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STORM trial shows response in penta-refractory myeloma
Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma, according to the principal investigator of the STORM trial.
Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%. The median progression-free survival was 3.7 months and the median overall survival was 8.6 months.
The trial’s principal investigator, Sundar Jagannath, MBBS, of the Icahn School of Medicine at Mount Sinai, New York, presented these results at the annual meeting of the Society of Hematologic Oncology.
“The additional phase 2b clinical results… are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said in a statement. “Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM [Selinexor Treatment of Refractory Myeloma] study.”
STORM (NCT02336815) included 122 patients with penta-refractory multiple myeloma. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.
The patients had received a median of seven prior treatment regimens. Their median age was 65 years, a little more than half were men, and more than half had high-risk cytogenetics. Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10–6 and one at 1 x 10–4.
Very good partial responses were seen in 4.9% of patients, 19.7% had partial responses, 13.1% had minimal responses (MRs), and 39.3% had stable disease. Progressive disease occurred in 13.1% of patients; 8.2% were not evaluable for response.
The overall response rate (partial response or better) was 26.2%, the clinical benefit rate (MR or better) was 39.3%, and the disease control rate (stable disease or better) was 78.7%.
The median duration of response was 4.4 months. The median progression-free survival was 3.7 months overall, 4.6 months in patients with an MR or better, and 1.1 months in patients who had progressive disease or were not evaluable.
The median overall survival was 8.6 months for the entire cohort. Overall survival was 15.6 months in patients with an MR or better and 1.7 months in patients who had progressive disease or were not evaluable (P less than .0001).
The “most important” grade 3/4 adverse events, according to Dr. Jagannath, were thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%). A total of 23 patients (19.5%) discontinued treatment because of a related adverse.
This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GlaxoSmithKline.
SOURCE: Jagannath S et al. SOHO 2018, Abstract MM-255
Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma, according to the principal investigator of the STORM trial.
Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%. The median progression-free survival was 3.7 months and the median overall survival was 8.6 months.
The trial’s principal investigator, Sundar Jagannath, MBBS, of the Icahn School of Medicine at Mount Sinai, New York, presented these results at the annual meeting of the Society of Hematologic Oncology.
“The additional phase 2b clinical results… are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said in a statement. “Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM [Selinexor Treatment of Refractory Myeloma] study.”
STORM (NCT02336815) included 122 patients with penta-refractory multiple myeloma. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.
The patients had received a median of seven prior treatment regimens. Their median age was 65 years, a little more than half were men, and more than half had high-risk cytogenetics. Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10–6 and one at 1 x 10–4.
Very good partial responses were seen in 4.9% of patients, 19.7% had partial responses, 13.1% had minimal responses (MRs), and 39.3% had stable disease. Progressive disease occurred in 13.1% of patients; 8.2% were not evaluable for response.
The overall response rate (partial response or better) was 26.2%, the clinical benefit rate (MR or better) was 39.3%, and the disease control rate (stable disease or better) was 78.7%.
The median duration of response was 4.4 months. The median progression-free survival was 3.7 months overall, 4.6 months in patients with an MR or better, and 1.1 months in patients who had progressive disease or were not evaluable.
The median overall survival was 8.6 months for the entire cohort. Overall survival was 15.6 months in patients with an MR or better and 1.7 months in patients who had progressive disease or were not evaluable (P less than .0001).
The “most important” grade 3/4 adverse events, according to Dr. Jagannath, were thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%). A total of 23 patients (19.5%) discontinued treatment because of a related adverse.
This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GlaxoSmithKline.
SOURCE: Jagannath S et al. SOHO 2018, Abstract MM-255
Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma, according to the principal investigator of the STORM trial.
Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%. The median progression-free survival was 3.7 months and the median overall survival was 8.6 months.
The trial’s principal investigator, Sundar Jagannath, MBBS, of the Icahn School of Medicine at Mount Sinai, New York, presented these results at the annual meeting of the Society of Hematologic Oncology.
“The additional phase 2b clinical results… are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said in a statement. “Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM [Selinexor Treatment of Refractory Myeloma] study.”
STORM (NCT02336815) included 122 patients with penta-refractory multiple myeloma. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.
The patients had received a median of seven prior treatment regimens. Their median age was 65 years, a little more than half were men, and more than half had high-risk cytogenetics. Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10–6 and one at 1 x 10–4.
Very good partial responses were seen in 4.9% of patients, 19.7% had partial responses, 13.1% had minimal responses (MRs), and 39.3% had stable disease. Progressive disease occurred in 13.1% of patients; 8.2% were not evaluable for response.
The overall response rate (partial response or better) was 26.2%, the clinical benefit rate (MR or better) was 39.3%, and the disease control rate (stable disease or better) was 78.7%.
The median duration of response was 4.4 months. The median progression-free survival was 3.7 months overall, 4.6 months in patients with an MR or better, and 1.1 months in patients who had progressive disease or were not evaluable.
The median overall survival was 8.6 months for the entire cohort. Overall survival was 15.6 months in patients with an MR or better and 1.7 months in patients who had progressive disease or were not evaluable (P less than .0001).
The “most important” grade 3/4 adverse events, according to Dr. Jagannath, were thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%). A total of 23 patients (19.5%) discontinued treatment because of a related adverse.
This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GlaxoSmithKline.
SOURCE: Jagannath S et al. SOHO 2018, Abstract MM-255
FROM SOHO 2018
Key clinical point:
Major finding: The overall response rate was 26.2% and the clinical benefit rate was 39.3%.
Study details: A phase 2 trial of 122 patients with penta-refractory multiple myeloma.
Disclosures: This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GlaxoSmithKline.
Source: Jagannath S et al. SOHO 2018, Abstract MM-255.
Impact of an Educational Seminar Series for VA Providers in Personalized Cancer Care Across Hematologic and Solid Tumors
Purpose/Rationale: To address educational needs of hematology/oncology providers in VA and other federal settings, we conducted a national series of accredited 6-hour seminars. Through surveys, we assessed baseline barriers and educational outcomes.
Background: Recent landmark advances in cancer therapies engender pressing needs for education among VA providers.
Methods: The educational seminars were held in 9 US cities with large VA facilities between November 2017 and March 2018. The agenda, covering hematologic malignancies (3 hours) and solid tumors (3 hours), emphasized evidenced-based and guideline-directed uses of new cancer therapies. Before and after the seminars, participants completed surveys designed to assess self-reported barriers, confidence, and competence regarding personalized medicine approaches to implementing the therapies.
Results: Survey respondents (n = 639) were physicians (29%), pharmacists (23%), nurses (21%), physician assistants (18%), and nurse practitioners (9%) who practice in VA clinics and other federal settings; providers reported seeing an average of 103 oncology patients per month. On the pre-seminar survey, gaps were indicated by relatively small proportions of respondents who reported that their decision-making involving new cancer therapies is guided by genetic/prognostic testing (21%) and assessing patientspecific characteristics including comorbidities (38%); 42% reported having inadequate staff training for personalized hematology/oncology care.
Across the pre- to post-seminar surveys, there were significant increases (P < .0001 for all comparisons) in the proportions of respondents who reported: (1) high confidence in using immunotherapies (17% to 38%), targeted therapies (19% to 37%), and hormonal therapies (20% to 36%); and (2) high competence in performing various clinical skills, including identifying genetic tests for patients with acute myeloid leukemia (8% to 42%), interpreting genetic tests to support personalized treatment decision-making for patients with chronic lymphocytic leukemia (7% to 42%), recognizing and managing adverse events associated with targeted therapies (15% to 48%), and applying precision medicine principles in managing patients with highgrade gliomas (17% to 44%).
Conclusions/Implications: These findings indicate the positive impact of intensive education on self-reported confidence and competence among VA providers in applying personalized medicine approaches to implementing new cancer therapies. We will present additional baseline barriers and educational outcomes, as well as the seminar participants’ gap-targeted action plans for improvement.
Purpose/Rationale: To address educational needs of hematology/oncology providers in VA and other federal settings, we conducted a national series of accredited 6-hour seminars. Through surveys, we assessed baseline barriers and educational outcomes.
Background: Recent landmark advances in cancer therapies engender pressing needs for education among VA providers.
Methods: The educational seminars were held in 9 US cities with large VA facilities between November 2017 and March 2018. The agenda, covering hematologic malignancies (3 hours) and solid tumors (3 hours), emphasized evidenced-based and guideline-directed uses of new cancer therapies. Before and after the seminars, participants completed surveys designed to assess self-reported barriers, confidence, and competence regarding personalized medicine approaches to implementing the therapies.
Results: Survey respondents (n = 639) were physicians (29%), pharmacists (23%), nurses (21%), physician assistants (18%), and nurse practitioners (9%) who practice in VA clinics and other federal settings; providers reported seeing an average of 103 oncology patients per month. On the pre-seminar survey, gaps were indicated by relatively small proportions of respondents who reported that their decision-making involving new cancer therapies is guided by genetic/prognostic testing (21%) and assessing patientspecific characteristics including comorbidities (38%); 42% reported having inadequate staff training for personalized hematology/oncology care.
Across the pre- to post-seminar surveys, there were significant increases (P < .0001 for all comparisons) in the proportions of respondents who reported: (1) high confidence in using immunotherapies (17% to 38%), targeted therapies (19% to 37%), and hormonal therapies (20% to 36%); and (2) high competence in performing various clinical skills, including identifying genetic tests for patients with acute myeloid leukemia (8% to 42%), interpreting genetic tests to support personalized treatment decision-making for patients with chronic lymphocytic leukemia (7% to 42%), recognizing and managing adverse events associated with targeted therapies (15% to 48%), and applying precision medicine principles in managing patients with highgrade gliomas (17% to 44%).
Conclusions/Implications: These findings indicate the positive impact of intensive education on self-reported confidence and competence among VA providers in applying personalized medicine approaches to implementing new cancer therapies. We will present additional baseline barriers and educational outcomes, as well as the seminar participants’ gap-targeted action plans for improvement.
Purpose/Rationale: To address educational needs of hematology/oncology providers in VA and other federal settings, we conducted a national series of accredited 6-hour seminars. Through surveys, we assessed baseline barriers and educational outcomes.
Background: Recent landmark advances in cancer therapies engender pressing needs for education among VA providers.
Methods: The educational seminars were held in 9 US cities with large VA facilities between November 2017 and March 2018. The agenda, covering hematologic malignancies (3 hours) and solid tumors (3 hours), emphasized evidenced-based and guideline-directed uses of new cancer therapies. Before and after the seminars, participants completed surveys designed to assess self-reported barriers, confidence, and competence regarding personalized medicine approaches to implementing the therapies.
Results: Survey respondents (n = 639) were physicians (29%), pharmacists (23%), nurses (21%), physician assistants (18%), and nurse practitioners (9%) who practice in VA clinics and other federal settings; providers reported seeing an average of 103 oncology patients per month. On the pre-seminar survey, gaps were indicated by relatively small proportions of respondents who reported that their decision-making involving new cancer therapies is guided by genetic/prognostic testing (21%) and assessing patientspecific characteristics including comorbidities (38%); 42% reported having inadequate staff training for personalized hematology/oncology care.
Across the pre- to post-seminar surveys, there were significant increases (P < .0001 for all comparisons) in the proportions of respondents who reported: (1) high confidence in using immunotherapies (17% to 38%), targeted therapies (19% to 37%), and hormonal therapies (20% to 36%); and (2) high competence in performing various clinical skills, including identifying genetic tests for patients with acute myeloid leukemia (8% to 42%), interpreting genetic tests to support personalized treatment decision-making for patients with chronic lymphocytic leukemia (7% to 42%), recognizing and managing adverse events associated with targeted therapies (15% to 48%), and applying precision medicine principles in managing patients with highgrade gliomas (17% to 44%).
Conclusions/Implications: These findings indicate the positive impact of intensive education on self-reported confidence and competence among VA providers in applying personalized medicine approaches to implementing new cancer therapies. We will present additional baseline barriers and educational outcomes, as well as the seminar participants’ gap-targeted action plans for improvement.
Implementation of a Hematology VA-ECHO Program
Purpose/Rationale: Lack of access to a hematology specialist is a barrier to care for veterans in rural and underserved areas. In light of the increasingly short supply of sub-specialists, there is a need to provide hematology education and outreach to primary care providers within the VA system.
Background: The ECHO program (Extension for Community Healthcare Outcomes) is a well-established and successful platform that audibly and visually links an area specialist to primary care providers and interdisciplinary team members, allowing for two-way specialty consultation combined with continuing education. Overall, our service network (VISN 20) has provided specialty education to more than 10 specialties and 171 clinical sites (26% rural or highly rural) through the VA-ECHO program. In fiscal year 2016, VISN 20 estimated that over 280,000 potential patient travel miles saved as a result of VA-ECHO.
Methods/Approach: As we could not identify an existing Hematology VA-ECHO program within VISN 20, nor to our knowledge nationally, we sought to develop and implement a Hematology VA-ECHO program based at the Puget Sound VA (Seattle, WA).
Results: We delivered an introductory 3-part VA-ECHO series to assess demand and solicit feedback about Hematology VA-ECHO. Session topics were iron deficiency anemia, polycythemia, and deep vein thrombosis/pulmonary embolism. We had participation from 17 sites in 9 states; 10 sites within VISN 20. Attendees included pharmacists, MDs, APRNs and RNs. We averaged 20 participants per session and welcomed 43 unique participants over 3 sessions. The vast majority (94%) of respondents (n=34) agreed or strongly agreed that the content in the sessions were relevant to their practice and 80% anticipated changing their practice as a result of session participation
Conclusion/Implications: A successful Hematology VA-ECHO program stands to de-monopolize specialty knowledge and help primary providers evaluate and manage common hematologic abnormalities, especially in underserved areas. We aim to expand Hematology VA-ECHO to include 8-9 sessions over the next calendar year. Uptake of Hematology VA-ECHO at additional VA sites in different geographical areas would help further increase hematology access for primary providers.
Purpose/Rationale: Lack of access to a hematology specialist is a barrier to care for veterans in rural and underserved areas. In light of the increasingly short supply of sub-specialists, there is a need to provide hematology education and outreach to primary care providers within the VA system.
Background: The ECHO program (Extension for Community Healthcare Outcomes) is a well-established and successful platform that audibly and visually links an area specialist to primary care providers and interdisciplinary team members, allowing for two-way specialty consultation combined with continuing education. Overall, our service network (VISN 20) has provided specialty education to more than 10 specialties and 171 clinical sites (26% rural or highly rural) through the VA-ECHO program. In fiscal year 2016, VISN 20 estimated that over 280,000 potential patient travel miles saved as a result of VA-ECHO.
Methods/Approach: As we could not identify an existing Hematology VA-ECHO program within VISN 20, nor to our knowledge nationally, we sought to develop and implement a Hematology VA-ECHO program based at the Puget Sound VA (Seattle, WA).
Results: We delivered an introductory 3-part VA-ECHO series to assess demand and solicit feedback about Hematology VA-ECHO. Session topics were iron deficiency anemia, polycythemia, and deep vein thrombosis/pulmonary embolism. We had participation from 17 sites in 9 states; 10 sites within VISN 20. Attendees included pharmacists, MDs, APRNs and RNs. We averaged 20 participants per session and welcomed 43 unique participants over 3 sessions. The vast majority (94%) of respondents (n=34) agreed or strongly agreed that the content in the sessions were relevant to their practice and 80% anticipated changing their practice as a result of session participation
Conclusion/Implications: A successful Hematology VA-ECHO program stands to de-monopolize specialty knowledge and help primary providers evaluate and manage common hematologic abnormalities, especially in underserved areas. We aim to expand Hematology VA-ECHO to include 8-9 sessions over the next calendar year. Uptake of Hematology VA-ECHO at additional VA sites in different geographical areas would help further increase hematology access for primary providers.
Purpose/Rationale: Lack of access to a hematology specialist is a barrier to care for veterans in rural and underserved areas. In light of the increasingly short supply of sub-specialists, there is a need to provide hematology education and outreach to primary care providers within the VA system.
Background: The ECHO program (Extension for Community Healthcare Outcomes) is a well-established and successful platform that audibly and visually links an area specialist to primary care providers and interdisciplinary team members, allowing for two-way specialty consultation combined with continuing education. Overall, our service network (VISN 20) has provided specialty education to more than 10 specialties and 171 clinical sites (26% rural or highly rural) through the VA-ECHO program. In fiscal year 2016, VISN 20 estimated that over 280,000 potential patient travel miles saved as a result of VA-ECHO.
Methods/Approach: As we could not identify an existing Hematology VA-ECHO program within VISN 20, nor to our knowledge nationally, we sought to develop and implement a Hematology VA-ECHO program based at the Puget Sound VA (Seattle, WA).
Results: We delivered an introductory 3-part VA-ECHO series to assess demand and solicit feedback about Hematology VA-ECHO. Session topics were iron deficiency anemia, polycythemia, and deep vein thrombosis/pulmonary embolism. We had participation from 17 sites in 9 states; 10 sites within VISN 20. Attendees included pharmacists, MDs, APRNs and RNs. We averaged 20 participants per session and welcomed 43 unique participants over 3 sessions. The vast majority (94%) of respondents (n=34) agreed or strongly agreed that the content in the sessions were relevant to their practice and 80% anticipated changing their practice as a result of session participation
Conclusion/Implications: A successful Hematology VA-ECHO program stands to de-monopolize specialty knowledge and help primary providers evaluate and manage common hematologic abnormalities, especially in underserved areas. We aim to expand Hematology VA-ECHO to include 8-9 sessions over the next calendar year. Uptake of Hematology VA-ECHO at additional VA sites in different geographical areas would help further increase hematology access for primary providers.
Cardiovascular Effects of Tyrosine Kinase Inhibitors in Advanced Renal Cell Carcinoma (RCC) Patients at VA San Diego Healthcare System (VASDHS)
Purpose: The purpose of this study was to characterize the incidence of cardiovascular events and time to first cardiovascular event due to tyrosine kinase inhibitors (TKIs) in patients with advanced RCC at VASDHS. Additional aims were to describe the current clinical practice management of cardiac monitoring via EKG or ECHO in this patient population.
Background: Over the past 12 years, the US Food and Drug Administration has approved six multitargeted TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib and sunitinib. Other than hypertension, most studies of these therapies did not report the incidence of cardiovascular events that occurred during early clinical trials.
Methodology: This was a retrospective study that evaluated the incidence of cardiovascular events in patients diagnosed with advanced RCC who received oral TKI therapy for at least 30 days. The incidence of cardiovascular events was collected in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) grading at predetermined time points from the start of each TKI therapy. Cardiovascular events were defined as hypertension, QT prolongation, congestive heart failure (CHF), stroke, myocardial infarction (MI) and pulmonary hypertension.
Results: Fifty-four patients were included in this study with a median age of 66 years. There were no cardiac events in patients without a history of cardiovascular disease. Eleven patients with a history of cardiovascular disease experienced an adverse cardiac event while taking pazopanib, sorafenib, or sunitinib. The most common adverse events were hypertension (n=6) and MI (n=2). The remaining three patients experienced a stroke, QT prolongation, or CHF. Seventy-three percent of events occurred within four months of starting therapy. Baseline EKG or ECHO were not available for most patients started on TKI therapy and obtained only when patients were symptomatic.
Conclusions: The results of this study indicate a need for baseline and routine monitoring in patients started on oral TKIs with a history of cardiovascular disease to align with the current recommendations as listed in the medication package inserts. Based on the results of this study, baseline and routine monitoring should be considered during the first four months of therapy in patients with a history of cardiovascular disease.
Purpose: The purpose of this study was to characterize the incidence of cardiovascular events and time to first cardiovascular event due to tyrosine kinase inhibitors (TKIs) in patients with advanced RCC at VASDHS. Additional aims were to describe the current clinical practice management of cardiac monitoring via EKG or ECHO in this patient population.
Background: Over the past 12 years, the US Food and Drug Administration has approved six multitargeted TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib and sunitinib. Other than hypertension, most studies of these therapies did not report the incidence of cardiovascular events that occurred during early clinical trials.
Methodology: This was a retrospective study that evaluated the incidence of cardiovascular events in patients diagnosed with advanced RCC who received oral TKI therapy for at least 30 days. The incidence of cardiovascular events was collected in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) grading at predetermined time points from the start of each TKI therapy. Cardiovascular events were defined as hypertension, QT prolongation, congestive heart failure (CHF), stroke, myocardial infarction (MI) and pulmonary hypertension.
Results: Fifty-four patients were included in this study with a median age of 66 years. There were no cardiac events in patients without a history of cardiovascular disease. Eleven patients with a history of cardiovascular disease experienced an adverse cardiac event while taking pazopanib, sorafenib, or sunitinib. The most common adverse events were hypertension (n=6) and MI (n=2). The remaining three patients experienced a stroke, QT prolongation, or CHF. Seventy-three percent of events occurred within four months of starting therapy. Baseline EKG or ECHO were not available for most patients started on TKI therapy and obtained only when patients were symptomatic.
Conclusions: The results of this study indicate a need for baseline and routine monitoring in patients started on oral TKIs with a history of cardiovascular disease to align with the current recommendations as listed in the medication package inserts. Based on the results of this study, baseline and routine monitoring should be considered during the first four months of therapy in patients with a history of cardiovascular disease.
Purpose: The purpose of this study was to characterize the incidence of cardiovascular events and time to first cardiovascular event due to tyrosine kinase inhibitors (TKIs) in patients with advanced RCC at VASDHS. Additional aims were to describe the current clinical practice management of cardiac monitoring via EKG or ECHO in this patient population.
Background: Over the past 12 years, the US Food and Drug Administration has approved six multitargeted TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib and sunitinib. Other than hypertension, most studies of these therapies did not report the incidence of cardiovascular events that occurred during early clinical trials.
Methodology: This was a retrospective study that evaluated the incidence of cardiovascular events in patients diagnosed with advanced RCC who received oral TKI therapy for at least 30 days. The incidence of cardiovascular events was collected in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) grading at predetermined time points from the start of each TKI therapy. Cardiovascular events were defined as hypertension, QT prolongation, congestive heart failure (CHF), stroke, myocardial infarction (MI) and pulmonary hypertension.
Results: Fifty-four patients were included in this study with a median age of 66 years. There were no cardiac events in patients without a history of cardiovascular disease. Eleven patients with a history of cardiovascular disease experienced an adverse cardiac event while taking pazopanib, sorafenib, or sunitinib. The most common adverse events were hypertension (n=6) and MI (n=2). The remaining three patients experienced a stroke, QT prolongation, or CHF. Seventy-three percent of events occurred within four months of starting therapy. Baseline EKG or ECHO were not available for most patients started on TKI therapy and obtained only when patients were symptomatic.
Conclusions: The results of this study indicate a need for baseline and routine monitoring in patients started on oral TKIs with a history of cardiovascular disease to align with the current recommendations as listed in the medication package inserts. Based on the results of this study, baseline and routine monitoring should be considered during the first four months of therapy in patients with a history of cardiovascular disease.
Hormonal contraceptive use linked to leukemia risk in offspring
A nationwide cohort study found an association between a woman’s use of hormonal contraceptives and a small increased risk of nonlymphoid leukemia in her offspring.
Maternal use of hormonal contraception either during pregnancy or in the 3 months beforehand was associated with a 46% higher risk of any leukemia in the children (P = .011), compared with no use, Marie Hargreave, PhD, of the Danish Cancer Society Research Center and her coauthors reported in Lancet Oncology.
The study of 1,185,157 children born between 1996 and 2014 included data from the Danish Cancer Registry and Danish National Prescription Registry and followed children for a median of 9.3 years.
Use during pregnancy was associated with a 78% higher risk of any leukemia in the offspring (P = .070), and contraception use that stopped more than 3 months before pregnancy was associated with a 25% higher risk of any leukemia (P = .039).
The researchers estimated that maternal use of hormonal contraceptives up to and including during pregnancy would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia in Denmark from contraceptive use from 1996 to 2014.
The increased risk appeared to be limited to nonlymphoid leukemia only. The risk with recent use was more than twofold higher (HR, 2.17), compared with nonuse, and use during pregnancy was associated with a nearly fourfold increase in the risk of leukemia (HR, 3.87).
“Sex hormones are considered to be potent carcinogens, and the causal association between in-utero exposure to the oestrogen analogue diethylstilbestrol and subsequent risk for adenocarcinoma of the vagina is firmly established,” Dr. Hargreave and her colleagues wrote. “The mechanism by which maternal use of hormones increases cancer risk in children is, however, still not clear.”
Recent use of combined oral contraceptive products was associated with a more than twofold increased risk of nonlymphoid leukemia in offspring, compared with no use. However progestin-only oral contraceptives and emergency contraception did not appear to increase in the risk of lymphoid or nonlymphoid leukemia.
The association was strongest in children aged 6-10 years, which the authors suggested was likely because the incidence of nonlymphoid leukemia increases after the age of 6 years.
While acknowledging that the small increase in leukemia risk was not a major safety concern for hormonal contraceptives, the authors commented that the results suggested the intrauterine hormonal environment could be a direction for research into the causes of leukemia.
The study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.
SOURCE: Hargreave M et al. Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045(18)30479-0.
Estrogenic compounds could have a number of effects on the genomic machinery, that could in turn lead to an increased risk of leukemia in offspring. It may be that oral contraceptives cause epigenetic changes to fetal hematopoietic stem cells that lead to gene rearrangements and oxidative damage, which could then influence the risk of developing childhood leukemia.
This study opens a new avenue of investigation for a risk factor that might increase a child’s susceptibility to leukemia and is important in shedding more light on dose-response associations of exposures.
Dr. Maria S. Pombo-de-Oliveira is from the pediatric hematology-oncology research program at the Instituto Nacional de Câncer in Rio de Janeiro. These comments are adapted from an accompanying editorial (Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045[18]30509-6). Dr. Pombo-de-Oliveira reported having no conflicts of interest.
Estrogenic compounds could have a number of effects on the genomic machinery, that could in turn lead to an increased risk of leukemia in offspring. It may be that oral contraceptives cause epigenetic changes to fetal hematopoietic stem cells that lead to gene rearrangements and oxidative damage, which could then influence the risk of developing childhood leukemia.
This study opens a new avenue of investigation for a risk factor that might increase a child’s susceptibility to leukemia and is important in shedding more light on dose-response associations of exposures.
Dr. Maria S. Pombo-de-Oliveira is from the pediatric hematology-oncology research program at the Instituto Nacional de Câncer in Rio de Janeiro. These comments are adapted from an accompanying editorial (Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045[18]30509-6). Dr. Pombo-de-Oliveira reported having no conflicts of interest.
Estrogenic compounds could have a number of effects on the genomic machinery, that could in turn lead to an increased risk of leukemia in offspring. It may be that oral contraceptives cause epigenetic changes to fetal hematopoietic stem cells that lead to gene rearrangements and oxidative damage, which could then influence the risk of developing childhood leukemia.
This study opens a new avenue of investigation for a risk factor that might increase a child’s susceptibility to leukemia and is important in shedding more light on dose-response associations of exposures.
Dr. Maria S. Pombo-de-Oliveira is from the pediatric hematology-oncology research program at the Instituto Nacional de Câncer in Rio de Janeiro. These comments are adapted from an accompanying editorial (Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045[18]30509-6). Dr. Pombo-de-Oliveira reported having no conflicts of interest.
A nationwide cohort study found an association between a woman’s use of hormonal contraceptives and a small increased risk of nonlymphoid leukemia in her offspring.
Maternal use of hormonal contraception either during pregnancy or in the 3 months beforehand was associated with a 46% higher risk of any leukemia in the children (P = .011), compared with no use, Marie Hargreave, PhD, of the Danish Cancer Society Research Center and her coauthors reported in Lancet Oncology.
The study of 1,185,157 children born between 1996 and 2014 included data from the Danish Cancer Registry and Danish National Prescription Registry and followed children for a median of 9.3 years.
Use during pregnancy was associated with a 78% higher risk of any leukemia in the offspring (P = .070), and contraception use that stopped more than 3 months before pregnancy was associated with a 25% higher risk of any leukemia (P = .039).
The researchers estimated that maternal use of hormonal contraceptives up to and including during pregnancy would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia in Denmark from contraceptive use from 1996 to 2014.
The increased risk appeared to be limited to nonlymphoid leukemia only. The risk with recent use was more than twofold higher (HR, 2.17), compared with nonuse, and use during pregnancy was associated with a nearly fourfold increase in the risk of leukemia (HR, 3.87).
“Sex hormones are considered to be potent carcinogens, and the causal association between in-utero exposure to the oestrogen analogue diethylstilbestrol and subsequent risk for adenocarcinoma of the vagina is firmly established,” Dr. Hargreave and her colleagues wrote. “The mechanism by which maternal use of hormones increases cancer risk in children is, however, still not clear.”
Recent use of combined oral contraceptive products was associated with a more than twofold increased risk of nonlymphoid leukemia in offspring, compared with no use. However progestin-only oral contraceptives and emergency contraception did not appear to increase in the risk of lymphoid or nonlymphoid leukemia.
The association was strongest in children aged 6-10 years, which the authors suggested was likely because the incidence of nonlymphoid leukemia increases after the age of 6 years.
While acknowledging that the small increase in leukemia risk was not a major safety concern for hormonal contraceptives, the authors commented that the results suggested the intrauterine hormonal environment could be a direction for research into the causes of leukemia.
The study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.
SOURCE: Hargreave M et al. Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045(18)30479-0.
A nationwide cohort study found an association between a woman’s use of hormonal contraceptives and a small increased risk of nonlymphoid leukemia in her offspring.
Maternal use of hormonal contraception either during pregnancy or in the 3 months beforehand was associated with a 46% higher risk of any leukemia in the children (P = .011), compared with no use, Marie Hargreave, PhD, of the Danish Cancer Society Research Center and her coauthors reported in Lancet Oncology.
The study of 1,185,157 children born between 1996 and 2014 included data from the Danish Cancer Registry and Danish National Prescription Registry and followed children for a median of 9.3 years.
Use during pregnancy was associated with a 78% higher risk of any leukemia in the offspring (P = .070), and contraception use that stopped more than 3 months before pregnancy was associated with a 25% higher risk of any leukemia (P = .039).
The researchers estimated that maternal use of hormonal contraceptives up to and including during pregnancy would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia in Denmark from contraceptive use from 1996 to 2014.
The increased risk appeared to be limited to nonlymphoid leukemia only. The risk with recent use was more than twofold higher (HR, 2.17), compared with nonuse, and use during pregnancy was associated with a nearly fourfold increase in the risk of leukemia (HR, 3.87).
“Sex hormones are considered to be potent carcinogens, and the causal association between in-utero exposure to the oestrogen analogue diethylstilbestrol and subsequent risk for adenocarcinoma of the vagina is firmly established,” Dr. Hargreave and her colleagues wrote. “The mechanism by which maternal use of hormones increases cancer risk in children is, however, still not clear.”
Recent use of combined oral contraceptive products was associated with a more than twofold increased risk of nonlymphoid leukemia in offspring, compared with no use. However progestin-only oral contraceptives and emergency contraception did not appear to increase in the risk of lymphoid or nonlymphoid leukemia.
The association was strongest in children aged 6-10 years, which the authors suggested was likely because the incidence of nonlymphoid leukemia increases after the age of 6 years.
While acknowledging that the small increase in leukemia risk was not a major safety concern for hormonal contraceptives, the authors commented that the results suggested the intrauterine hormonal environment could be a direction for research into the causes of leukemia.
The study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.
SOURCE: Hargreave M et al. Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045(18)30479-0.
FROM LANCET ONCOLOGY
Key clinical point:
Major finding: Recent maternal hormonal contraceptive use was linked to one additional case of leukemia per 47,170 children.
Study details: Danish nationwide cohort study in 1,185,157 children.
Disclosures: The study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.
Source: Hargreave M et al. Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045(18)30479-0.
ASCO updates guidance on prophylaxis for adults with cancer-related immunosuppression
Fluoroquinolones are recommended for adults with cancer-related immunosuppression if they are at high risk of infection, according to an updated clinical practice guideline on antimicrobial prophylaxis.
By contrast, patients with solid tumors are not routinely recommended to receive antibiotic prophylaxis, according to the guideline, developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA).
The guideline includes antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions such as hand hygiene that may reduce infection risk.
Released in the Journal of Clinical Oncology, the updated guidelines were developed by an expert panel cochaired by Christopher R. Flowers, MD of Emory University, Atlanta, and Randy A. Taplitz, MD of the University of California, San Diego, Health.
For the most part, the panel endorsed the previous ASCO recommendations, published in 2013. However, the panel considered six new high-quality studies and six new or updated meta-analyses to make modifications and add some new recommendations.
Fluoroquinolones, in the 2013 guideline, were recommended over trimethoprim-sulfamethoxazole because of fewer adverse events leading to treatment discontinuation. Panelists for the new guidelines said they continued to support that recommendation, based on an updated literature review.
That review showed significant reductions in both febrile neutropenia incidence and all-cause mortality, not only for patients at high risk of febrile neutropenia or profound, protracted neutropenia but also for lower-risk patients with solid tumors, they said.
However, the benefits did not sufficiently outweigh the harms to justify recommending fluoroquinolone prophylaxis for all patients with solid tumors or lymphoma, according to the report from the expert panel.
Those harms could include antibiotic-associated adverse effects, emergence of resistance, and Clostridium difficile infections, they said.
Accordingly, they recommended fluoroquinolone prophylaxis for the high-risk patients, including most patients with acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) or those undergoing hematopoietic stem-cell transplantation (HSCT).
Similarly, the panel recommended that high-risk patients should receive antifungal prophylaxis with an oral triazole or parenteral echinocandin, while prophylaxis would not be routinely recommended for solid tumor patients.
By contrast, all patients undergoing chemotherapy for malignancy should receive yearly influenza vaccination with an inactivated quadrivalent vaccine, the panel said in its antiviral prophylaxis recommendations.
Family members, household contacts, and health care providers also should receive influenza vaccinations, said the panel, endorsing recommendations from the Centers for Disease Control and Prevention that were also cited in the 2013 ASCO guidelines.
Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce risk of pathogen transmission, the panel said, endorsing CDC recommendations cited in the previous guideline.
However, the panel said they recommend against interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks.
“Evidence of clinical benefit is lacking” for those interventions, they said.
Participants in the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.
SOURCE: Taplitz RA et al. J Clin Oncol. 2018 Sept 4. doi: 10.1200/JCO.18.00374.
Fluoroquinolones are recommended for adults with cancer-related immunosuppression if they are at high risk of infection, according to an updated clinical practice guideline on antimicrobial prophylaxis.
By contrast, patients with solid tumors are not routinely recommended to receive antibiotic prophylaxis, according to the guideline, developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA).
The guideline includes antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions such as hand hygiene that may reduce infection risk.
Released in the Journal of Clinical Oncology, the updated guidelines were developed by an expert panel cochaired by Christopher R. Flowers, MD of Emory University, Atlanta, and Randy A. Taplitz, MD of the University of California, San Diego, Health.
For the most part, the panel endorsed the previous ASCO recommendations, published in 2013. However, the panel considered six new high-quality studies and six new or updated meta-analyses to make modifications and add some new recommendations.
Fluoroquinolones, in the 2013 guideline, were recommended over trimethoprim-sulfamethoxazole because of fewer adverse events leading to treatment discontinuation. Panelists for the new guidelines said they continued to support that recommendation, based on an updated literature review.
That review showed significant reductions in both febrile neutropenia incidence and all-cause mortality, not only for patients at high risk of febrile neutropenia or profound, protracted neutropenia but also for lower-risk patients with solid tumors, they said.
However, the benefits did not sufficiently outweigh the harms to justify recommending fluoroquinolone prophylaxis for all patients with solid tumors or lymphoma, according to the report from the expert panel.
Those harms could include antibiotic-associated adverse effects, emergence of resistance, and Clostridium difficile infections, they said.
Accordingly, they recommended fluoroquinolone prophylaxis for the high-risk patients, including most patients with acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) or those undergoing hematopoietic stem-cell transplantation (HSCT).
Similarly, the panel recommended that high-risk patients should receive antifungal prophylaxis with an oral triazole or parenteral echinocandin, while prophylaxis would not be routinely recommended for solid tumor patients.
By contrast, all patients undergoing chemotherapy for malignancy should receive yearly influenza vaccination with an inactivated quadrivalent vaccine, the panel said in its antiviral prophylaxis recommendations.
Family members, household contacts, and health care providers also should receive influenza vaccinations, said the panel, endorsing recommendations from the Centers for Disease Control and Prevention that were also cited in the 2013 ASCO guidelines.
Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce risk of pathogen transmission, the panel said, endorsing CDC recommendations cited in the previous guideline.
However, the panel said they recommend against interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks.
“Evidence of clinical benefit is lacking” for those interventions, they said.
Participants in the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.
SOURCE: Taplitz RA et al. J Clin Oncol. 2018 Sept 4. doi: 10.1200/JCO.18.00374.
Fluoroquinolones are recommended for adults with cancer-related immunosuppression if they are at high risk of infection, according to an updated clinical practice guideline on antimicrobial prophylaxis.
By contrast, patients with solid tumors are not routinely recommended to receive antibiotic prophylaxis, according to the guideline, developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA).
The guideline includes antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions such as hand hygiene that may reduce infection risk.
Released in the Journal of Clinical Oncology, the updated guidelines were developed by an expert panel cochaired by Christopher R. Flowers, MD of Emory University, Atlanta, and Randy A. Taplitz, MD of the University of California, San Diego, Health.
For the most part, the panel endorsed the previous ASCO recommendations, published in 2013. However, the panel considered six new high-quality studies and six new or updated meta-analyses to make modifications and add some new recommendations.
Fluoroquinolones, in the 2013 guideline, were recommended over trimethoprim-sulfamethoxazole because of fewer adverse events leading to treatment discontinuation. Panelists for the new guidelines said they continued to support that recommendation, based on an updated literature review.
That review showed significant reductions in both febrile neutropenia incidence and all-cause mortality, not only for patients at high risk of febrile neutropenia or profound, protracted neutropenia but also for lower-risk patients with solid tumors, they said.
However, the benefits did not sufficiently outweigh the harms to justify recommending fluoroquinolone prophylaxis for all patients with solid tumors or lymphoma, according to the report from the expert panel.
Those harms could include antibiotic-associated adverse effects, emergence of resistance, and Clostridium difficile infections, they said.
Accordingly, they recommended fluoroquinolone prophylaxis for the high-risk patients, including most patients with acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) or those undergoing hematopoietic stem-cell transplantation (HSCT).
Similarly, the panel recommended that high-risk patients should receive antifungal prophylaxis with an oral triazole or parenteral echinocandin, while prophylaxis would not be routinely recommended for solid tumor patients.
By contrast, all patients undergoing chemotherapy for malignancy should receive yearly influenza vaccination with an inactivated quadrivalent vaccine, the panel said in its antiviral prophylaxis recommendations.
Family members, household contacts, and health care providers also should receive influenza vaccinations, said the panel, endorsing recommendations from the Centers for Disease Control and Prevention that were also cited in the 2013 ASCO guidelines.
Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce risk of pathogen transmission, the panel said, endorsing CDC recommendations cited in the previous guideline.
However, the panel said they recommend against interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks.
“Evidence of clinical benefit is lacking” for those interventions, they said.
Participants in the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.
SOURCE: Taplitz RA et al. J Clin Oncol. 2018 Sept 4. doi: 10.1200/JCO.18.00374.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Caplacizumab approved in Europe to treat aTTP
The , a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.
Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.
The drug has been accepted for priority review in the United States and the Food and Drug Administration is expected to make a decision by Feb. 6, 2019.
The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.
The TITAN trial included 75 aTTP patients who were randomized to caplacizumab (n = 36) or placebo (n = 39), with all patients receiving the current standard of care – daily plasma exchange and immunosuppressive therapy (N Engl J Med. 2016;374:511-22).
Patients in the caplacizumab arm had a 39% reduction in the median time to response, compared with patients in the placebo arm (P = .005).
The rate of adverse events (AEs) thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.
There were no deaths in the caplacizumab arm and two in the placebo arm. One death was attributable to severe, refractory TTP, and the other was attributable to cerebral hemorrhage.Results from the HERCULES trial were presented at the 2017 annual meeting of the American Society of Hematology.
The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73) in addition to standard care – plasma exchange and immunosuppression.
The study’s primary endpoint was the time to platelet count response (normalization). There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm. The platelet normalization rate ratio was 1.55 (P less than .01).
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n = 9) in the caplacizumab arm and 49.3% (n = 36) in the placebo arm (P less than .0001).
The incidence of aTTP-related death was 0% (n = 0) in the caplacizumab arm and 4.1% (n = 3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n = 3) in the caplacizumab arm and 38.4% in the placebo arm (n = 28), and the incidence of at least one major thromboembolic event was 8.5% (n = 6) and 8.2% (n = 6), respectively.
The , a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.
Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.
The drug has been accepted for priority review in the United States and the Food and Drug Administration is expected to make a decision by Feb. 6, 2019.
The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.
The TITAN trial included 75 aTTP patients who were randomized to caplacizumab (n = 36) or placebo (n = 39), with all patients receiving the current standard of care – daily plasma exchange and immunosuppressive therapy (N Engl J Med. 2016;374:511-22).
Patients in the caplacizumab arm had a 39% reduction in the median time to response, compared with patients in the placebo arm (P = .005).
The rate of adverse events (AEs) thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.
There were no deaths in the caplacizumab arm and two in the placebo arm. One death was attributable to severe, refractory TTP, and the other was attributable to cerebral hemorrhage.Results from the HERCULES trial were presented at the 2017 annual meeting of the American Society of Hematology.
The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73) in addition to standard care – plasma exchange and immunosuppression.
The study’s primary endpoint was the time to platelet count response (normalization). There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm. The platelet normalization rate ratio was 1.55 (P less than .01).
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n = 9) in the caplacizumab arm and 49.3% (n = 36) in the placebo arm (P less than .0001).
The incidence of aTTP-related death was 0% (n = 0) in the caplacizumab arm and 4.1% (n = 3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n = 3) in the caplacizumab arm and 38.4% in the placebo arm (n = 28), and the incidence of at least one major thromboembolic event was 8.5% (n = 6) and 8.2% (n = 6), respectively.
The , a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.
Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.
The drug has been accepted for priority review in the United States and the Food and Drug Administration is expected to make a decision by Feb. 6, 2019.
The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.
The TITAN trial included 75 aTTP patients who were randomized to caplacizumab (n = 36) or placebo (n = 39), with all patients receiving the current standard of care – daily plasma exchange and immunosuppressive therapy (N Engl J Med. 2016;374:511-22).
Patients in the caplacizumab arm had a 39% reduction in the median time to response, compared with patients in the placebo arm (P = .005).
The rate of adverse events (AEs) thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.
There were no deaths in the caplacizumab arm and two in the placebo arm. One death was attributable to severe, refractory TTP, and the other was attributable to cerebral hemorrhage.Results from the HERCULES trial were presented at the 2017 annual meeting of the American Society of Hematology.
The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73) in addition to standard care – plasma exchange and immunosuppression.
The study’s primary endpoint was the time to platelet count response (normalization). There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm. The platelet normalization rate ratio was 1.55 (P less than .01).
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n = 9) in the caplacizumab arm and 49.3% (n = 36) in the placebo arm (P less than .0001).
The incidence of aTTP-related death was 0% (n = 0) in the caplacizumab arm and 4.1% (n = 3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n = 3) in the caplacizumab arm and 38.4% in the placebo arm (n = 28), and the incidence of at least one major thromboembolic event was 8.5% (n = 6) and 8.2% (n = 6), respectively.
When is the right time to stop treatment?
Martha Boxer (not her real name) had mentally prepared herself that this could happen, but the news still hit hard. Her doctors on the leukemia service broke the facts as gently as we could: The chemotherapy she had been suffering through for the last 2 weeks hadn’t worked. The results of her latest bone marrow biopsy showed it remained packed with cancer cells.
As Martha absorbed the news quietly, her son, sitting next to her bedside with his hand on hers, spoke first. “What now?”
I looked at my attending and nodded, as we were fully ready to answer this question. From the outset, we knew that Martha’s leukemia carried a genetic mutation that unfortunately put her in a high-risk category. The chances of her cancer responding to the first round of chemotherapy were low. When this happens, what we typically do next is reinduction, we explained. It’s a different combination of chemotherapy drugs, with a somewhat different side effect profile. But it would give her the best chance of response, we believed. We could start the new chemotherapy as early as today, we said.
Martha took this in. “Okay,” she said pensively. “I’ve been thinking. And I think maybe … I won’t do chemotherapy anymore.”
Her words caught me off guard because, frankly, they seemed premature. Her leukemia had not budged with the first round of treatment. But we still had an option B, and then an option C. It was usually at a later, more dire stage – when multiple lines of treatment had not worked, and instead had only caused harm – or, when the decision was forced by the medical system’s admission that we had nothing left to offer – that I’d heard patients express similar preferences. It was then that I’d seen patients and their loved ones flip a mental switch and choose to focus the time they had left on what really mattered to them.
It didn’t feel like we were at that point.
And so, as we debriefed outside her room, my first instinct was to convince her otherwise.
However, Martha had other priorities, as I would come to learn. Above all else, she hated the hospital. She hated feeling trapped in a strange room that wasn’t hers; she hated how the chemotherapy stole her energy and made her feel too weak to even shower. She wanted to be in her own home. She wanted to eat her own food, sleep in her own bed, and be surrounded by what she recognized.
But, she also wanted to live. Two paths lay ahead of her. It was a trade-off of more suffering with a small chance at remission, versus accepting no chance of cure but feeling well for as long as she could. She soon clarified that she wasn’t definitely against chemotherapy. She couldn’t decide. She needed more information from us to make this decision, the hardest of her life.
Over the next few days, I watched as our attending physician expertly provided just that. There were actually three options, she laid out. There was aggressive chemotherapy, entailing at least 3 more weeks in the hospital and coming with significant risk of infection, nausea, vomiting, and fatigue. The chances of inducing a remission were about one in three to one in two, and that remission would likely last between several months and 2 years before the leukemia would relapse. The second option was a chemotherapy pill she could take at home, an option with fewer side effects but no longer aimed at cure. The third option was home hospice support, focused on symptoms, without any anticancer medication.
I noticed a few things during those conversations. I noticed how my attending took a navigator role, not pushing Martha in one direction or another, but rather imparting all the relevant information to empower Martha to decide for herself. I noticed how she provided realistic estimates, not hedging away from numbers, but giving the honest, nitty-gritty facts, as best as she could predict. I noticed how she took the time and never rushed, even in spite of external pressures to discharge the patient from the hospital.
There was no right or wrong answer. I no longer felt that we had something in our grasp – a clear-cut, best decision – to persuade Martha toward. Is one in three good odds, or bad odds? Is 2 years a long period of time, or a short one? Of course, there is no actual answer to these questions; the answer is as elusive and personal as if we had asked Martha: What do you think?
What I learned from Martha is that, with a devastating diagnosis, there isn’t a right time to make this decision. There isn’t one defining moment where we flip a switch and change course. It isn’t only when we run out of treatment options that the choice to forgo it makes sense. That option is on a flexible line, different for every person and priority. As my attending later said, with Martha’s diagnosis and her values, it wouldn’t have been unreasonable to decide against chemotherapy from the start.
The language we use can sometimes mask that reality. As doctors, we may casually slip in words like “need” and “have to” in response to patients’ questions about what to do next. “You need more chemotherapy,” we might say. “We’d have to treat it.” We have “treatment,” after all, and so we go down the line of offering what’s next in the medical algorithm. That word, too, can be deceivingly tempting, enticing down a road that makes it seem like the obvious answer – or the only one. If the choices are treatment versus not, who wouldn’t want the treatment? But the details are where things get murky. What does that treatment involve? What are the chances it will work, and for how long?
Surreptitiously missing from this language is the fact that there’s a choice. There’s always a choice, and it’s on the table at any point. You can start chemotherapy without committing to stick it out until the end. You can go home, if that is what’s important to you. The best treatment option is the one the patient wants.
After 4 days, Martha decided to go home with palliative chemotherapy and a bridge to hospice. Each member of our team hugged her goodbye and wished her luck. She was nervous. But she packed her hospital room, and she left.
I recently pulled up her medical chart, bracing myself for bad news. But the interesting thing about hospice is that even though the focus is no longer on prolonging life, people sometimes live longer.
She felt well, the most recent palliative note said. She was spending her time writing, getting her finances in order, and finishing a legacy project for her grandchildren.
For Martha, it seemed to be the right choice.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
Martha Boxer (not her real name) had mentally prepared herself that this could happen, but the news still hit hard. Her doctors on the leukemia service broke the facts as gently as we could: The chemotherapy she had been suffering through for the last 2 weeks hadn’t worked. The results of her latest bone marrow biopsy showed it remained packed with cancer cells.
As Martha absorbed the news quietly, her son, sitting next to her bedside with his hand on hers, spoke first. “What now?”
I looked at my attending and nodded, as we were fully ready to answer this question. From the outset, we knew that Martha’s leukemia carried a genetic mutation that unfortunately put her in a high-risk category. The chances of her cancer responding to the first round of chemotherapy were low. When this happens, what we typically do next is reinduction, we explained. It’s a different combination of chemotherapy drugs, with a somewhat different side effect profile. But it would give her the best chance of response, we believed. We could start the new chemotherapy as early as today, we said.
Martha took this in. “Okay,” she said pensively. “I’ve been thinking. And I think maybe … I won’t do chemotherapy anymore.”
Her words caught me off guard because, frankly, they seemed premature. Her leukemia had not budged with the first round of treatment. But we still had an option B, and then an option C. It was usually at a later, more dire stage – when multiple lines of treatment had not worked, and instead had only caused harm – or, when the decision was forced by the medical system’s admission that we had nothing left to offer – that I’d heard patients express similar preferences. It was then that I’d seen patients and their loved ones flip a mental switch and choose to focus the time they had left on what really mattered to them.
It didn’t feel like we were at that point.
And so, as we debriefed outside her room, my first instinct was to convince her otherwise.
However, Martha had other priorities, as I would come to learn. Above all else, she hated the hospital. She hated feeling trapped in a strange room that wasn’t hers; she hated how the chemotherapy stole her energy and made her feel too weak to even shower. She wanted to be in her own home. She wanted to eat her own food, sleep in her own bed, and be surrounded by what she recognized.
But, she also wanted to live. Two paths lay ahead of her. It was a trade-off of more suffering with a small chance at remission, versus accepting no chance of cure but feeling well for as long as she could. She soon clarified that she wasn’t definitely against chemotherapy. She couldn’t decide. She needed more information from us to make this decision, the hardest of her life.
Over the next few days, I watched as our attending physician expertly provided just that. There were actually three options, she laid out. There was aggressive chemotherapy, entailing at least 3 more weeks in the hospital and coming with significant risk of infection, nausea, vomiting, and fatigue. The chances of inducing a remission were about one in three to one in two, and that remission would likely last between several months and 2 years before the leukemia would relapse. The second option was a chemotherapy pill she could take at home, an option with fewer side effects but no longer aimed at cure. The third option was home hospice support, focused on symptoms, without any anticancer medication.
I noticed a few things during those conversations. I noticed how my attending took a navigator role, not pushing Martha in one direction or another, but rather imparting all the relevant information to empower Martha to decide for herself. I noticed how she provided realistic estimates, not hedging away from numbers, but giving the honest, nitty-gritty facts, as best as she could predict. I noticed how she took the time and never rushed, even in spite of external pressures to discharge the patient from the hospital.
There was no right or wrong answer. I no longer felt that we had something in our grasp – a clear-cut, best decision – to persuade Martha toward. Is one in three good odds, or bad odds? Is 2 years a long period of time, or a short one? Of course, there is no actual answer to these questions; the answer is as elusive and personal as if we had asked Martha: What do you think?
What I learned from Martha is that, with a devastating diagnosis, there isn’t a right time to make this decision. There isn’t one defining moment where we flip a switch and change course. It isn’t only when we run out of treatment options that the choice to forgo it makes sense. That option is on a flexible line, different for every person and priority. As my attending later said, with Martha’s diagnosis and her values, it wouldn’t have been unreasonable to decide against chemotherapy from the start.
The language we use can sometimes mask that reality. As doctors, we may casually slip in words like “need” and “have to” in response to patients’ questions about what to do next. “You need more chemotherapy,” we might say. “We’d have to treat it.” We have “treatment,” after all, and so we go down the line of offering what’s next in the medical algorithm. That word, too, can be deceivingly tempting, enticing down a road that makes it seem like the obvious answer – or the only one. If the choices are treatment versus not, who wouldn’t want the treatment? But the details are where things get murky. What does that treatment involve? What are the chances it will work, and for how long?
Surreptitiously missing from this language is the fact that there’s a choice. There’s always a choice, and it’s on the table at any point. You can start chemotherapy without committing to stick it out until the end. You can go home, if that is what’s important to you. The best treatment option is the one the patient wants.
After 4 days, Martha decided to go home with palliative chemotherapy and a bridge to hospice. Each member of our team hugged her goodbye and wished her luck. She was nervous. But she packed her hospital room, and she left.
I recently pulled up her medical chart, bracing myself for bad news. But the interesting thing about hospice is that even though the focus is no longer on prolonging life, people sometimes live longer.
She felt well, the most recent palliative note said. She was spending her time writing, getting her finances in order, and finishing a legacy project for her grandchildren.
For Martha, it seemed to be the right choice.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
Martha Boxer (not her real name) had mentally prepared herself that this could happen, but the news still hit hard. Her doctors on the leukemia service broke the facts as gently as we could: The chemotherapy she had been suffering through for the last 2 weeks hadn’t worked. The results of her latest bone marrow biopsy showed it remained packed with cancer cells.
As Martha absorbed the news quietly, her son, sitting next to her bedside with his hand on hers, spoke first. “What now?”
I looked at my attending and nodded, as we were fully ready to answer this question. From the outset, we knew that Martha’s leukemia carried a genetic mutation that unfortunately put her in a high-risk category. The chances of her cancer responding to the first round of chemotherapy were low. When this happens, what we typically do next is reinduction, we explained. It’s a different combination of chemotherapy drugs, with a somewhat different side effect profile. But it would give her the best chance of response, we believed. We could start the new chemotherapy as early as today, we said.
Martha took this in. “Okay,” she said pensively. “I’ve been thinking. And I think maybe … I won’t do chemotherapy anymore.”
Her words caught me off guard because, frankly, they seemed premature. Her leukemia had not budged with the first round of treatment. But we still had an option B, and then an option C. It was usually at a later, more dire stage – when multiple lines of treatment had not worked, and instead had only caused harm – or, when the decision was forced by the medical system’s admission that we had nothing left to offer – that I’d heard patients express similar preferences. It was then that I’d seen patients and their loved ones flip a mental switch and choose to focus the time they had left on what really mattered to them.
It didn’t feel like we were at that point.
And so, as we debriefed outside her room, my first instinct was to convince her otherwise.
However, Martha had other priorities, as I would come to learn. Above all else, she hated the hospital. She hated feeling trapped in a strange room that wasn’t hers; she hated how the chemotherapy stole her energy and made her feel too weak to even shower. She wanted to be in her own home. She wanted to eat her own food, sleep in her own bed, and be surrounded by what she recognized.
But, she also wanted to live. Two paths lay ahead of her. It was a trade-off of more suffering with a small chance at remission, versus accepting no chance of cure but feeling well for as long as she could. She soon clarified that she wasn’t definitely against chemotherapy. She couldn’t decide. She needed more information from us to make this decision, the hardest of her life.
Over the next few days, I watched as our attending physician expertly provided just that. There were actually three options, she laid out. There was aggressive chemotherapy, entailing at least 3 more weeks in the hospital and coming with significant risk of infection, nausea, vomiting, and fatigue. The chances of inducing a remission were about one in three to one in two, and that remission would likely last between several months and 2 years before the leukemia would relapse. The second option was a chemotherapy pill she could take at home, an option with fewer side effects but no longer aimed at cure. The third option was home hospice support, focused on symptoms, without any anticancer medication.
I noticed a few things during those conversations. I noticed how my attending took a navigator role, not pushing Martha in one direction or another, but rather imparting all the relevant information to empower Martha to decide for herself. I noticed how she provided realistic estimates, not hedging away from numbers, but giving the honest, nitty-gritty facts, as best as she could predict. I noticed how she took the time and never rushed, even in spite of external pressures to discharge the patient from the hospital.
There was no right or wrong answer. I no longer felt that we had something in our grasp – a clear-cut, best decision – to persuade Martha toward. Is one in three good odds, or bad odds? Is 2 years a long period of time, or a short one? Of course, there is no actual answer to these questions; the answer is as elusive and personal as if we had asked Martha: What do you think?
What I learned from Martha is that, with a devastating diagnosis, there isn’t a right time to make this decision. There isn’t one defining moment where we flip a switch and change course. It isn’t only when we run out of treatment options that the choice to forgo it makes sense. That option is on a flexible line, different for every person and priority. As my attending later said, with Martha’s diagnosis and her values, it wouldn’t have been unreasonable to decide against chemotherapy from the start.
The language we use can sometimes mask that reality. As doctors, we may casually slip in words like “need” and “have to” in response to patients’ questions about what to do next. “You need more chemotherapy,” we might say. “We’d have to treat it.” We have “treatment,” after all, and so we go down the line of offering what’s next in the medical algorithm. That word, too, can be deceivingly tempting, enticing down a road that makes it seem like the obvious answer – or the only one. If the choices are treatment versus not, who wouldn’t want the treatment? But the details are where things get murky. What does that treatment involve? What are the chances it will work, and for how long?
Surreptitiously missing from this language is the fact that there’s a choice. There’s always a choice, and it’s on the table at any point. You can start chemotherapy without committing to stick it out until the end. You can go home, if that is what’s important to you. The best treatment option is the one the patient wants.
After 4 days, Martha decided to go home with palliative chemotherapy and a bridge to hospice. Each member of our team hugged her goodbye and wished her luck. She was nervous. But she packed her hospital room, and she left.
I recently pulled up her medical chart, bracing myself for bad news. But the interesting thing about hospice is that even though the focus is no longer on prolonging life, people sometimes live longer.
She felt well, the most recent palliative note said. She was spending her time writing, getting her finances in order, and finishing a legacy project for her grandchildren.
For Martha, it seemed to be the right choice.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
Abstracts Presented at the 2018 AVAHO Annual Meeting (Digital Edition)
Avatrombopag cut procedure-related transfusions in patients with thrombocytopenia, chronic liver disease
Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).
These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.
The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 109 per liter, and 40 mg if their baseline platelet count was 40-50 x 109 per liter. Procedures were scheduled for 10-13 days after treatment initiation.
“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 109 platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).
Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 109 per liter, and they all remained asymptomatic, the investigators said.
Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.
SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.
Thrombocytopenia in cirrhosis is frequent and multifactorial and includes sequestration in the spleen, reduced liver-derived thrombopoietin, bone marrow toxicity, and autoimmunity towards platelets. Severe thrombocytopenia (less than 50/nL) is rare in cirrhotic patients, but when it occurs may prevent required procedures from being performed or require platelet transfusions, which are associated with significant risks.
Previous attempts to increase platelets in cirrhotic patients with thrombopoietin agonists were halted because of increased frequency of portal vein thrombosis and hepatic decompensation.
Now avatrombopag has been specifically licensed with a 5-day regimen to increase platelets prior to elective interventions in severely thrombocytopenic (less than 50/nL) patients with chronic liver disease with a seemingly better safety profile than earlier treatments and good efficacy. The patient groups studied in the licensing trial had slightly milder but not significantly different liver disease, compared with those in the eltrombopag studies. The key difference was a pretreatment requirement of a portal vein flow of more than 10 cm/sec prior to enrollment, which likely reduced the risk of portal vein thrombosis. It is important that providers ready to use avatrombopag are aware of this.
Importantly, no data are currently available for patients with a Model for End-Stage Liver Disease score greater than 24, and very limited data are available for patients with Child B and Child C cirrhosis.
Given this limitation, careful judgment will be needed; a pretreatment portal vein flow may be advisable, though not a label requirement.
An observational study, NCT03554759, in patients with chronic liver disease and thrombocytopenia is ongoing and will further confirm the likely safety of avatrombopag.
Hans L. Tillmann, MD, is a clinical associate professor, East Carolina University, Greenville, and staff physician, Greenville (N.C.) VA Health Care Center. He has no relevant conflicts of interest.
Thrombocytopenia in cirrhosis is frequent and multifactorial and includes sequestration in the spleen, reduced liver-derived thrombopoietin, bone marrow toxicity, and autoimmunity towards platelets. Severe thrombocytopenia (less than 50/nL) is rare in cirrhotic patients, but when it occurs may prevent required procedures from being performed or require platelet transfusions, which are associated with significant risks.
Previous attempts to increase platelets in cirrhotic patients with thrombopoietin agonists were halted because of increased frequency of portal vein thrombosis and hepatic decompensation.
Now avatrombopag has been specifically licensed with a 5-day regimen to increase platelets prior to elective interventions in severely thrombocytopenic (less than 50/nL) patients with chronic liver disease with a seemingly better safety profile than earlier treatments and good efficacy. The patient groups studied in the licensing trial had slightly milder but not significantly different liver disease, compared with those in the eltrombopag studies. The key difference was a pretreatment requirement of a portal vein flow of more than 10 cm/sec prior to enrollment, which likely reduced the risk of portal vein thrombosis. It is important that providers ready to use avatrombopag are aware of this.
Importantly, no data are currently available for patients with a Model for End-Stage Liver Disease score greater than 24, and very limited data are available for patients with Child B and Child C cirrhosis.
Given this limitation, careful judgment will be needed; a pretreatment portal vein flow may be advisable, though not a label requirement.
An observational study, NCT03554759, in patients with chronic liver disease and thrombocytopenia is ongoing and will further confirm the likely safety of avatrombopag.
Hans L. Tillmann, MD, is a clinical associate professor, East Carolina University, Greenville, and staff physician, Greenville (N.C.) VA Health Care Center. He has no relevant conflicts of interest.
Thrombocytopenia in cirrhosis is frequent and multifactorial and includes sequestration in the spleen, reduced liver-derived thrombopoietin, bone marrow toxicity, and autoimmunity towards platelets. Severe thrombocytopenia (less than 50/nL) is rare in cirrhotic patients, but when it occurs may prevent required procedures from being performed or require platelet transfusions, which are associated with significant risks.
Previous attempts to increase platelets in cirrhotic patients with thrombopoietin agonists were halted because of increased frequency of portal vein thrombosis and hepatic decompensation.
Now avatrombopag has been specifically licensed with a 5-day regimen to increase platelets prior to elective interventions in severely thrombocytopenic (less than 50/nL) patients with chronic liver disease with a seemingly better safety profile than earlier treatments and good efficacy. The patient groups studied in the licensing trial had slightly milder but not significantly different liver disease, compared with those in the eltrombopag studies. The key difference was a pretreatment requirement of a portal vein flow of more than 10 cm/sec prior to enrollment, which likely reduced the risk of portal vein thrombosis. It is important that providers ready to use avatrombopag are aware of this.
Importantly, no data are currently available for patients with a Model for End-Stage Liver Disease score greater than 24, and very limited data are available for patients with Child B and Child C cirrhosis.
Given this limitation, careful judgment will be needed; a pretreatment portal vein flow may be advisable, though not a label requirement.
An observational study, NCT03554759, in patients with chronic liver disease and thrombocytopenia is ongoing and will further confirm the likely safety of avatrombopag.
Hans L. Tillmann, MD, is a clinical associate professor, East Carolina University, Greenville, and staff physician, Greenville (N.C.) VA Health Care Center. He has no relevant conflicts of interest.
Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).
These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.
The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 109 per liter, and 40 mg if their baseline platelet count was 40-50 x 109 per liter. Procedures were scheduled for 10-13 days after treatment initiation.
“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 109 platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).
Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 109 per liter, and they all remained asymptomatic, the investigators said.
Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.
SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.
Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).
These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.
The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 109 per liter, and 40 mg if their baseline platelet count was 40-50 x 109 per liter. Procedures were scheduled for 10-13 days after treatment initiation.
“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 109 platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).
Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 109 per liter, and they all remained asymptomatic, the investigators said.
Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.
SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.
FROM GASTROENTEROLOGY
Key clinical point: Once-daily treatment with oral avatrombopag significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures.
Major finding: In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).
Study details: ADAPT-1 and ADAPT-2, international, randomized, double-blind, placebo-controlled, phase III trials.
Disclosures: Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, BMS, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.
Source: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.
