides who are at high risk for cardiovascular events. 
as an add-on to maximally tolerated statin therapy,” the agency said in an announcement.
The decision, announced on Dec. 13, was based primarily on results of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. It showed that patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (N Engl J Med. 2019 Jan 3;380[1]:11-22).
In a November meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously for approval.
The agency notes that, in clinical trials, icosapent ethyl was linked to an increased risk of atrial fibrillation or atrial flutter requiring hospitalization, especially in patients with a history of either condition. The highly purified form of the ethyl ester of eicosapentaenoic acid was also associated with an increased risk of bleeding events, particularly in those taking blood-thinning drugs that increase the risk of bleeding, such as aspirin, clopidogrel, or warfarin.
The most common side effects reported in the clinical trials for icosapent ethyl were musculoskeletal pain, peripheral edema, atrial fibrillation, and arthralgia.
The complete indication is “as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (at least 150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease,” according to a statement from Amalin, which markets Vascepa.
The drug was approved in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.
Icosapent ethyl (Vascepa) has gained an indication from the Food and Drug Administration for reduction of cardiovascular events in patients with high triglycerides who are at high risk for cardiovascular events.
as an add-on to maximally tolerated statin therapy,” the agency said in an announcement.
The decision, announced on Dec. 13, was based primarily on results of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. It showed that patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (N Engl J Med. 2019 Jan 3;380[1]:11-22).
In a November meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously for approval.
The agency notes that, in clinical trials, icosapent ethyl was linked to an increased risk of atrial fibrillation or atrial flutter requiring hospitalization, especially in patients with a history of either condition. The highly purified form of the ethyl ester of eicosapentaenoic acid was also associated with an increased risk of bleeding events, particularly in those taking blood-thinning drugs that increase the risk of bleeding, such as aspirin, clopidogrel, or warfarin.
The most common side effects reported in the clinical trials for icosapent ethyl were musculoskeletal pain, peripheral edema, atrial fibrillation, and arthralgia.
The complete indication is “as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (at least 150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease,” according to a statement from Amalin, which markets Vascepa.
The drug was approved in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.
Icosapent ethyl (Vascepa) has gained an indication from the Food and Drug Administration for reduction of cardiovascular events in patients with high triglycerides who are at high risk for cardiovascular events.
as an add-on to maximally tolerated statin therapy,” the agency said in an announcement.
The decision, announced on Dec. 13, was based primarily on results of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. It showed that patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (N Engl J Med. 2019 Jan 3;380[1]:11-22).
In a November meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously for approval.
The agency notes that, in clinical trials, icosapent ethyl was linked to an increased risk of atrial fibrillation or atrial flutter requiring hospitalization, especially in patients with a history of either condition. The highly purified form of the ethyl ester of eicosapentaenoic acid was also associated with an increased risk of bleeding events, particularly in those taking blood-thinning drugs that increase the risk of bleeding, such as aspirin, clopidogrel, or warfarin.
The most common side effects reported in the clinical trials for icosapent ethyl were musculoskeletal pain, peripheral edema, atrial fibrillation, and arthralgia.
The complete indication is “as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (at least 150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease,” according to a statement from Amalin, which markets Vascepa.
The drug was approved in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.
Medtwitter embraces incoming student’s excitement
When Melissa Gonzalez excitedly tweeted that she had been accepted to medical school earlier this year, she had no idea the tweet would draw attention and responses from people across the country.
The tweet, which shared that Ms. Gonzalez was the daughter of Mexican immigrants, received more than 300,000 likes and another 23,000 retweets from physicians, medical associations, students, and graduates alike. In this video, Ms. Gonzalez, who was accepted to Keck School of Medicine of the University of Southern California, Los Angeles, speaks of her journey to medical school.
When Melissa Gonzalez excitedly tweeted that she had been accepted to medical school earlier this year, she had no idea the tweet would draw attention and responses from people across the country.
The tweet, which shared that Ms. Gonzalez was the daughter of Mexican immigrants, received more than 300,000 likes and another 23,000 retweets from physicians, medical associations, students, and graduates alike. In this video, Ms. Gonzalez, who was accepted to Keck School of Medicine of the University of Southern California, Los Angeles, speaks of her journey to medical school.
When Melissa Gonzalez excitedly tweeted that she had been accepted to medical school earlier this year, she had no idea the tweet would draw attention and responses from people across the country.
The tweet, which shared that Ms. Gonzalez was the daughter of Mexican immigrants, received more than 300,000 likes and another 23,000 retweets from physicians, medical associations, students, and graduates alike. In this video, Ms. Gonzalez, who was accepted to Keck School of Medicine of the University of Southern California, Los Angeles, speaks of her journey to medical school.
Clinic goes to bat for bullied kids
NEW ORLEANS – After Massachusetts passed antibullying legislation in 2009, Peter C. Raffalli, MD, saw an opportunity to improve care for the increasing numbers of children presenting to his neurology practice at Boston Children’s Hospital who were victims of bullying – especially those with developmental disabilities.
“I had been thinking of a clinic to help kids with these issues, aside from just helping them deal with the fallout: the depression, anxiety, et cetera, that comes with being bullied,” Dr. Raffalli recalled at the annual meeting of the American Academy of Pediatrics. “I wanted to do something to help present to families the evidence-based strategies regarding bullying prevention, detection, and intervention that might help to stop the bullying.”
This led him to launch the Bullying and Cyberbullying Prevention and Advocacy Collaborative (BACPAC) at Boston Children’s Hospital, which began in 2009 as an educational resource for families, medical colleagues, and schools. Dr. Raffalli also formed an alliance with the Massachusetts Aggression Reduction Center at Bridgewater State University (Ann Neurol. 2016;79[2]:167-8).
Two years later in 2011, BACPAC became a formal clinic at Boston Children’s that serves as a subspecialty consult service for victims of bullying and their families. The clinic team consists of a child neurologist, a social worker, and an education resource specialist who meet with the bullying victim and his/her family in initial consultation for 90 minutes. The goal is to develop an evidence-based plan for bullying prevention, detection, and intervention that is individualized to the patient’s developmental and social needs.
“We tell families that bullying is recognized medically and legally as a form of abuse,” said Dr. Raffalli. “The medical and psychological consequences are similar to other forms of abuse. You’d be surprised how often patients do think the bullying is their fault.”
The extent of the problem
Researchers estimate that 25%-30% of children will experience some form of bullying between kindergarten and grade 12, and about 8% will engage in bullying themselves. When BACPAC began in 2009, Dr. Raffalli conducted an informal search of peer-reviewed literature on bullying in children with special needs; it yielded just four articles. “Since then, there’s been an exponential explosion of literature on various aspects of bullying,” he said. Now there is ample evidence in the peer-reviewed literature to show the increased risk for bullying/cyberbullying in children/teens, not just with neurodevelopmental disorders, but also for kids with other medical disorders such as obesity, asthma, and allergies.
“We’ve had a good number of kids over the years with peanut allergy who were literally threatened physically with peanut butter at school,” he said. “It’s incredible how callous some kids can be. Kids with oppositional defiant disorder, impulse control disorder, and callous/unemotional traits from a psychological standpoint are hardest to reach when it comes to getting them to stop bullying. You’d be surprised how frequently bullies use the phrase [to their victims], ‘You should kill yourself.’ They don’t realize the damage they’re doing to people. Bullying can lead to severe psychological but also long-term medical problems, including suicidal ideation.”
Published studies show that the highest incidences of bullying occur in children with neurodevelopmental conditions such as ADHD, autistic spectrum disorders, Tourette syndrome, and other learning disabilities (Eur J Spec Needs Ed. 2010;25[1]:77-91). This population of children is overrepresented in bullying “because the services they receive at school make their disabilities more visible,” explained Dr. Raffalli, who is also an assistant professor of neurology at Harvard Medical School, Boston. “They stand out, and they have social information–processing deficits or distortions that exacerbate bullying involvement. They also have difficulty interpreting social cues or attributing hostile characteristics to their peer’s behavior.”
The consequences of bullying
The psychological and educational consequences of bullying among children in general include being more likely to develop depression, loneliness, low self-esteem, alcohol and drug abuse, sleeping difficulties, self-harm, and suicidal ideation and attempts. “We’re social creatures, and when we don’t have those social connections, we get very depressed.”
Bullying victims also are more likely to develop school avoidance and absence, decreased school performance, poor concentration, high anxiety, and social withdrawal – all of which limit their opportunities to learn. “The No. 1 thing you can do to help these kids is to believe their story – to explain to them that it’s not their fault, and to explain that you are there for them and that you support them,” he said. “When a kid gets the feeling that someone is willing to listen to them and believe them, it does an enormous good for their emotional state.”
Dr. Raffalli added that a toxic stress response can occur when a child experiences strong, frequent, and/or prolonged adversity – such as physical or emotional abuse, chronic neglect, caregiver substance abuse or mental illness, exposure to violence, and/or the accumulated burdens of family economic hardship – without adequate adult support. This kind of prolonged activation of the stress response systems can disrupt the development of brain architecture and other organ systems, and increase the risk for stress-related disease and cognitive impairment well into the adult years.
In the Harvard Review of Psychiatry, researchers set out to investigate what’s known about the long-term health effects of childhood bullying. They found that bullying can induce “aspects of the stress response, via epigenetic, inflammatory, and metabolic mediators [that] have the capacity to compromise mental and physical health, and to increase the risk of disease.” The researchers advised clinicians who care for children to assess the mental and physical health effects of bullying (Harv Rev Psychiatry. 2017;25[2]:89-95).
Additional vulnerabilities for bullying victims include parents and children whose primary language is not English, as well as parents with mental illness or substance abuse and families living in poverty. “We have to keep in mind how much additional stress they may be dealing with. This can make it harder for them to cope. Bullies also are shown to be at higher risk for psychological and legal trouble into adulthood, so we should be trying to help them too. We have to keep in mind that these are all developing kids.”
Cyberbullying
In Dr. Raffalli’s clinical experience, cyberbullying has become the bully’s weapon of choice. “I call it the stealth bomber of bullying,” he said. “Cyberbullying can start as early as the second or third grade. Most parents are not giving phones to second-graders. I’m worried that it’s going to get worse, though, with the excuse that ‘I feel safer if they have a cell phone so they can call me.’ I tell parents that they still make flip phones. You don’t have to get a smartphone for a second- or third-grader, or even for a sixth-grader.”
By the time kids reach fourth and fifth grade, he continued, they begin to form their opinion “about what they believe is cool and not cool, and they begin to get into cliques that have similar beliefs, and support each other, and may break off from old friends.” He added that, while adult predation “makes the news and is certainly something we should all be concerned about, the incidence of being harassed and bullied by someone in your own age group at school is actually much higher and still has serious outcomes, including the possibility of death.”
The Massachusetts antibullying law stipulates that all teachers and all school personnel have to participate in mandatory bullying training. Schools also are required to draft and follow a bullying investigative protocol.
“Apparently the schools have all done this, yet the number of times that schools use interventions that are not advisable, such as mediation, is incredible to me,” Dr. Raffalli said. “Bringing the bully and the victim together for a ‘cup of coffee and a handshake’ is not advisable. Mediation has been shown in a number of studies to be detrimental in bullying situations. Things can easily get worse.”
Often, family members who bring their child to the BACPAC “feel that their child’s school is not helping them,” he said. “We should try to figure out why those schools are having such a hard time and see if we can help them.”
Dr. Raffalli reported having no financial disclosures.
NEW ORLEANS – After Massachusetts passed antibullying legislation in 2009, Peter C. Raffalli, MD, saw an opportunity to improve care for the increasing numbers of children presenting to his neurology practice at Boston Children’s Hospital who were victims of bullying – especially those with developmental disabilities.
“I had been thinking of a clinic to help kids with these issues, aside from just helping them deal with the fallout: the depression, anxiety, et cetera, that comes with being bullied,” Dr. Raffalli recalled at the annual meeting of the American Academy of Pediatrics. “I wanted to do something to help present to families the evidence-based strategies regarding bullying prevention, detection, and intervention that might help to stop the bullying.”
This led him to launch the Bullying and Cyberbullying Prevention and Advocacy Collaborative (BACPAC) at Boston Children’s Hospital, which began in 2009 as an educational resource for families, medical colleagues, and schools. Dr. Raffalli also formed an alliance with the Massachusetts Aggression Reduction Center at Bridgewater State University (Ann Neurol. 2016;79[2]:167-8).
Two years later in 2011, BACPAC became a formal clinic at Boston Children’s that serves as a subspecialty consult service for victims of bullying and their families. The clinic team consists of a child neurologist, a social worker, and an education resource specialist who meet with the bullying victim and his/her family in initial consultation for 90 minutes. The goal is to develop an evidence-based plan for bullying prevention, detection, and intervention that is individualized to the patient’s developmental and social needs.
“We tell families that bullying is recognized medically and legally as a form of abuse,” said Dr. Raffalli. “The medical and psychological consequences are similar to other forms of abuse. You’d be surprised how often patients do think the bullying is their fault.”
The extent of the problem
Researchers estimate that 25%-30% of children will experience some form of bullying between kindergarten and grade 12, and about 8% will engage in bullying themselves. When BACPAC began in 2009, Dr. Raffalli conducted an informal search of peer-reviewed literature on bullying in children with special needs; it yielded just four articles. “Since then, there’s been an exponential explosion of literature on various aspects of bullying,” he said. Now there is ample evidence in the peer-reviewed literature to show the increased risk for bullying/cyberbullying in children/teens, not just with neurodevelopmental disorders, but also for kids with other medical disorders such as obesity, asthma, and allergies.
“We’ve had a good number of kids over the years with peanut allergy who were literally threatened physically with peanut butter at school,” he said. “It’s incredible how callous some kids can be. Kids with oppositional defiant disorder, impulse control disorder, and callous/unemotional traits from a psychological standpoint are hardest to reach when it comes to getting them to stop bullying. You’d be surprised how frequently bullies use the phrase [to their victims], ‘You should kill yourself.’ They don’t realize the damage they’re doing to people. Bullying can lead to severe psychological but also long-term medical problems, including suicidal ideation.”
Published studies show that the highest incidences of bullying occur in children with neurodevelopmental conditions such as ADHD, autistic spectrum disorders, Tourette syndrome, and other learning disabilities (Eur J Spec Needs Ed. 2010;25[1]:77-91). This population of children is overrepresented in bullying “because the services they receive at school make their disabilities more visible,” explained Dr. Raffalli, who is also an assistant professor of neurology at Harvard Medical School, Boston. “They stand out, and they have social information–processing deficits or distortions that exacerbate bullying involvement. They also have difficulty interpreting social cues or attributing hostile characteristics to their peer’s behavior.”
The consequences of bullying
The psychological and educational consequences of bullying among children in general include being more likely to develop depression, loneliness, low self-esteem, alcohol and drug abuse, sleeping difficulties, self-harm, and suicidal ideation and attempts. “We’re social creatures, and when we don’t have those social connections, we get very depressed.”
Bullying victims also are more likely to develop school avoidance and absence, decreased school performance, poor concentration, high anxiety, and social withdrawal – all of which limit their opportunities to learn. “The No. 1 thing you can do to help these kids is to believe their story – to explain to them that it’s not their fault, and to explain that you are there for them and that you support them,” he said. “When a kid gets the feeling that someone is willing to listen to them and believe them, it does an enormous good for their emotional state.”
Dr. Raffalli added that a toxic stress response can occur when a child experiences strong, frequent, and/or prolonged adversity – such as physical or emotional abuse, chronic neglect, caregiver substance abuse or mental illness, exposure to violence, and/or the accumulated burdens of family economic hardship – without adequate adult support. This kind of prolonged activation of the stress response systems can disrupt the development of brain architecture and other organ systems, and increase the risk for stress-related disease and cognitive impairment well into the adult years.
In the Harvard Review of Psychiatry, researchers set out to investigate what’s known about the long-term health effects of childhood bullying. They found that bullying can induce “aspects of the stress response, via epigenetic, inflammatory, and metabolic mediators [that] have the capacity to compromise mental and physical health, and to increase the risk of disease.” The researchers advised clinicians who care for children to assess the mental and physical health effects of bullying (Harv Rev Psychiatry. 2017;25[2]:89-95).
Additional vulnerabilities for bullying victims include parents and children whose primary language is not English, as well as parents with mental illness or substance abuse and families living in poverty. “We have to keep in mind how much additional stress they may be dealing with. This can make it harder for them to cope. Bullies also are shown to be at higher risk for psychological and legal trouble into adulthood, so we should be trying to help them too. We have to keep in mind that these are all developing kids.”
Cyberbullying
In Dr. Raffalli’s clinical experience, cyberbullying has become the bully’s weapon of choice. “I call it the stealth bomber of bullying,” he said. “Cyberbullying can start as early as the second or third grade. Most parents are not giving phones to second-graders. I’m worried that it’s going to get worse, though, with the excuse that ‘I feel safer if they have a cell phone so they can call me.’ I tell parents that they still make flip phones. You don’t have to get a smartphone for a second- or third-grader, or even for a sixth-grader.”
By the time kids reach fourth and fifth grade, he continued, they begin to form their opinion “about what they believe is cool and not cool, and they begin to get into cliques that have similar beliefs, and support each other, and may break off from old friends.” He added that, while adult predation “makes the news and is certainly something we should all be concerned about, the incidence of being harassed and bullied by someone in your own age group at school is actually much higher and still has serious outcomes, including the possibility of death.”
The Massachusetts antibullying law stipulates that all teachers and all school personnel have to participate in mandatory bullying training. Schools also are required to draft and follow a bullying investigative protocol.
“Apparently the schools have all done this, yet the number of times that schools use interventions that are not advisable, such as mediation, is incredible to me,” Dr. Raffalli said. “Bringing the bully and the victim together for a ‘cup of coffee and a handshake’ is not advisable. Mediation has been shown in a number of studies to be detrimental in bullying situations. Things can easily get worse.”
Often, family members who bring their child to the BACPAC “feel that their child’s school is not helping them,” he said. “We should try to figure out why those schools are having such a hard time and see if we can help them.”
Dr. Raffalli reported having no financial disclosures.
NEW ORLEANS – After Massachusetts passed antibullying legislation in 2009, Peter C. Raffalli, MD, saw an opportunity to improve care for the increasing numbers of children presenting to his neurology practice at Boston Children’s Hospital who were victims of bullying – especially those with developmental disabilities.
“I had been thinking of a clinic to help kids with these issues, aside from just helping them deal with the fallout: the depression, anxiety, et cetera, that comes with being bullied,” Dr. Raffalli recalled at the annual meeting of the American Academy of Pediatrics. “I wanted to do something to help present to families the evidence-based strategies regarding bullying prevention, detection, and intervention that might help to stop the bullying.”
This led him to launch the Bullying and Cyberbullying Prevention and Advocacy Collaborative (BACPAC) at Boston Children’s Hospital, which began in 2009 as an educational resource for families, medical colleagues, and schools. Dr. Raffalli also formed an alliance with the Massachusetts Aggression Reduction Center at Bridgewater State University (Ann Neurol. 2016;79[2]:167-8).
Two years later in 2011, BACPAC became a formal clinic at Boston Children’s that serves as a subspecialty consult service for victims of bullying and their families. The clinic team consists of a child neurologist, a social worker, and an education resource specialist who meet with the bullying victim and his/her family in initial consultation for 90 minutes. The goal is to develop an evidence-based plan for bullying prevention, detection, and intervention that is individualized to the patient’s developmental and social needs.
“We tell families that bullying is recognized medically and legally as a form of abuse,” said Dr. Raffalli. “The medical and psychological consequences are similar to other forms of abuse. You’d be surprised how often patients do think the bullying is their fault.”
The extent of the problem
Researchers estimate that 25%-30% of children will experience some form of bullying between kindergarten and grade 12, and about 8% will engage in bullying themselves. When BACPAC began in 2009, Dr. Raffalli conducted an informal search of peer-reviewed literature on bullying in children with special needs; it yielded just four articles. “Since then, there’s been an exponential explosion of literature on various aspects of bullying,” he said. Now there is ample evidence in the peer-reviewed literature to show the increased risk for bullying/cyberbullying in children/teens, not just with neurodevelopmental disorders, but also for kids with other medical disorders such as obesity, asthma, and allergies.
“We’ve had a good number of kids over the years with peanut allergy who were literally threatened physically with peanut butter at school,” he said. “It’s incredible how callous some kids can be. Kids with oppositional defiant disorder, impulse control disorder, and callous/unemotional traits from a psychological standpoint are hardest to reach when it comes to getting them to stop bullying. You’d be surprised how frequently bullies use the phrase [to their victims], ‘You should kill yourself.’ They don’t realize the damage they’re doing to people. Bullying can lead to severe psychological but also long-term medical problems, including suicidal ideation.”
Published studies show that the highest incidences of bullying occur in children with neurodevelopmental conditions such as ADHD, autistic spectrum disorders, Tourette syndrome, and other learning disabilities (Eur J Spec Needs Ed. 2010;25[1]:77-91). This population of children is overrepresented in bullying “because the services they receive at school make their disabilities more visible,” explained Dr. Raffalli, who is also an assistant professor of neurology at Harvard Medical School, Boston. “They stand out, and they have social information–processing deficits or distortions that exacerbate bullying involvement. They also have difficulty interpreting social cues or attributing hostile characteristics to their peer’s behavior.”
The consequences of bullying
The psychological and educational consequences of bullying among children in general include being more likely to develop depression, loneliness, low self-esteem, alcohol and drug abuse, sleeping difficulties, self-harm, and suicidal ideation and attempts. “We’re social creatures, and when we don’t have those social connections, we get very depressed.”
Bullying victims also are more likely to develop school avoidance and absence, decreased school performance, poor concentration, high anxiety, and social withdrawal – all of which limit their opportunities to learn. “The No. 1 thing you can do to help these kids is to believe their story – to explain to them that it’s not their fault, and to explain that you are there for them and that you support them,” he said. “When a kid gets the feeling that someone is willing to listen to them and believe them, it does an enormous good for their emotional state.”
Dr. Raffalli added that a toxic stress response can occur when a child experiences strong, frequent, and/or prolonged adversity – such as physical or emotional abuse, chronic neglect, caregiver substance abuse or mental illness, exposure to violence, and/or the accumulated burdens of family economic hardship – without adequate adult support. This kind of prolonged activation of the stress response systems can disrupt the development of brain architecture and other organ systems, and increase the risk for stress-related disease and cognitive impairment well into the adult years.
In the Harvard Review of Psychiatry, researchers set out to investigate what’s known about the long-term health effects of childhood bullying. They found that bullying can induce “aspects of the stress response, via epigenetic, inflammatory, and metabolic mediators [that] have the capacity to compromise mental and physical health, and to increase the risk of disease.” The researchers advised clinicians who care for children to assess the mental and physical health effects of bullying (Harv Rev Psychiatry. 2017;25[2]:89-95).
Additional vulnerabilities for bullying victims include parents and children whose primary language is not English, as well as parents with mental illness or substance abuse and families living in poverty. “We have to keep in mind how much additional stress they may be dealing with. This can make it harder for them to cope. Bullies also are shown to be at higher risk for psychological and legal trouble into adulthood, so we should be trying to help them too. We have to keep in mind that these are all developing kids.”
Cyberbullying
In Dr. Raffalli’s clinical experience, cyberbullying has become the bully’s weapon of choice. “I call it the stealth bomber of bullying,” he said. “Cyberbullying can start as early as the second or third grade. Most parents are not giving phones to second-graders. I’m worried that it’s going to get worse, though, with the excuse that ‘I feel safer if they have a cell phone so they can call me.’ I tell parents that they still make flip phones. You don’t have to get a smartphone for a second- or third-grader, or even for a sixth-grader.”
By the time kids reach fourth and fifth grade, he continued, they begin to form their opinion “about what they believe is cool and not cool, and they begin to get into cliques that have similar beliefs, and support each other, and may break off from old friends.” He added that, while adult predation “makes the news and is certainly something we should all be concerned about, the incidence of being harassed and bullied by someone in your own age group at school is actually much higher and still has serious outcomes, including the possibility of death.”
The Massachusetts antibullying law stipulates that all teachers and all school personnel have to participate in mandatory bullying training. Schools also are required to draft and follow a bullying investigative protocol.
“Apparently the schools have all done this, yet the number of times that schools use interventions that are not advisable, such as mediation, is incredible to me,” Dr. Raffalli said. “Bringing the bully and the victim together for a ‘cup of coffee and a handshake’ is not advisable. Mediation has been shown in a number of studies to be detrimental in bullying situations. Things can easily get worse.”
Often, family members who bring their child to the BACPAC “feel that their child’s school is not helping them,” he said. “We should try to figure out why those schools are having such a hard time and see if we can help them.”
Dr. Raffalli reported having no financial disclosures.
EXPERT ANALYSIS FROM AAP 2019
Flu activity dropped in early December
according to the Centers for Disease Control and Prevention.
Nationally, 3.2% of outpatient visits were for influenza-like illness (ILI) during the week of Dec. 1-7, the CDC reported. That is down from 3.4% the week before, which was the highest November rate in 10 years. The national baseline rate is 2.4%, and the current 3.2% marks the fifth consecutive week that the outpatient ILI rate has been at or above the baseline level, the CDC report noted.
The drop in activity “may be influenced in part by a reduction in routine healthcare visits surrounding the Thanksgiving holiday. … as has occurred during previous seasons,” the CDC influenza division said Dec. 13 in its weekly flu report.
The early spike in “activity is being caused mostly by influenza B/Victoria viruses, which is unusual for this time of year,” the report said. Since the beginning of the 2019-2020 season a little over 2 months ago, almost 70% of specimens that have been positive for influenza have been identified as type B.
The nationwide decline in activity doesn’t, however, show up at the state level. For the week ending Dec. 7, there were eight states along with Puerto Rico at level 10 on the CDC’s 1-10 scale of flu activity, as there were the previous week. Washington state moved up from 9 to 10, but Louisiana, which was at level 10 last week, had insufficient data to be included this week, the CDC data show.
There were four flu-related pediatric deaths reported to the CDC during the week ending Dec. 7, all occurring in previous weeks, which brings the total to 10 for the season. In 2018-2019, there were 143 pediatric deaths caused by influenza, the CDC said.
according to the Centers for Disease Control and Prevention.
Nationally, 3.2% of outpatient visits were for influenza-like illness (ILI) during the week of Dec. 1-7, the CDC reported. That is down from 3.4% the week before, which was the highest November rate in 10 years. The national baseline rate is 2.4%, and the current 3.2% marks the fifth consecutive week that the outpatient ILI rate has been at or above the baseline level, the CDC report noted.
The drop in activity “may be influenced in part by a reduction in routine healthcare visits surrounding the Thanksgiving holiday. … as has occurred during previous seasons,” the CDC influenza division said Dec. 13 in its weekly flu report.
The early spike in “activity is being caused mostly by influenza B/Victoria viruses, which is unusual for this time of year,” the report said. Since the beginning of the 2019-2020 season a little over 2 months ago, almost 70% of specimens that have been positive for influenza have been identified as type B.
The nationwide decline in activity doesn’t, however, show up at the state level. For the week ending Dec. 7, there were eight states along with Puerto Rico at level 10 on the CDC’s 1-10 scale of flu activity, as there were the previous week. Washington state moved up from 9 to 10, but Louisiana, which was at level 10 last week, had insufficient data to be included this week, the CDC data show.
There were four flu-related pediatric deaths reported to the CDC during the week ending Dec. 7, all occurring in previous weeks, which brings the total to 10 for the season. In 2018-2019, there were 143 pediatric deaths caused by influenza, the CDC said.
according to the Centers for Disease Control and Prevention.
Nationally, 3.2% of outpatient visits were for influenza-like illness (ILI) during the week of Dec. 1-7, the CDC reported. That is down from 3.4% the week before, which was the highest November rate in 10 years. The national baseline rate is 2.4%, and the current 3.2% marks the fifth consecutive week that the outpatient ILI rate has been at or above the baseline level, the CDC report noted.
The drop in activity “may be influenced in part by a reduction in routine healthcare visits surrounding the Thanksgiving holiday. … as has occurred during previous seasons,” the CDC influenza division said Dec. 13 in its weekly flu report.
The early spike in “activity is being caused mostly by influenza B/Victoria viruses, which is unusual for this time of year,” the report said. Since the beginning of the 2019-2020 season a little over 2 months ago, almost 70% of specimens that have been positive for influenza have been identified as type B.
The nationwide decline in activity doesn’t, however, show up at the state level. For the week ending Dec. 7, there were eight states along with Puerto Rico at level 10 on the CDC’s 1-10 scale of flu activity, as there were the previous week. Washington state moved up from 9 to 10, but Louisiana, which was at level 10 last week, had insufficient data to be included this week, the CDC data show.
There were four flu-related pediatric deaths reported to the CDC during the week ending Dec. 7, all occurring in previous weeks, which brings the total to 10 for the season. In 2018-2019, there were 143 pediatric deaths caused by influenza, the CDC said.