B-Cell Lymphoma ICYMI

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Introduction

SMARCA4-deficient thoracic sarcomas are a rare entity, first described in 2015 in a study of 19 patients with a median age of 41 years who presented with large compressive masses with frequent infiltration into surrounding tissues [1]. This malignancy is more frequent in younger males (median 41-59 years) with an extensive smoking history and has an aggressive course with a median overall survival of 4-7 months [1-3]. There is currently no established treatment, but case reports show promise for immunotherapy and immuno- chemotherapy [4-8].

Case Report

We present the case of a 62 year old male with a 44 pack year smoking history who first presented to the emergency department (ED) with left shoulder pain in December 2020. He was initially treated with muscle relaxers but returned to the ED ten days later with hemoptysis and rapid weight loss. X-ray showed a 14.2 X 11.7 cm mass with rightward deviation of the trachea. PET scan showed extensive central necrosis with a surrounding pleural effusion and local pleural and nodal metastasis but no distant disease. He underwent thoracentesis which was negative for malignant cells. He underwent CT-guided biopsy in 1/2021, which showed predominantly discohesive small blue cells with pleomorphic cell contour and slightly plasmacytoid features. Extensive pathology review led to a diagnosis of SMARCA4 deficient thoracic sarcoma. On presentation to oncology clinic in 2/2021 his functional status had markedly deteriorated. He was started on ipilimumab/ nivolumab (ipi/nivo) and 1 week after his first cycle was admitted for severe left arm swelling and pain. Imaging showed significant progression of disease and new adrenal metastasis. He received cycle two of ipi/ nivo and was able to be discharged home on oxygen. By his follow-up appointment for cycle three of ipi/nivo in 3/2021, the patient was wheelchair bound with severe dyspnea. X-ray showed the mass now occupied the majority of the left hemi-thorax with worsening tracheal deviation. After discussion, the patient went home on hospice and died 8 days later. As demonstrated by this case, SMARCA4-deficient sarcoma requires high clinical suspicion with prompt diagnosis and treatment given its remarkably rapid progression and poor outcomes.

Introduction

SMARCA4-deficient thoracic sarcomas are a rare entity, first described in 2015 in a study of 19 patients with a median age of 41 years who presented with large compressive masses with frequent infiltration into surrounding tissues [1]. This malignancy is more frequent in younger males (median 41-59 years) with an extensive smoking history and has an aggressive course with a median overall survival of 4-7 months [1-3]. There is currently no established treatment, but case reports show promise for immunotherapy and immuno- chemotherapy [4-8].

Case Report

We present the case of a 62 year old male with a 44 pack year smoking history who first presented to the emergency department (ED) with left shoulder pain in December 2020. He was initially treated with muscle relaxers but returned to the ED ten days later with hemoptysis and rapid weight loss. X-ray showed a 14.2 X 11.7 cm mass with rightward deviation of the trachea. PET scan showed extensive central necrosis with a surrounding pleural effusion and local pleural and nodal metastasis but no distant disease. He underwent thoracentesis which was negative for malignant cells. He underwent CT-guided biopsy in 1/2021, which showed predominantly discohesive small blue cells with pleomorphic cell contour and slightly plasmacytoid features. Extensive pathology review led to a diagnosis of SMARCA4 deficient thoracic sarcoma. On presentation to oncology clinic in 2/2021 his functional status had markedly deteriorated. He was started on ipilimumab/ nivolumab (ipi/nivo) and 1 week after his first cycle was admitted for severe left arm swelling and pain. Imaging showed significant progression of disease and new adrenal metastasis. He received cycle two of ipi/ nivo and was able to be discharged home on oxygen. By his follow-up appointment for cycle three of ipi/nivo in 3/2021, the patient was wheelchair bound with severe dyspnea. X-ray showed the mass now occupied the majority of the left hemi-thorax with worsening tracheal deviation. After discussion, the patient went home on hospice and died 8 days later. As demonstrated by this case, SMARCA4-deficient sarcoma requires high clinical suspicion with prompt diagnosis and treatment given its remarkably rapid progression and poor outcomes.

Introduction

SMARCA4-deficient thoracic sarcomas are a rare entity, first described in 2015 in a study of 19 patients with a median age of 41 years who presented with large compressive masses with frequent infiltration into surrounding tissues [1]. This malignancy is more frequent in younger males (median 41-59 years) with an extensive smoking history and has an aggressive course with a median overall survival of 4-7 months [1-3]. There is currently no established treatment, but case reports show promise for immunotherapy and immuno- chemotherapy [4-8].

Case Report

We present the case of a 62 year old male with a 44 pack year smoking history who first presented to the emergency department (ED) with left shoulder pain in December 2020. He was initially treated with muscle relaxers but returned to the ED ten days later with hemoptysis and rapid weight loss. X-ray showed a 14.2 X 11.7 cm mass with rightward deviation of the trachea. PET scan showed extensive central necrosis with a surrounding pleural effusion and local pleural and nodal metastasis but no distant disease. He underwent thoracentesis which was negative for malignant cells. He underwent CT-guided biopsy in 1/2021, which showed predominantly discohesive small blue cells with pleomorphic cell contour and slightly plasmacytoid features. Extensive pathology review led to a diagnosis of SMARCA4 deficient thoracic sarcoma. On presentation to oncology clinic in 2/2021 his functional status had markedly deteriorated. He was started on ipilimumab/ nivolumab (ipi/nivo) and 1 week after his first cycle was admitted for severe left arm swelling and pain. Imaging showed significant progression of disease and new adrenal metastasis. He received cycle two of ipi/ nivo and was able to be discharged home on oxygen. By his follow-up appointment for cycle three of ipi/nivo in 3/2021, the patient was wheelchair bound with severe dyspnea. X-ray showed the mass now occupied the majority of the left hemi-thorax with worsening tracheal deviation. After discussion, the patient went home on hospice and died 8 days later. As demonstrated by this case, SMARCA4-deficient sarcoma requires high clinical suspicion with prompt diagnosis and treatment given its remarkably rapid progression and poor outcomes.

The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.

The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.

The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.

The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.

The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.

The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.

In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.

The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.

The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.

An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).

The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
 

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.

The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.

The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.

The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.

The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.

The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.

In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.

The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.

The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.

An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).

The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
 

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.

The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.

The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.

The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.

The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.

The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.

In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.

The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.

The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.

An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).

The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
 

A version of this article first appeared on Medscape.com.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

People with multiple sclerosis (MS) and depression have an increased risk of death, compared with those with one or neither condition, as well as an increased risk of vascular disease, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.

The study was published in Neurology.

To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.

People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.

As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
 

Does treating depression decrease the likelihood of vascular disease?

“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?

“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?

“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
 

Evaluating the biological interaction between MS and depression

Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.

“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.

“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.

Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.

In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”

Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.

People with multiple sclerosis (MS) and depression have an increased risk of death, compared with those with one or neither condition, as well as an increased risk of vascular disease, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.

The study was published in Neurology.

To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.

People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.

As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
 

Does treating depression decrease the likelihood of vascular disease?

“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?

“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?

“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
 

Evaluating the biological interaction between MS and depression

Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.

“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.

“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.

Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.

In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”

Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.

People with multiple sclerosis (MS) and depression have an increased risk of death, compared with those with one or neither condition, as well as an increased risk of vascular disease, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.

The study was published in Neurology.

To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.

People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.

As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
 

Does treating depression decrease the likelihood of vascular disease?

“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?

“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?

“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
 

Evaluating the biological interaction between MS and depression

Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.

“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.

“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.

Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.

In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”

Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.

The U.S. Food and Drug Administration has expanded the indication for brivaracetam (Briviact, UCB) as both monotherapy or adjunctive therapy for partial-onset seizures in patients as young as 1 month of age.

All three brivaracetam formulations (tablets, oral solution, and IV) may now be used. The approval marks the first time that the IV formulation will be available for children, the company said in a news release.

The medication is already approved in the United States as monotherapy and adjunctive therapy in adults with epilepsy.

In an open-label follow-up pediatric study, an estimated 71.4% of patients aged 1 month to 17 years with partial-onset seizures remained on brivaracetam therapy at 1 year, and 64.3% did so at 2 years, the company reported.

“We often see children with seizures hospitalized, so it’s important to have a therapy like Briviact IV that can offer rapid administration in an effective dose when needed and does not require titration,” Raman Sankar, MD, PhD, distinguished professor and chief of pediatric neurology, University of California, Los Angeles, said in the release.

“The availability of the oral dose forms also allows continuity of treatment when these young patients are transitioning from hospital to home,” he added.
 

Safety profile

Dr. Sankar noted that with approval now of both the IV and oral formulations for partial-onset seizures in such young children, “we have a new option that helps meet a critical need in pediatric epilepsy.”

The most common adverse reactions with brivaracetam include somnolence and sedation, dizziness, fatigue, nausea, and vomiting. In the pediatric clinical trials, the safety profile for pediatric patients was similar to adults.

In the adult trials, psychiatric adverse reactions, including nonpsychotic and psychotic symptoms, were reported in approximately 13% of adults taking at least 50 mg/day of brivaracetam compared with 8% taking placebo.

Psychiatric adverse reactions were also observed in open-label pediatric trials and were generally similar to those observed in adults.

Patients should be advised to report these symptoms immediately to a health care professional, the company noted.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has expanded the indication for brivaracetam (Briviact, UCB) as both monotherapy or adjunctive therapy for partial-onset seizures in patients as young as 1 month of age.

All three brivaracetam formulations (tablets, oral solution, and IV) may now be used. The approval marks the first time that the IV formulation will be available for children, the company said in a news release.

The medication is already approved in the United States as monotherapy and adjunctive therapy in adults with epilepsy.

In an open-label follow-up pediatric study, an estimated 71.4% of patients aged 1 month to 17 years with partial-onset seizures remained on brivaracetam therapy at 1 year, and 64.3% did so at 2 years, the company reported.

“We often see children with seizures hospitalized, so it’s important to have a therapy like Briviact IV that can offer rapid administration in an effective dose when needed and does not require titration,” Raman Sankar, MD, PhD, distinguished professor and chief of pediatric neurology, University of California, Los Angeles, said in the release.

“The availability of the oral dose forms also allows continuity of treatment when these young patients are transitioning from hospital to home,” he added.
 

Safety profile

Dr. Sankar noted that with approval now of both the IV and oral formulations for partial-onset seizures in such young children, “we have a new option that helps meet a critical need in pediatric epilepsy.”

The most common adverse reactions with brivaracetam include somnolence and sedation, dizziness, fatigue, nausea, and vomiting. In the pediatric clinical trials, the safety profile for pediatric patients was similar to adults.

In the adult trials, psychiatric adverse reactions, including nonpsychotic and psychotic symptoms, were reported in approximately 13% of adults taking at least 50 mg/day of brivaracetam compared with 8% taking placebo.

Psychiatric adverse reactions were also observed in open-label pediatric trials and were generally similar to those observed in adults.

Patients should be advised to report these symptoms immediately to a health care professional, the company noted.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has expanded the indication for brivaracetam (Briviact, UCB) as both monotherapy or adjunctive therapy for partial-onset seizures in patients as young as 1 month of age.

All three brivaracetam formulations (tablets, oral solution, and IV) may now be used. The approval marks the first time that the IV formulation will be available for children, the company said in a news release.

The medication is already approved in the United States as monotherapy and adjunctive therapy in adults with epilepsy.

In an open-label follow-up pediatric study, an estimated 71.4% of patients aged 1 month to 17 years with partial-onset seizures remained on brivaracetam therapy at 1 year, and 64.3% did so at 2 years, the company reported.

“We often see children with seizures hospitalized, so it’s important to have a therapy like Briviact IV that can offer rapid administration in an effective dose when needed and does not require titration,” Raman Sankar, MD, PhD, distinguished professor and chief of pediatric neurology, University of California, Los Angeles, said in the release.

“The availability of the oral dose forms also allows continuity of treatment when these young patients are transitioning from hospital to home,” he added.
 

Safety profile

Dr. Sankar noted that with approval now of both the IV and oral formulations for partial-onset seizures in such young children, “we have a new option that helps meet a critical need in pediatric epilepsy.”

The most common adverse reactions with brivaracetam include somnolence and sedation, dizziness, fatigue, nausea, and vomiting. In the pediatric clinical trials, the safety profile for pediatric patients was similar to adults.

In the adult trials, psychiatric adverse reactions, including nonpsychotic and psychotic symptoms, were reported in approximately 13% of adults taking at least 50 mg/day of brivaracetam compared with 8% taking placebo.

Psychiatric adverse reactions were also observed in open-label pediatric trials and were generally similar to those observed in adults.

Patients should be advised to report these symptoms immediately to a health care professional, the company noted.

A version of this article first appeared on Medscape.com.