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FDA calls for withdrawal of multiple myeloma drug Pepaxto
(melphalan flufenamide), the company announced in a press release.
The drug was granted an accelerated approval by the FDA in February 2021, for use in combination with dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy.
However, the phase 3 OCEAN study raised concerns about safety, as it showed a higher mortality associated with melphalan flufenamide in the experimental arm, compared with pomalidomide (Pomalyst).
The FDA already flagged this issue in July 2021, issuing a safety alert flagging the increased risk for death observed in the OCEAN trial among patients receiving melphalan flufenamide versus pomalidomide (47.6% vs. 43.4%) and a 5.3-month shorter overall survival.
The issue was also discussed in September 2022 by FDA’s Oncologic Drugs Advisory Committee, which voted 14-to-2 against maintaining the accelerated approval, citing an unfavorable risk/benefit profile.
The company stopped marketing the drug in the United States in October 2021 at the FDA’s request but continued to make it available for patients already undergoing treatment.
However, in March 2022, Oncopeptides rescinded the letter that voluntarily withdrew the agent from market, after further review of overall survival data from the OCEAN trial led the company to reconsider its decision. Notably, marketing efforts were still discontinued while the company worked with the FDA to interpret the data, it stated in the press release.
That review of the data showed that progression-free survival was 42% higher with melphalan flufenamide versus pomalidomide and overall response rates were 32.1% versus 26.5%, respectively.
Now, the FDA has requested that the company withdraw its U.S. marketing authorization.
“We respect FDA’s accelerated approval regulations,” Jakob Lindberg, CEO of Oncopeptides commented in the press release.
However, he also added, “multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for nontransplanted elderly patients where the unmet medical need remains very high.”
Commercialization of the drug in Europe, under the brand name Pepaxti, is ongoing.
“Pepaxti has a full approval from the European Medicines Agency, EMA, since Aug. 18, 2022, and was approved by the Medicines and Healthcare Products Regulatory Agency, MHRA, in the U.K. on Nov 11, 2022,” the company noted.
A version of this article first appeared on Medscape.com.
(melphalan flufenamide), the company announced in a press release.
The drug was granted an accelerated approval by the FDA in February 2021, for use in combination with dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy.
However, the phase 3 OCEAN study raised concerns about safety, as it showed a higher mortality associated with melphalan flufenamide in the experimental arm, compared with pomalidomide (Pomalyst).
The FDA already flagged this issue in July 2021, issuing a safety alert flagging the increased risk for death observed in the OCEAN trial among patients receiving melphalan flufenamide versus pomalidomide (47.6% vs. 43.4%) and a 5.3-month shorter overall survival.
The issue was also discussed in September 2022 by FDA’s Oncologic Drugs Advisory Committee, which voted 14-to-2 against maintaining the accelerated approval, citing an unfavorable risk/benefit profile.
The company stopped marketing the drug in the United States in October 2021 at the FDA’s request but continued to make it available for patients already undergoing treatment.
However, in March 2022, Oncopeptides rescinded the letter that voluntarily withdrew the agent from market, after further review of overall survival data from the OCEAN trial led the company to reconsider its decision. Notably, marketing efforts were still discontinued while the company worked with the FDA to interpret the data, it stated in the press release.
That review of the data showed that progression-free survival was 42% higher with melphalan flufenamide versus pomalidomide and overall response rates were 32.1% versus 26.5%, respectively.
Now, the FDA has requested that the company withdraw its U.S. marketing authorization.
“We respect FDA’s accelerated approval regulations,” Jakob Lindberg, CEO of Oncopeptides commented in the press release.
However, he also added, “multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for nontransplanted elderly patients where the unmet medical need remains very high.”
Commercialization of the drug in Europe, under the brand name Pepaxti, is ongoing.
“Pepaxti has a full approval from the European Medicines Agency, EMA, since Aug. 18, 2022, and was approved by the Medicines and Healthcare Products Regulatory Agency, MHRA, in the U.K. on Nov 11, 2022,” the company noted.
A version of this article first appeared on Medscape.com.
(melphalan flufenamide), the company announced in a press release.
The drug was granted an accelerated approval by the FDA in February 2021, for use in combination with dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy.
However, the phase 3 OCEAN study raised concerns about safety, as it showed a higher mortality associated with melphalan flufenamide in the experimental arm, compared with pomalidomide (Pomalyst).
The FDA already flagged this issue in July 2021, issuing a safety alert flagging the increased risk for death observed in the OCEAN trial among patients receiving melphalan flufenamide versus pomalidomide (47.6% vs. 43.4%) and a 5.3-month shorter overall survival.
The issue was also discussed in September 2022 by FDA’s Oncologic Drugs Advisory Committee, which voted 14-to-2 against maintaining the accelerated approval, citing an unfavorable risk/benefit profile.
The company stopped marketing the drug in the United States in October 2021 at the FDA’s request but continued to make it available for patients already undergoing treatment.
However, in March 2022, Oncopeptides rescinded the letter that voluntarily withdrew the agent from market, after further review of overall survival data from the OCEAN trial led the company to reconsider its decision. Notably, marketing efforts were still discontinued while the company worked with the FDA to interpret the data, it stated in the press release.
That review of the data showed that progression-free survival was 42% higher with melphalan flufenamide versus pomalidomide and overall response rates were 32.1% versus 26.5%, respectively.
Now, the FDA has requested that the company withdraw its U.S. marketing authorization.
“We respect FDA’s accelerated approval regulations,” Jakob Lindberg, CEO of Oncopeptides commented in the press release.
However, he also added, “multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for nontransplanted elderly patients where the unmet medical need remains very high.”
Commercialization of the drug in Europe, under the brand name Pepaxti, is ongoing.
“Pepaxti has a full approval from the European Medicines Agency, EMA, since Aug. 18, 2022, and was approved by the Medicines and Healthcare Products Regulatory Agency, MHRA, in the U.K. on Nov 11, 2022,” the company noted.
A version of this article first appeared on Medscape.com.
‘Clear answer’: ALL study defies conventional wisdom
The same study also addressed two other issues related to standard care for these patients: 1) the dosage of dexamethasone used during the first treatment phase (results of which had already been reported some years ago) and 2) the impact of omitting monthly pulses of dexamethasone and vincristine after initial treatment.
“The trial did not give us the answers we were looking for, but that’s why we do randomized trials, and at least we have one clear answer, which is that high-dose methotrexate does not seem to have benefit in reducing the risk of CNS relapse,” reported study investigator Ajay Vora, MSc, from Great Ormond Street Hospital, London.
Among 1,570 patients randomly assigned in one group of the UKALL2011 trial, 5-year rates of CNS relapse were identical at 5.6% for patients treated with either high-dose methotrexate or standard interim maintenance with oral mercaptopurine and oral and intrathecal methotrexate.
There was a hint, however, that high-dose methotrexate could have a beneficial effect by reducing relapses in bone marrow for some subgroups of patients with B-lineage disease after dexamethasone induction, Dr. Vora commented.
He was speaking at a press briefing at the annual meeting of the American Society of Hematology, prior to the presentation of the data by Amy A. Kirkwood, MSc, from the University College London Cancer Institute.
Reacting to the results, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute in Bethesda, Md., emphasized that “in patients treated with the UKALL regimen, high doses of methotrexate did not reduce the rate of CNS relapse, contrary to our long-standing beliefs.”
“Going forward, patients can be spared the risk of high-dose methotrexate without increasing their risk of recurrence in the central nervous system,” she said.
“As researchers in hematology, we look at it as our duty to question the standard approaches that we use to treat patients, even those that we thought of as tried-and-true,” said briefing moderator Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami. This is one of the abstracts that “challenge some of those standards and in fact reveal that in many cases, giving less therapy and being less restrictive is actually better for patients or at least no worse.”
Complex design
The UKALL2011 trial had a byzantine design, with the overarching goal of finding out which treatment and maintenance strategy best finds the sweet spot between efficacy and toxicity in children and young adults (up to age 25) with ALL and lymphoblastic lymphoma.
One question that was already answered, as investigators reported at the 2017 ASH annual meeting, came from the first randomization in the study, designed to see whether a shorter course of dexamethasone – 14 days versus the standard 28 days – could reduce induction toxicity. It did not.
Now, at ASH 2022, the investigators reported outcomes from the second phase of the trial, which included two randomizations: one comparing high-dose methotrexate with standard interim maintenance to reduce CNS relapse risk, and one to see whether forgoing pulses of vincristine/dexamethasone could reduce maintenance morbidity.
Patients were stratified by National Cancer Institute minimal residual disease (MRD) risk categories, cytogenetics, and end-of-induction MRD to receive one of three treatment regimens. Patients with MRD high risk, defined as MRD greater than 0.5% at the end of consolidation, were not eligible for second-phase randomization and instead received off-protocol therapies.The second randomization was factorial, stratified by NCI and MRD risk groups, resulting in four arms: high-dose methotrexate with or without pulses and standard interim maintenance with our without pulses.
Standard interim maintenance in this trial was 2 months of oral mercaptopurine/methotrexate monthly pulses and single intrathecal methotrexate in two of the regimens, as well as five doses of escalating intravenous methotrexate plus vincristine and two doses of pegylated asparaginase in the third.
High-dose methotrexate was given at a dose of 5 g/m2 for four doses 2 weeks apart, low dose 6-mercaptopurine, plus two doses of pegylated asparaginase in one regimen only.
Equivocal conclusions
As noted above, CNS relapse, the primary endpoint for the interim maintenance randomization, did not differ between the groups, with identical 5-year relapse rates. Similarly, 5-year event-free survival (EFS) rates were 90.3% in the high-dose group and 89.5% in the standard group, a difference that was not statistically significant (P = .68).
There was, however, an interaction between the first (short- vs. standard-course dexamethasone) and the interim maintenance randomizations, indicating significantly inferior EFS outcomes for patients who had received the short dose of dexamethasone followed by high-dose methotrexate, especially among patients who did not receive pulses (P = .006).
An analysis of patients treated with standard dexamethasone showed that those who received high-dose methotrexate had a lower risk for bone marrow relapse, with a hazard ratio of 0.62 (P = .029), and trends, albeit nonsignificant, toward better EFS and overall survival.
In addition, the overall results suggested that steroid pulses could be safely omitted without leading to an increase in bone marrow relapses: the 5-year rates of bone marrow relapse were 10.2% with pulses and 12.2% without, although omitting pulses was associated with a slight but significant decrease in EFS overall (P = .01). The effect was attenuated among patients who had received standard-course dexamethasone and high-dose methotrexate. Leaving out the pulses also reduced rates of grade 3 or 4 adverse events, including febrile neutropenia, Ms. Kirkwood noted in her presentation.
The investigators plan to analyze quality-of-life outcomes related to dexamethasone-vincristine pulses to see whether doing so could tip the balance in favor of leaving them out of therapy, and they will continue to follow patients to see whether their findings hold.
UKALL2011 was funded by Children with Cancer UK, Blood Cancer UK, and Cancer Research UK. Ms. Kirkwood disclosed consulting for and receiving honoraria from Kite. Dr. Vora reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The same study also addressed two other issues related to standard care for these patients: 1) the dosage of dexamethasone used during the first treatment phase (results of which had already been reported some years ago) and 2) the impact of omitting monthly pulses of dexamethasone and vincristine after initial treatment.
“The trial did not give us the answers we were looking for, but that’s why we do randomized trials, and at least we have one clear answer, which is that high-dose methotrexate does not seem to have benefit in reducing the risk of CNS relapse,” reported study investigator Ajay Vora, MSc, from Great Ormond Street Hospital, London.
Among 1,570 patients randomly assigned in one group of the UKALL2011 trial, 5-year rates of CNS relapse were identical at 5.6% for patients treated with either high-dose methotrexate or standard interim maintenance with oral mercaptopurine and oral and intrathecal methotrexate.
There was a hint, however, that high-dose methotrexate could have a beneficial effect by reducing relapses in bone marrow for some subgroups of patients with B-lineage disease after dexamethasone induction, Dr. Vora commented.
He was speaking at a press briefing at the annual meeting of the American Society of Hematology, prior to the presentation of the data by Amy A. Kirkwood, MSc, from the University College London Cancer Institute.
Reacting to the results, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute in Bethesda, Md., emphasized that “in patients treated with the UKALL regimen, high doses of methotrexate did not reduce the rate of CNS relapse, contrary to our long-standing beliefs.”
“Going forward, patients can be spared the risk of high-dose methotrexate without increasing their risk of recurrence in the central nervous system,” she said.
“As researchers in hematology, we look at it as our duty to question the standard approaches that we use to treat patients, even those that we thought of as tried-and-true,” said briefing moderator Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami. This is one of the abstracts that “challenge some of those standards and in fact reveal that in many cases, giving less therapy and being less restrictive is actually better for patients or at least no worse.”
Complex design
The UKALL2011 trial had a byzantine design, with the overarching goal of finding out which treatment and maintenance strategy best finds the sweet spot between efficacy and toxicity in children and young adults (up to age 25) with ALL and lymphoblastic lymphoma.
One question that was already answered, as investigators reported at the 2017 ASH annual meeting, came from the first randomization in the study, designed to see whether a shorter course of dexamethasone – 14 days versus the standard 28 days – could reduce induction toxicity. It did not.
Now, at ASH 2022, the investigators reported outcomes from the second phase of the trial, which included two randomizations: one comparing high-dose methotrexate with standard interim maintenance to reduce CNS relapse risk, and one to see whether forgoing pulses of vincristine/dexamethasone could reduce maintenance morbidity.
Patients were stratified by National Cancer Institute minimal residual disease (MRD) risk categories, cytogenetics, and end-of-induction MRD to receive one of three treatment regimens. Patients with MRD high risk, defined as MRD greater than 0.5% at the end of consolidation, were not eligible for second-phase randomization and instead received off-protocol therapies.The second randomization was factorial, stratified by NCI and MRD risk groups, resulting in four arms: high-dose methotrexate with or without pulses and standard interim maintenance with our without pulses.
Standard interim maintenance in this trial was 2 months of oral mercaptopurine/methotrexate monthly pulses and single intrathecal methotrexate in two of the regimens, as well as five doses of escalating intravenous methotrexate plus vincristine and two doses of pegylated asparaginase in the third.
High-dose methotrexate was given at a dose of 5 g/m2 for four doses 2 weeks apart, low dose 6-mercaptopurine, plus two doses of pegylated asparaginase in one regimen only.
Equivocal conclusions
As noted above, CNS relapse, the primary endpoint for the interim maintenance randomization, did not differ between the groups, with identical 5-year relapse rates. Similarly, 5-year event-free survival (EFS) rates were 90.3% in the high-dose group and 89.5% in the standard group, a difference that was not statistically significant (P = .68).
There was, however, an interaction between the first (short- vs. standard-course dexamethasone) and the interim maintenance randomizations, indicating significantly inferior EFS outcomes for patients who had received the short dose of dexamethasone followed by high-dose methotrexate, especially among patients who did not receive pulses (P = .006).
An analysis of patients treated with standard dexamethasone showed that those who received high-dose methotrexate had a lower risk for bone marrow relapse, with a hazard ratio of 0.62 (P = .029), and trends, albeit nonsignificant, toward better EFS and overall survival.
In addition, the overall results suggested that steroid pulses could be safely omitted without leading to an increase in bone marrow relapses: the 5-year rates of bone marrow relapse were 10.2% with pulses and 12.2% without, although omitting pulses was associated with a slight but significant decrease in EFS overall (P = .01). The effect was attenuated among patients who had received standard-course dexamethasone and high-dose methotrexate. Leaving out the pulses also reduced rates of grade 3 or 4 adverse events, including febrile neutropenia, Ms. Kirkwood noted in her presentation.
The investigators plan to analyze quality-of-life outcomes related to dexamethasone-vincristine pulses to see whether doing so could tip the balance in favor of leaving them out of therapy, and they will continue to follow patients to see whether their findings hold.
UKALL2011 was funded by Children with Cancer UK, Blood Cancer UK, and Cancer Research UK. Ms. Kirkwood disclosed consulting for and receiving honoraria from Kite. Dr. Vora reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The same study also addressed two other issues related to standard care for these patients: 1) the dosage of dexamethasone used during the first treatment phase (results of which had already been reported some years ago) and 2) the impact of omitting monthly pulses of dexamethasone and vincristine after initial treatment.
“The trial did not give us the answers we were looking for, but that’s why we do randomized trials, and at least we have one clear answer, which is that high-dose methotrexate does not seem to have benefit in reducing the risk of CNS relapse,” reported study investigator Ajay Vora, MSc, from Great Ormond Street Hospital, London.
Among 1,570 patients randomly assigned in one group of the UKALL2011 trial, 5-year rates of CNS relapse were identical at 5.6% for patients treated with either high-dose methotrexate or standard interim maintenance with oral mercaptopurine and oral and intrathecal methotrexate.
There was a hint, however, that high-dose methotrexate could have a beneficial effect by reducing relapses in bone marrow for some subgroups of patients with B-lineage disease after dexamethasone induction, Dr. Vora commented.
He was speaking at a press briefing at the annual meeting of the American Society of Hematology, prior to the presentation of the data by Amy A. Kirkwood, MSc, from the University College London Cancer Institute.
Reacting to the results, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute in Bethesda, Md., emphasized that “in patients treated with the UKALL regimen, high doses of methotrexate did not reduce the rate of CNS relapse, contrary to our long-standing beliefs.”
“Going forward, patients can be spared the risk of high-dose methotrexate without increasing their risk of recurrence in the central nervous system,” she said.
“As researchers in hematology, we look at it as our duty to question the standard approaches that we use to treat patients, even those that we thought of as tried-and-true,” said briefing moderator Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami. This is one of the abstracts that “challenge some of those standards and in fact reveal that in many cases, giving less therapy and being less restrictive is actually better for patients or at least no worse.”
Complex design
The UKALL2011 trial had a byzantine design, with the overarching goal of finding out which treatment and maintenance strategy best finds the sweet spot between efficacy and toxicity in children and young adults (up to age 25) with ALL and lymphoblastic lymphoma.
One question that was already answered, as investigators reported at the 2017 ASH annual meeting, came from the first randomization in the study, designed to see whether a shorter course of dexamethasone – 14 days versus the standard 28 days – could reduce induction toxicity. It did not.
Now, at ASH 2022, the investigators reported outcomes from the second phase of the trial, which included two randomizations: one comparing high-dose methotrexate with standard interim maintenance to reduce CNS relapse risk, and one to see whether forgoing pulses of vincristine/dexamethasone could reduce maintenance morbidity.
Patients were stratified by National Cancer Institute minimal residual disease (MRD) risk categories, cytogenetics, and end-of-induction MRD to receive one of three treatment regimens. Patients with MRD high risk, defined as MRD greater than 0.5% at the end of consolidation, were not eligible for second-phase randomization and instead received off-protocol therapies.The second randomization was factorial, stratified by NCI and MRD risk groups, resulting in four arms: high-dose methotrexate with or without pulses and standard interim maintenance with our without pulses.
Standard interim maintenance in this trial was 2 months of oral mercaptopurine/methotrexate monthly pulses and single intrathecal methotrexate in two of the regimens, as well as five doses of escalating intravenous methotrexate plus vincristine and two doses of pegylated asparaginase in the third.
High-dose methotrexate was given at a dose of 5 g/m2 for four doses 2 weeks apart, low dose 6-mercaptopurine, plus two doses of pegylated asparaginase in one regimen only.
Equivocal conclusions
As noted above, CNS relapse, the primary endpoint for the interim maintenance randomization, did not differ between the groups, with identical 5-year relapse rates. Similarly, 5-year event-free survival (EFS) rates were 90.3% in the high-dose group and 89.5% in the standard group, a difference that was not statistically significant (P = .68).
There was, however, an interaction between the first (short- vs. standard-course dexamethasone) and the interim maintenance randomizations, indicating significantly inferior EFS outcomes for patients who had received the short dose of dexamethasone followed by high-dose methotrexate, especially among patients who did not receive pulses (P = .006).
An analysis of patients treated with standard dexamethasone showed that those who received high-dose methotrexate had a lower risk for bone marrow relapse, with a hazard ratio of 0.62 (P = .029), and trends, albeit nonsignificant, toward better EFS and overall survival.
In addition, the overall results suggested that steroid pulses could be safely omitted without leading to an increase in bone marrow relapses: the 5-year rates of bone marrow relapse were 10.2% with pulses and 12.2% without, although omitting pulses was associated with a slight but significant decrease in EFS overall (P = .01). The effect was attenuated among patients who had received standard-course dexamethasone and high-dose methotrexate. Leaving out the pulses also reduced rates of grade 3 or 4 adverse events, including febrile neutropenia, Ms. Kirkwood noted in her presentation.
The investigators plan to analyze quality-of-life outcomes related to dexamethasone-vincristine pulses to see whether doing so could tip the balance in favor of leaving them out of therapy, and they will continue to follow patients to see whether their findings hold.
UKALL2011 was funded by Children with Cancer UK, Blood Cancer UK, and Cancer Research UK. Ms. Kirkwood disclosed consulting for and receiving honoraria from Kite. Dr. Vora reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASH 2022
Postpartum hemorrhage rates and risk factors rising
The rate of postpartum hemorrhage for hospital deliveries in the United States increased significantly over a 20-year period, according to data from more than 76 million delivery hospitalizations from the National Inpatient Sample.
Postpartum hemorrhage remains the leading cause of maternal morbidity and mortality worldwide, and many clinical and patient-level risk factors appear to be on the rise, wrote Chiara M. Corbetta-Rastelli, MD, of the University of California, San Francisco, and colleagues.
Although practice changes have been introduced to reduce postpartum hemorrhage, recent trends in postpartum hemorrhage risk and outcomes in the context of such changes as hemorrhage safety bundles have not been examined, they said.
In a study published in Obstetrics & Gynecology, the researchers reviewed data from hospitalizations for females aged 15-54 years for deliveries between 2000 and 2019 using the National Inpatient Sample. They used a regression analysis to estimate average annual percentage changes (AAPC). Their objectives were to characterize trends and also to assess the association between risk factors and the occurrence of postpartum hemorrhage and related interventions. Demographics, clinical factors, and hospital characteristics were mainly similar between the group of patients with postpartum hemorrhage and those with no postpartum hemorrhage.
Approximately 3% (2.3 million) of 76.7 million hospitalizations for delivery were complicated by postpartum hemorrhage during the study period, and the annual rate increased from 2.7% to 4.3%.
Overall, 21.4% of individuals with delivery hospitalizations complicated by postpartum hemorrhage had one postpartum risk factor, and 1.4% had two or more risk factors. The number of individuals with at least one risk factor for postpartum hemorrhage increased significantly, from 18.6% to 26.9%, during the study period, with an annual percentage change of 1.9%.
Compared with deliveries in individuals without risk factors, individuals with one risk factor had slightly higher odds of postpartum hemorrhage (odds ratio, 1.14), but those with two or more risk factors were more than twice as likely to experience postpartum hemorrhage as those with no risk factors (OR, 2.31).
The researchers also examined the association of specific risk factors and interventions related to hemorrhage, notably blood transfusion and peripartum hysterectomy. Blood transfusions in individuals with postpartum hemorrhage increased from 5.4% to 16.7% between 2000 and 2011, (AAPC, 10.2%) then decreased from 16.7% to 12.6% from 2011 to 2019 (AAPC, –3.9%).
Peripartum hysterectomy in the study population increased from 1.4% to 2.4% from 2000 to 2009 (AAPC 5.0%), remained steady from 2009 to 2016, and then decreased from 2.1% to 0.9% from 2016 to 2019 (AAPC –27%).
Other risk factors associated with postpartum hemorrhage itself and with blood transfusion and hysterectomy in the setting of postpartum hemorrhage included prior cesarean delivery with placenta previa or accreta, placenta previa without prior cesarean delivery, and antepartum hemorrhage or placental abruption, the researchers noted.
“In addition to placental abnormalities, risk factors such as preeclampsia with severe features, polyhydramnios, and uterine leiomyomas demonstrated the highest rates of increase in our data,” they wrote in their discussion. These trends may lead to continuing increases in postpartum hemorrhage risk, which was not fully explained by the increase in risk factors seen in the current study, the researchers said.
The study findings were limited by several factors, including the use of billing codes that could lead to misclassification of diagnoses, as well as possible differences in the definition and coding for postpartum hemorrhage among hospitals, the researchers noted. Other limitations were the exclusion of cases of readmission for postpartum hemorrhage and lack of clinical details involving use of medications or nonoperative interventions, they said.
Notably, the study finding of stable to decreasing peripartum hysterectomy rates in hospitalized patients with postpartum hemorrhage conflicts with another recent study showing an increase in peripartum hysterectomy from 2009 to 2020, but this difference may reflect changes in billing, indications for hysterectomy, or study modeling, they said.
The current study was strengthened by the use of a large database to analyze population trends, a contemporary study period, and the inclusion of meaningful outcomes such as peripartum hysterectomy, the researchers wrote.
The shift in blood transfusion and peripartum hysterectomy may reflect the implementation of protocols to promote early intervention and identification of postpartum hemorrhage, they concluded.
Interventions can have an effect
“Hemorrhage remains a leading cause of maternal mortality in the United States and blood transfusion is the most common severe maternal morbidity,” Catherine M. Albright, MD, MS, associate professor of maternal-fetal medicine at the University of Washington, Seattle, said in an interview. “It is important to understand the current state, especially given that many hospitals have implemented policies and procedures to better identify and treat postpartum hemorrhage,” she said.
Dr. Albright said, “I was pleased to see that they did not just look at a diagnosis of postpartum hemorrhage but rather also looked at complications arising from postpartum hemorrhage, such as blood transfusion or hysterectomy.”
Postpartum hemorrhage is often a clinical diagnosis that uses estimated blood loss, a notoriously inaccurate measure, said Dr. Albright. “Additionally, the definitions of postpartum hemorrhage, as well as the ICD codes, changed during the time period of the study,” she noted. “These factors all could lead to both underreporting and overreporting of the true incidence of postpartum hemorrhage. Blood transfusion and hysterectomy are more objective outcomes and demonstrate true morbidity,” she said.
“Most of the risk factors that are listed in the article are not modifiable during that pregnancy,” said Dr. Albright. For example, a history of a prior cesarean or having a twin pregnancy is not something that can be changed, she said. “Many of the other risk factors or associated clinical factors, such as obesity, chronic hypertension, and pregestational diabetes, are modifiable, but before pregnancy. Universal and easy access to primary medical care prior to and between pregnancies may help to mitigate some of these factors,” she noted.
Looking ahead, “It would be helpful to ensure that these types of data are available at the state and hospital level; this will allow for local evaluation of programs that are in place to reduce postpartum hemorrhage risk and improve identification and treatment,” Dr. Albright said.
The study received no outside funding. Dr. Corbetta-Rastelli and Dr. Albright had no financial conflicts to disclose.
The rate of postpartum hemorrhage for hospital deliveries in the United States increased significantly over a 20-year period, according to data from more than 76 million delivery hospitalizations from the National Inpatient Sample.
Postpartum hemorrhage remains the leading cause of maternal morbidity and mortality worldwide, and many clinical and patient-level risk factors appear to be on the rise, wrote Chiara M. Corbetta-Rastelli, MD, of the University of California, San Francisco, and colleagues.
Although practice changes have been introduced to reduce postpartum hemorrhage, recent trends in postpartum hemorrhage risk and outcomes in the context of such changes as hemorrhage safety bundles have not been examined, they said.
In a study published in Obstetrics & Gynecology, the researchers reviewed data from hospitalizations for females aged 15-54 years for deliveries between 2000 and 2019 using the National Inpatient Sample. They used a regression analysis to estimate average annual percentage changes (AAPC). Their objectives were to characterize trends and also to assess the association between risk factors and the occurrence of postpartum hemorrhage and related interventions. Demographics, clinical factors, and hospital characteristics were mainly similar between the group of patients with postpartum hemorrhage and those with no postpartum hemorrhage.
Approximately 3% (2.3 million) of 76.7 million hospitalizations for delivery were complicated by postpartum hemorrhage during the study period, and the annual rate increased from 2.7% to 4.3%.
Overall, 21.4% of individuals with delivery hospitalizations complicated by postpartum hemorrhage had one postpartum risk factor, and 1.4% had two or more risk factors. The number of individuals with at least one risk factor for postpartum hemorrhage increased significantly, from 18.6% to 26.9%, during the study period, with an annual percentage change of 1.9%.
Compared with deliveries in individuals without risk factors, individuals with one risk factor had slightly higher odds of postpartum hemorrhage (odds ratio, 1.14), but those with two or more risk factors were more than twice as likely to experience postpartum hemorrhage as those with no risk factors (OR, 2.31).
The researchers also examined the association of specific risk factors and interventions related to hemorrhage, notably blood transfusion and peripartum hysterectomy. Blood transfusions in individuals with postpartum hemorrhage increased from 5.4% to 16.7% between 2000 and 2011, (AAPC, 10.2%) then decreased from 16.7% to 12.6% from 2011 to 2019 (AAPC, –3.9%).
Peripartum hysterectomy in the study population increased from 1.4% to 2.4% from 2000 to 2009 (AAPC 5.0%), remained steady from 2009 to 2016, and then decreased from 2.1% to 0.9% from 2016 to 2019 (AAPC –27%).
Other risk factors associated with postpartum hemorrhage itself and with blood transfusion and hysterectomy in the setting of postpartum hemorrhage included prior cesarean delivery with placenta previa or accreta, placenta previa without prior cesarean delivery, and antepartum hemorrhage or placental abruption, the researchers noted.
“In addition to placental abnormalities, risk factors such as preeclampsia with severe features, polyhydramnios, and uterine leiomyomas demonstrated the highest rates of increase in our data,” they wrote in their discussion. These trends may lead to continuing increases in postpartum hemorrhage risk, which was not fully explained by the increase in risk factors seen in the current study, the researchers said.
The study findings were limited by several factors, including the use of billing codes that could lead to misclassification of diagnoses, as well as possible differences in the definition and coding for postpartum hemorrhage among hospitals, the researchers noted. Other limitations were the exclusion of cases of readmission for postpartum hemorrhage and lack of clinical details involving use of medications or nonoperative interventions, they said.
Notably, the study finding of stable to decreasing peripartum hysterectomy rates in hospitalized patients with postpartum hemorrhage conflicts with another recent study showing an increase in peripartum hysterectomy from 2009 to 2020, but this difference may reflect changes in billing, indications for hysterectomy, or study modeling, they said.
The current study was strengthened by the use of a large database to analyze population trends, a contemporary study period, and the inclusion of meaningful outcomes such as peripartum hysterectomy, the researchers wrote.
The shift in blood transfusion and peripartum hysterectomy may reflect the implementation of protocols to promote early intervention and identification of postpartum hemorrhage, they concluded.
Interventions can have an effect
“Hemorrhage remains a leading cause of maternal mortality in the United States and blood transfusion is the most common severe maternal morbidity,” Catherine M. Albright, MD, MS, associate professor of maternal-fetal medicine at the University of Washington, Seattle, said in an interview. “It is important to understand the current state, especially given that many hospitals have implemented policies and procedures to better identify and treat postpartum hemorrhage,” she said.
Dr. Albright said, “I was pleased to see that they did not just look at a diagnosis of postpartum hemorrhage but rather also looked at complications arising from postpartum hemorrhage, such as blood transfusion or hysterectomy.”
Postpartum hemorrhage is often a clinical diagnosis that uses estimated blood loss, a notoriously inaccurate measure, said Dr. Albright. “Additionally, the definitions of postpartum hemorrhage, as well as the ICD codes, changed during the time period of the study,” she noted. “These factors all could lead to both underreporting and overreporting of the true incidence of postpartum hemorrhage. Blood transfusion and hysterectomy are more objective outcomes and demonstrate true morbidity,” she said.
“Most of the risk factors that are listed in the article are not modifiable during that pregnancy,” said Dr. Albright. For example, a history of a prior cesarean or having a twin pregnancy is not something that can be changed, she said. “Many of the other risk factors or associated clinical factors, such as obesity, chronic hypertension, and pregestational diabetes, are modifiable, but before pregnancy. Universal and easy access to primary medical care prior to and between pregnancies may help to mitigate some of these factors,” she noted.
Looking ahead, “It would be helpful to ensure that these types of data are available at the state and hospital level; this will allow for local evaluation of programs that are in place to reduce postpartum hemorrhage risk and improve identification and treatment,” Dr. Albright said.
The study received no outside funding. Dr. Corbetta-Rastelli and Dr. Albright had no financial conflicts to disclose.
The rate of postpartum hemorrhage for hospital deliveries in the United States increased significantly over a 20-year period, according to data from more than 76 million delivery hospitalizations from the National Inpatient Sample.
Postpartum hemorrhage remains the leading cause of maternal morbidity and mortality worldwide, and many clinical and patient-level risk factors appear to be on the rise, wrote Chiara M. Corbetta-Rastelli, MD, of the University of California, San Francisco, and colleagues.
Although practice changes have been introduced to reduce postpartum hemorrhage, recent trends in postpartum hemorrhage risk and outcomes in the context of such changes as hemorrhage safety bundles have not been examined, they said.
In a study published in Obstetrics & Gynecology, the researchers reviewed data from hospitalizations for females aged 15-54 years for deliveries between 2000 and 2019 using the National Inpatient Sample. They used a regression analysis to estimate average annual percentage changes (AAPC). Their objectives were to characterize trends and also to assess the association between risk factors and the occurrence of postpartum hemorrhage and related interventions. Demographics, clinical factors, and hospital characteristics were mainly similar between the group of patients with postpartum hemorrhage and those with no postpartum hemorrhage.
Approximately 3% (2.3 million) of 76.7 million hospitalizations for delivery were complicated by postpartum hemorrhage during the study period, and the annual rate increased from 2.7% to 4.3%.
Overall, 21.4% of individuals with delivery hospitalizations complicated by postpartum hemorrhage had one postpartum risk factor, and 1.4% had two or more risk factors. The number of individuals with at least one risk factor for postpartum hemorrhage increased significantly, from 18.6% to 26.9%, during the study period, with an annual percentage change of 1.9%.
Compared with deliveries in individuals without risk factors, individuals with one risk factor had slightly higher odds of postpartum hemorrhage (odds ratio, 1.14), but those with two or more risk factors were more than twice as likely to experience postpartum hemorrhage as those with no risk factors (OR, 2.31).
The researchers also examined the association of specific risk factors and interventions related to hemorrhage, notably blood transfusion and peripartum hysterectomy. Blood transfusions in individuals with postpartum hemorrhage increased from 5.4% to 16.7% between 2000 and 2011, (AAPC, 10.2%) then decreased from 16.7% to 12.6% from 2011 to 2019 (AAPC, –3.9%).
Peripartum hysterectomy in the study population increased from 1.4% to 2.4% from 2000 to 2009 (AAPC 5.0%), remained steady from 2009 to 2016, and then decreased from 2.1% to 0.9% from 2016 to 2019 (AAPC –27%).
Other risk factors associated with postpartum hemorrhage itself and with blood transfusion and hysterectomy in the setting of postpartum hemorrhage included prior cesarean delivery with placenta previa or accreta, placenta previa without prior cesarean delivery, and antepartum hemorrhage or placental abruption, the researchers noted.
“In addition to placental abnormalities, risk factors such as preeclampsia with severe features, polyhydramnios, and uterine leiomyomas demonstrated the highest rates of increase in our data,” they wrote in their discussion. These trends may lead to continuing increases in postpartum hemorrhage risk, which was not fully explained by the increase in risk factors seen in the current study, the researchers said.
The study findings were limited by several factors, including the use of billing codes that could lead to misclassification of diagnoses, as well as possible differences in the definition and coding for postpartum hemorrhage among hospitals, the researchers noted. Other limitations were the exclusion of cases of readmission for postpartum hemorrhage and lack of clinical details involving use of medications or nonoperative interventions, they said.
Notably, the study finding of stable to decreasing peripartum hysterectomy rates in hospitalized patients with postpartum hemorrhage conflicts with another recent study showing an increase in peripartum hysterectomy from 2009 to 2020, but this difference may reflect changes in billing, indications for hysterectomy, or study modeling, they said.
The current study was strengthened by the use of a large database to analyze population trends, a contemporary study period, and the inclusion of meaningful outcomes such as peripartum hysterectomy, the researchers wrote.
The shift in blood transfusion and peripartum hysterectomy may reflect the implementation of protocols to promote early intervention and identification of postpartum hemorrhage, they concluded.
Interventions can have an effect
“Hemorrhage remains a leading cause of maternal mortality in the United States and blood transfusion is the most common severe maternal morbidity,” Catherine M. Albright, MD, MS, associate professor of maternal-fetal medicine at the University of Washington, Seattle, said in an interview. “It is important to understand the current state, especially given that many hospitals have implemented policies and procedures to better identify and treat postpartum hemorrhage,” she said.
Dr. Albright said, “I was pleased to see that they did not just look at a diagnosis of postpartum hemorrhage but rather also looked at complications arising from postpartum hemorrhage, such as blood transfusion or hysterectomy.”
Postpartum hemorrhage is often a clinical diagnosis that uses estimated blood loss, a notoriously inaccurate measure, said Dr. Albright. “Additionally, the definitions of postpartum hemorrhage, as well as the ICD codes, changed during the time period of the study,” she noted. “These factors all could lead to both underreporting and overreporting of the true incidence of postpartum hemorrhage. Blood transfusion and hysterectomy are more objective outcomes and demonstrate true morbidity,” she said.
“Most of the risk factors that are listed in the article are not modifiable during that pregnancy,” said Dr. Albright. For example, a history of a prior cesarean or having a twin pregnancy is not something that can be changed, she said. “Many of the other risk factors or associated clinical factors, such as obesity, chronic hypertension, and pregestational diabetes, are modifiable, but before pregnancy. Universal and easy access to primary medical care prior to and between pregnancies may help to mitigate some of these factors,” she noted.
Looking ahead, “It would be helpful to ensure that these types of data are available at the state and hospital level; this will allow for local evaluation of programs that are in place to reduce postpartum hemorrhage risk and improve identification and treatment,” Dr. Albright said.
The study received no outside funding. Dr. Corbetta-Rastelli and Dr. Albright had no financial conflicts to disclose.
FROM OBSTETRICS & GYNECOLOGY
High cost and demand for old cancer drug sparks crisis
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
FDA approves first gene therapy for hemophilia B
“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”
Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.
The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.
Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.
Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.
Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.
Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.
The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.
Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.
This article was updated 11/23/22.
Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.
“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”
Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.
The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.
Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.
Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.
Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.
Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.
The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.
Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.
This article was updated 11/23/22.
Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.
“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”
Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.
The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.
Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.
Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.
Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.
Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.
The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.
Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.
This article was updated 11/23/22.
Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.
Leukocytoclastic Vasculitis Masquerading as Chronic ITP
Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated acquired condition affecting both adults and children.1 Acute ITP is the most common form, which happens in the presence of a precipitant, leading to a drop in platelet counts. However, chronic ITP can occur when all the causes that might precipitate thrombocytopenia have been ruled out, and it is persistent for ≥ 12 months.2 Its presence can mask other diseases that exhibit somewhat similar signs and symptoms. We present a case of a patient presenting with chronic ITP with diffuse rash and was later diagnosed with idiopathic leukocytoclastic vasculitis (LCV).
Case Presentation
A 79-year-old presented to the hospital with 2-day history of a rash. The rash was purpureal and petechial and located on the trunk and bilateral upper and lower extremities. The rash was associated with itchiness and pain in the wrists, ankles, and small joints of the hands. The patient reported no changes in medication or diet,
The patient mentioned that at the time of diagnosis the platelet count was about 90,000 but had been fluctuating between 50 and 60,000 recently. The patient also reported no history of gum bleeding, nosebleeds, hemoptysis, hematemesis, or any miscarriages. She also had difficulty voiding for 2 to 3 days but no dysuria, frequency, urgency, or incontinence.
Laboratory results were significant for 57,000/µL platelet count (normal range, 150,000-450,000), elevated d-dimer (6.07), < 6 mg/dL C4 (normal range, 88-201). Hemoglobin level, coagulation panel, hemolytic panel, and fibrinogen level results were unremarkable. The hepatitis panel, Lyme disease, and HIV test were negative. The peripheral blood smear showed moderate thrombocytopenia, mild monocytosis, and borderline normochromic normocytic anemia without schistocytes. The autoimmune panel to evaluate thrombocytopenia showed platelet antibody against glycoprotein (GP) IIb/IIIa, GP Ib/Ix, GP Ia/IIa, suggestive toward a diagnosis of chronic idiopathic ITP. However, the skin biopsy of the rash was indicative of LCV.
An autoimmune panel for vasculitis, including antinuclear antibody and antidouble-stranded DNA, was negative. While in the hospital, the patient completed the course of ciprofloxacin for the UTI, the rash started to fade without any intervention, and the platelet count improved to 69,000/µL. The patient was discharged after 3 days with the recommendation to follow up with her hematologist.
Discussion
LCV is a small vessel vasculitis of the dermal capillaries and venules. Histologically, LCV is characterized by fibrinoid necrosis of the vessel wall with frequent neutrophils, nuclear dust, and extravasated erythrocytes.3
Although a thorough evaluation is recommended to determine etiology, about 50% of cases are idiopathic. The most common precipitants are acute infection or a new medication. Postinfectious LCV is most commonly seen after streptococcal upper respiratory tract infection. Among other infectious triggers, Mycobacterium, Staphylococcus aureus, chlamydia, Neisseria, HIV, hepatitis B, hepatitis C, and syphilis are noteworthy. Foods, autoimmune disease, collagen vascular disease, and malignancy are also associated with LCV.4
In our patient we could not find any specific identifiable triggers. However, the presence of a UTI as a precipitating factor cannot be ruled out.5 Moreover, the patient received ciprofloxacin and there have been several case reports of LCV associated with use of a fluroquinolone.6 Nevertheless, in the presence of chronic ITP, which also is an auto-immune condition, an idiopathic cause seemed a reasonable explanation for the patient’s etiopathogenesis.
The cutaneous manifestations of LCV may appear about 1 to 3 weeks after the triggering event if present. The major clinical findings include palpable purpura and/or petechiae that are nonblanching. These findings can easily be confused with other diagnoses especially in the presence of a similar preexisting diagnosis. For example, our patient already had chronic ITP, and in such circumstances, a diagnosis of superimposed LCV can be easily missed without a thorough investigation. Extracutaneous manifestations with LCV are less common. Systemic symptoms may include low-grade fevers, malaise, weight loss, myalgia, and arthralgia. These findings have been noted in about 30% of affected patients, with arthralgia the most common manifestation.7 Our patient also presented with pain involving multiple joints.
The mainstay of diagnosis for LCV is a skin biopsy with direct immunofluorescence. However, a workup for an underlying condition should be considered based on clinical suspicion. If a secondary cause is found, management should target treating the underlying cause, including withdrawal of the offending drug, treatment or control of the underlying infection, malignancy, or connective tissue disease. Most cases of idiopathic cutaneous LCV resolve with supportive measures, including leg elevation, rest, compression stockings, and antihistamines. In resistant cases, a 4- to 6-week tapering dose of corticosteroids and immunosuppressive steroid-sparing agents may be needed.8
Conclusions
Although most cases of LCV are mild and resolve without intervention, many cases go undiagnosed due to a delay in performing a biopsy. However, we should always look for the root cause of a patient’s condition to rule out underlying contributing conditions. Differentiating LCV from any other preexisting condition presenting similarly is important.
1. Gaurav K, Keith RM. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3): 495-520. doi:10.1016/j.hoc.2013.03.001
2. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386-2393.
3. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Saunders/Elsevier; 2011.
4. Einhorn J, Levis JT. Dermatologic diagnosis: leukocytoclastic vasculitis. Perm J. 2015;19(3):77-78. doi:10.7812/TPP/15-001
5. The role of infectious agents in the pathogenesis of vasculitis. Nicolò P, Carlo S. Best Pract Res Clin Rheumatol. 2008;22(5):897-911. doi:10.7812/TPP/15-001
6. Maunz G, Conzett T, Zimmerli W. Cutaneous vasculitis associated with fluoroquinolones. Infection. 2009;37(5):466-468. doi:10.1007/s15010-009-8437-4
7. Baigrie D, Goyal A, Crane J.C. Leukocytoclastic vasculitis. StatPearls [internet]. Updated May 8, 2022. Accessed October 10, 2022. https://www.ncbi.nlm.nih.gov/books/NBK482159
8. Micheletti RG, Pagnoux C. Management of cutaneous vasculitis. Presse Med. 2020; 49(3):104033. doi:10.1016/j.lpm.2020.104033
Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated acquired condition affecting both adults and children.1 Acute ITP is the most common form, which happens in the presence of a precipitant, leading to a drop in platelet counts. However, chronic ITP can occur when all the causes that might precipitate thrombocytopenia have been ruled out, and it is persistent for ≥ 12 months.2 Its presence can mask other diseases that exhibit somewhat similar signs and symptoms. We present a case of a patient presenting with chronic ITP with diffuse rash and was later diagnosed with idiopathic leukocytoclastic vasculitis (LCV).
Case Presentation
A 79-year-old presented to the hospital with 2-day history of a rash. The rash was purpureal and petechial and located on the trunk and bilateral upper and lower extremities. The rash was associated with itchiness and pain in the wrists, ankles, and small joints of the hands. The patient reported no changes in medication or diet,
The patient mentioned that at the time of diagnosis the platelet count was about 90,000 but had been fluctuating between 50 and 60,000 recently. The patient also reported no history of gum bleeding, nosebleeds, hemoptysis, hematemesis, or any miscarriages. She also had difficulty voiding for 2 to 3 days but no dysuria, frequency, urgency, or incontinence.
Laboratory results were significant for 57,000/µL platelet count (normal range, 150,000-450,000), elevated d-dimer (6.07), < 6 mg/dL C4 (normal range, 88-201). Hemoglobin level, coagulation panel, hemolytic panel, and fibrinogen level results were unremarkable. The hepatitis panel, Lyme disease, and HIV test were negative. The peripheral blood smear showed moderate thrombocytopenia, mild monocytosis, and borderline normochromic normocytic anemia without schistocytes. The autoimmune panel to evaluate thrombocytopenia showed platelet antibody against glycoprotein (GP) IIb/IIIa, GP Ib/Ix, GP Ia/IIa, suggestive toward a diagnosis of chronic idiopathic ITP. However, the skin biopsy of the rash was indicative of LCV.
An autoimmune panel for vasculitis, including antinuclear antibody and antidouble-stranded DNA, was negative. While in the hospital, the patient completed the course of ciprofloxacin for the UTI, the rash started to fade without any intervention, and the platelet count improved to 69,000/µL. The patient was discharged after 3 days with the recommendation to follow up with her hematologist.
Discussion
LCV is a small vessel vasculitis of the dermal capillaries and venules. Histologically, LCV is characterized by fibrinoid necrosis of the vessel wall with frequent neutrophils, nuclear dust, and extravasated erythrocytes.3
Although a thorough evaluation is recommended to determine etiology, about 50% of cases are idiopathic. The most common precipitants are acute infection or a new medication. Postinfectious LCV is most commonly seen after streptococcal upper respiratory tract infection. Among other infectious triggers, Mycobacterium, Staphylococcus aureus, chlamydia, Neisseria, HIV, hepatitis B, hepatitis C, and syphilis are noteworthy. Foods, autoimmune disease, collagen vascular disease, and malignancy are also associated with LCV.4
In our patient we could not find any specific identifiable triggers. However, the presence of a UTI as a precipitating factor cannot be ruled out.5 Moreover, the patient received ciprofloxacin and there have been several case reports of LCV associated with use of a fluroquinolone.6 Nevertheless, in the presence of chronic ITP, which also is an auto-immune condition, an idiopathic cause seemed a reasonable explanation for the patient’s etiopathogenesis.
The cutaneous manifestations of LCV may appear about 1 to 3 weeks after the triggering event if present. The major clinical findings include palpable purpura and/or petechiae that are nonblanching. These findings can easily be confused with other diagnoses especially in the presence of a similar preexisting diagnosis. For example, our patient already had chronic ITP, and in such circumstances, a diagnosis of superimposed LCV can be easily missed without a thorough investigation. Extracutaneous manifestations with LCV are less common. Systemic symptoms may include low-grade fevers, malaise, weight loss, myalgia, and arthralgia. These findings have been noted in about 30% of affected patients, with arthralgia the most common manifestation.7 Our patient also presented with pain involving multiple joints.
The mainstay of diagnosis for LCV is a skin biopsy with direct immunofluorescence. However, a workup for an underlying condition should be considered based on clinical suspicion. If a secondary cause is found, management should target treating the underlying cause, including withdrawal of the offending drug, treatment or control of the underlying infection, malignancy, or connective tissue disease. Most cases of idiopathic cutaneous LCV resolve with supportive measures, including leg elevation, rest, compression stockings, and antihistamines. In resistant cases, a 4- to 6-week tapering dose of corticosteroids and immunosuppressive steroid-sparing agents may be needed.8
Conclusions
Although most cases of LCV are mild and resolve without intervention, many cases go undiagnosed due to a delay in performing a biopsy. However, we should always look for the root cause of a patient’s condition to rule out underlying contributing conditions. Differentiating LCV from any other preexisting condition presenting similarly is important.
Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated acquired condition affecting both adults and children.1 Acute ITP is the most common form, which happens in the presence of a precipitant, leading to a drop in platelet counts. However, chronic ITP can occur when all the causes that might precipitate thrombocytopenia have been ruled out, and it is persistent for ≥ 12 months.2 Its presence can mask other diseases that exhibit somewhat similar signs and symptoms. We present a case of a patient presenting with chronic ITP with diffuse rash and was later diagnosed with idiopathic leukocytoclastic vasculitis (LCV).
Case Presentation
A 79-year-old presented to the hospital with 2-day history of a rash. The rash was purpureal and petechial and located on the trunk and bilateral upper and lower extremities. The rash was associated with itchiness and pain in the wrists, ankles, and small joints of the hands. The patient reported no changes in medication or diet,
The patient mentioned that at the time of diagnosis the platelet count was about 90,000 but had been fluctuating between 50 and 60,000 recently. The patient also reported no history of gum bleeding, nosebleeds, hemoptysis, hematemesis, or any miscarriages. She also had difficulty voiding for 2 to 3 days but no dysuria, frequency, urgency, or incontinence.
Laboratory results were significant for 57,000/µL platelet count (normal range, 150,000-450,000), elevated d-dimer (6.07), < 6 mg/dL C4 (normal range, 88-201). Hemoglobin level, coagulation panel, hemolytic panel, and fibrinogen level results were unremarkable. The hepatitis panel, Lyme disease, and HIV test were negative. The peripheral blood smear showed moderate thrombocytopenia, mild monocytosis, and borderline normochromic normocytic anemia without schistocytes. The autoimmune panel to evaluate thrombocytopenia showed platelet antibody against glycoprotein (GP) IIb/IIIa, GP Ib/Ix, GP Ia/IIa, suggestive toward a diagnosis of chronic idiopathic ITP. However, the skin biopsy of the rash was indicative of LCV.
An autoimmune panel for vasculitis, including antinuclear antibody and antidouble-stranded DNA, was negative. While in the hospital, the patient completed the course of ciprofloxacin for the UTI, the rash started to fade without any intervention, and the platelet count improved to 69,000/µL. The patient was discharged after 3 days with the recommendation to follow up with her hematologist.
Discussion
LCV is a small vessel vasculitis of the dermal capillaries and venules. Histologically, LCV is characterized by fibrinoid necrosis of the vessel wall with frequent neutrophils, nuclear dust, and extravasated erythrocytes.3
Although a thorough evaluation is recommended to determine etiology, about 50% of cases are idiopathic. The most common precipitants are acute infection or a new medication. Postinfectious LCV is most commonly seen after streptococcal upper respiratory tract infection. Among other infectious triggers, Mycobacterium, Staphylococcus aureus, chlamydia, Neisseria, HIV, hepatitis B, hepatitis C, and syphilis are noteworthy. Foods, autoimmune disease, collagen vascular disease, and malignancy are also associated with LCV.4
In our patient we could not find any specific identifiable triggers. However, the presence of a UTI as a precipitating factor cannot be ruled out.5 Moreover, the patient received ciprofloxacin and there have been several case reports of LCV associated with use of a fluroquinolone.6 Nevertheless, in the presence of chronic ITP, which also is an auto-immune condition, an idiopathic cause seemed a reasonable explanation for the patient’s etiopathogenesis.
The cutaneous manifestations of LCV may appear about 1 to 3 weeks after the triggering event if present. The major clinical findings include palpable purpura and/or petechiae that are nonblanching. These findings can easily be confused with other diagnoses especially in the presence of a similar preexisting diagnosis. For example, our patient already had chronic ITP, and in such circumstances, a diagnosis of superimposed LCV can be easily missed without a thorough investigation. Extracutaneous manifestations with LCV are less common. Systemic symptoms may include low-grade fevers, malaise, weight loss, myalgia, and arthralgia. These findings have been noted in about 30% of affected patients, with arthralgia the most common manifestation.7 Our patient also presented with pain involving multiple joints.
The mainstay of diagnosis for LCV is a skin biopsy with direct immunofluorescence. However, a workup for an underlying condition should be considered based on clinical suspicion. If a secondary cause is found, management should target treating the underlying cause, including withdrawal of the offending drug, treatment or control of the underlying infection, malignancy, or connective tissue disease. Most cases of idiopathic cutaneous LCV resolve with supportive measures, including leg elevation, rest, compression stockings, and antihistamines. In resistant cases, a 4- to 6-week tapering dose of corticosteroids and immunosuppressive steroid-sparing agents may be needed.8
Conclusions
Although most cases of LCV are mild and resolve without intervention, many cases go undiagnosed due to a delay in performing a biopsy. However, we should always look for the root cause of a patient’s condition to rule out underlying contributing conditions. Differentiating LCV from any other preexisting condition presenting similarly is important.
1. Gaurav K, Keith RM. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3): 495-520. doi:10.1016/j.hoc.2013.03.001
2. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386-2393.
3. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Saunders/Elsevier; 2011.
4. Einhorn J, Levis JT. Dermatologic diagnosis: leukocytoclastic vasculitis. Perm J. 2015;19(3):77-78. doi:10.7812/TPP/15-001
5. The role of infectious agents in the pathogenesis of vasculitis. Nicolò P, Carlo S. Best Pract Res Clin Rheumatol. 2008;22(5):897-911. doi:10.7812/TPP/15-001
6. Maunz G, Conzett T, Zimmerli W. Cutaneous vasculitis associated with fluoroquinolones. Infection. 2009;37(5):466-468. doi:10.1007/s15010-009-8437-4
7. Baigrie D, Goyal A, Crane J.C. Leukocytoclastic vasculitis. StatPearls [internet]. Updated May 8, 2022. Accessed October 10, 2022. https://www.ncbi.nlm.nih.gov/books/NBK482159
8. Micheletti RG, Pagnoux C. Management of cutaneous vasculitis. Presse Med. 2020; 49(3):104033. doi:10.1016/j.lpm.2020.104033
1. Gaurav K, Keith RM. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3): 495-520. doi:10.1016/j.hoc.2013.03.001
2. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386-2393.
3. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Saunders/Elsevier; 2011.
4. Einhorn J, Levis JT. Dermatologic diagnosis: leukocytoclastic vasculitis. Perm J. 2015;19(3):77-78. doi:10.7812/TPP/15-001
5. The role of infectious agents in the pathogenesis of vasculitis. Nicolò P, Carlo S. Best Pract Res Clin Rheumatol. 2008;22(5):897-911. doi:10.7812/TPP/15-001
6. Maunz G, Conzett T, Zimmerli W. Cutaneous vasculitis associated with fluoroquinolones. Infection. 2009;37(5):466-468. doi:10.1007/s15010-009-8437-4
7. Baigrie D, Goyal A, Crane J.C. Leukocytoclastic vasculitis. StatPearls [internet]. Updated May 8, 2022. Accessed October 10, 2022. https://www.ncbi.nlm.nih.gov/books/NBK482159
8. Micheletti RG, Pagnoux C. Management of cutaneous vasculitis. Presse Med. 2020; 49(3):104033. doi:10.1016/j.lpm.2020.104033
EHR-based thromboembolism risk tool boosted prophylaxis
CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.
“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.
Even so, outside experts expressed concerns about certain results and the trial design.
Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.
This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.
The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.
Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
A ‘powerful message’
“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”
But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.
For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
But wait – more detail and analysis needed
“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.
With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.
“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.
Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
The IMPROVE-DD VTE risk assessment tool
The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.
The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.
Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.
IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.
“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”
Enrollment focused on higher-risk patients
The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.
The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.
“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.
The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.
CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.
“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.
Even so, outside experts expressed concerns about certain results and the trial design.
Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.
This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.
The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.
Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
A ‘powerful message’
“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”
But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.
For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
But wait – more detail and analysis needed
“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.
With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.
“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.
Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
The IMPROVE-DD VTE risk assessment tool
The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.
The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.
Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.
IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.
“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”
Enrollment focused on higher-risk patients
The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.
The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.
“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.
The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.
CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.
“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.
Even so, outside experts expressed concerns about certain results and the trial design.
Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.
This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.
The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.
Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
A ‘powerful message’
“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”
But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.
For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
But wait – more detail and analysis needed
“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.
With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.
“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.
Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
The IMPROVE-DD VTE risk assessment tool
The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.
The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.
Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.
IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.
“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”
Enrollment focused on higher-risk patients
The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.
The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.
“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.
The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.
AT AHA 2022
Apixaban outmatches rivaroxaban in patients with AFib and valvular heart disease
Compared with rivaroxaban, apixaban cut risks nearly in half, suggesting that clinicians should consider these new data when choosing an anticoagulant, reported lead author Ghadeer K. Dawwas, PhD, of the University of Pennsylvania, Philadelphia, and colleagues.
In the new retrospective study involving almost 20,000 patients, Dr. Dawwas and her colleagues “emulated a target trial” using private insurance claims from Optum’s deidentified Clinformatics Data Mart Database. The cohort was narrowed from a screened population of 58,210 patients with concurrent AFib and VHD to 9,947 new apixaban users who could be closely matched with 9,947 new rivaroxaban users. Covariates included provider specialty, type of VHD, demographic characteristics, measures of health care use, baseline use of medications, and baseline comorbidities.
The primary effectiveness outcome was a composite of systemic embolism and ischemic stroke, while the primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
“Although several ongoing trials aim to compare apixaban with warfarin in patients with AFib and VHD, none of these trials will directly compare apixaban and rivaroxaban,” the investigators wrote. Their report is in Annals of Internal Medicine.
Dr. Dawwas and colleagues previously showed that direct oral anticoagulants (DOACs) were safer and more effective than warfarin in the same patient population. Comparing apixaban and rivaroxaban – the two most common DOACs – was the next logical step, Dr. Dawwas said in an interview.
Study results
Compared with rivaroxaban, patients who received apixaban had a 43% reduced risk of stroke or embolism (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40-0.80). Apixaban’s ability to protect against bleeding appeared even more pronounced, with a 49% reduced risk over rivaroxaban (HR, 0.51; 95% CI, 0.41-0.62).
Comparing the two agents on an absolute basis, apixaban reduced risk of embolism or stroke by 0.2% within the first 6 months of treatment initiation, and 1.1% within the first year of initiation. At the same time points, absolute risk reductions for bleeding were 1.2% and 1.9%, respectively.
The investigators noted that their results held consistent in an alternative analysis that considered separate types of VHD.
“Based on the results from our analysis, we showed that apixaban is effective and safe in patients with atrial fibrillation and valvular heart diseases,” Dr. Dawwas said.
Head-to-head trial needed to change practice
Christopher M. Bianco, DO, associate professor of medicine at West Virginia University Heart and Vascular Institute, Morgantown, said the findings “add to the growing body of literature,” but “a head-to-head trial would be necessary to make a definitive change to clinical practice.”
Dr. Bianco, who recently conducted a retrospective analysis of apixaban and rivaroxaban that found no difference in safety and efficacy among a different patient population, said these kinds of studies are helpful in generating hypotheses, but they can’t account for all relevant clinical factors.
“There are just so many things that go into the decision-making process of [prescribing] apixaban and rivaroxaban,” he said. “Even though [Dr. Dawwas and colleagues] used propensity matching, you’re never going to be able to sort that out with a retrospective analysis.”
Specifically, Dr. Bianco noted that the findings did not include dose data. This is a key gap, he said, considering how often real-world datasets have shown that providers underdose DOACs for a number of unaccountable reasons, and how frequently patients exhibit poor adherence.
The study also lacked detail concerning the degree of renal dysfunction, which can determine drug eligibility, Dr. Bianco said. Furthermore, attempts to stratify patients based on thrombosis and bleeding risk were likely “insufficient,” he added.
Dr. Bianco also cautioned that the investigators defined valvular heart disease as any valve-related disease of any severity. In contrast, previous studies have generally restricted valvular heart disease to patients with mitral stenosis or prosthetic valves.
“This is definitely not the traditional definition of valvular heart disease, so the title is a little bit misleading in that sense, although they certainly do disclose that in the methods,” Dr. Bianco said.
On a more positive note, he highlighted the size of the patient population, and the real-world data, which included many patients who would be excluded from clinical trials.
More broadly, the study helps drive research forward, Dr. Bianco concluded; namely, by attracting financial support for a more powerful head-to-head trial that drug makers are unlikely to fund due to inherent market risk.
This study was supported by the National Institutes of Health. The investigators disclosed additional relationships with Takeda, Spark, Sanofi, and others. Dr. Bianco disclosed no conflicts of interest.
Compared with rivaroxaban, apixaban cut risks nearly in half, suggesting that clinicians should consider these new data when choosing an anticoagulant, reported lead author Ghadeer K. Dawwas, PhD, of the University of Pennsylvania, Philadelphia, and colleagues.
In the new retrospective study involving almost 20,000 patients, Dr. Dawwas and her colleagues “emulated a target trial” using private insurance claims from Optum’s deidentified Clinformatics Data Mart Database. The cohort was narrowed from a screened population of 58,210 patients with concurrent AFib and VHD to 9,947 new apixaban users who could be closely matched with 9,947 new rivaroxaban users. Covariates included provider specialty, type of VHD, demographic characteristics, measures of health care use, baseline use of medications, and baseline comorbidities.
The primary effectiveness outcome was a composite of systemic embolism and ischemic stroke, while the primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
“Although several ongoing trials aim to compare apixaban with warfarin in patients with AFib and VHD, none of these trials will directly compare apixaban and rivaroxaban,” the investigators wrote. Their report is in Annals of Internal Medicine.
Dr. Dawwas and colleagues previously showed that direct oral anticoagulants (DOACs) were safer and more effective than warfarin in the same patient population. Comparing apixaban and rivaroxaban – the two most common DOACs – was the next logical step, Dr. Dawwas said in an interview.
Study results
Compared with rivaroxaban, patients who received apixaban had a 43% reduced risk of stroke or embolism (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40-0.80). Apixaban’s ability to protect against bleeding appeared even more pronounced, with a 49% reduced risk over rivaroxaban (HR, 0.51; 95% CI, 0.41-0.62).
Comparing the two agents on an absolute basis, apixaban reduced risk of embolism or stroke by 0.2% within the first 6 months of treatment initiation, and 1.1% within the first year of initiation. At the same time points, absolute risk reductions for bleeding were 1.2% and 1.9%, respectively.
The investigators noted that their results held consistent in an alternative analysis that considered separate types of VHD.
“Based on the results from our analysis, we showed that apixaban is effective and safe in patients with atrial fibrillation and valvular heart diseases,” Dr. Dawwas said.
Head-to-head trial needed to change practice
Christopher M. Bianco, DO, associate professor of medicine at West Virginia University Heart and Vascular Institute, Morgantown, said the findings “add to the growing body of literature,” but “a head-to-head trial would be necessary to make a definitive change to clinical practice.”
Dr. Bianco, who recently conducted a retrospective analysis of apixaban and rivaroxaban that found no difference in safety and efficacy among a different patient population, said these kinds of studies are helpful in generating hypotheses, but they can’t account for all relevant clinical factors.
“There are just so many things that go into the decision-making process of [prescribing] apixaban and rivaroxaban,” he said. “Even though [Dr. Dawwas and colleagues] used propensity matching, you’re never going to be able to sort that out with a retrospective analysis.”
Specifically, Dr. Bianco noted that the findings did not include dose data. This is a key gap, he said, considering how often real-world datasets have shown that providers underdose DOACs for a number of unaccountable reasons, and how frequently patients exhibit poor adherence.
The study also lacked detail concerning the degree of renal dysfunction, which can determine drug eligibility, Dr. Bianco said. Furthermore, attempts to stratify patients based on thrombosis and bleeding risk were likely “insufficient,” he added.
Dr. Bianco also cautioned that the investigators defined valvular heart disease as any valve-related disease of any severity. In contrast, previous studies have generally restricted valvular heart disease to patients with mitral stenosis or prosthetic valves.
“This is definitely not the traditional definition of valvular heart disease, so the title is a little bit misleading in that sense, although they certainly do disclose that in the methods,” Dr. Bianco said.
On a more positive note, he highlighted the size of the patient population, and the real-world data, which included many patients who would be excluded from clinical trials.
More broadly, the study helps drive research forward, Dr. Bianco concluded; namely, by attracting financial support for a more powerful head-to-head trial that drug makers are unlikely to fund due to inherent market risk.
This study was supported by the National Institutes of Health. The investigators disclosed additional relationships with Takeda, Spark, Sanofi, and others. Dr. Bianco disclosed no conflicts of interest.
Compared with rivaroxaban, apixaban cut risks nearly in half, suggesting that clinicians should consider these new data when choosing an anticoagulant, reported lead author Ghadeer K. Dawwas, PhD, of the University of Pennsylvania, Philadelphia, and colleagues.
In the new retrospective study involving almost 20,000 patients, Dr. Dawwas and her colleagues “emulated a target trial” using private insurance claims from Optum’s deidentified Clinformatics Data Mart Database. The cohort was narrowed from a screened population of 58,210 patients with concurrent AFib and VHD to 9,947 new apixaban users who could be closely matched with 9,947 new rivaroxaban users. Covariates included provider specialty, type of VHD, demographic characteristics, measures of health care use, baseline use of medications, and baseline comorbidities.
The primary effectiveness outcome was a composite of systemic embolism and ischemic stroke, while the primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
“Although several ongoing trials aim to compare apixaban with warfarin in patients with AFib and VHD, none of these trials will directly compare apixaban and rivaroxaban,” the investigators wrote. Their report is in Annals of Internal Medicine.
Dr. Dawwas and colleagues previously showed that direct oral anticoagulants (DOACs) were safer and more effective than warfarin in the same patient population. Comparing apixaban and rivaroxaban – the two most common DOACs – was the next logical step, Dr. Dawwas said in an interview.
Study results
Compared with rivaroxaban, patients who received apixaban had a 43% reduced risk of stroke or embolism (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40-0.80). Apixaban’s ability to protect against bleeding appeared even more pronounced, with a 49% reduced risk over rivaroxaban (HR, 0.51; 95% CI, 0.41-0.62).
Comparing the two agents on an absolute basis, apixaban reduced risk of embolism or stroke by 0.2% within the first 6 months of treatment initiation, and 1.1% within the first year of initiation. At the same time points, absolute risk reductions for bleeding were 1.2% and 1.9%, respectively.
The investigators noted that their results held consistent in an alternative analysis that considered separate types of VHD.
“Based on the results from our analysis, we showed that apixaban is effective and safe in patients with atrial fibrillation and valvular heart diseases,” Dr. Dawwas said.
Head-to-head trial needed to change practice
Christopher M. Bianco, DO, associate professor of medicine at West Virginia University Heart and Vascular Institute, Morgantown, said the findings “add to the growing body of literature,” but “a head-to-head trial would be necessary to make a definitive change to clinical practice.”
Dr. Bianco, who recently conducted a retrospective analysis of apixaban and rivaroxaban that found no difference in safety and efficacy among a different patient population, said these kinds of studies are helpful in generating hypotheses, but they can’t account for all relevant clinical factors.
“There are just so many things that go into the decision-making process of [prescribing] apixaban and rivaroxaban,” he said. “Even though [Dr. Dawwas and colleagues] used propensity matching, you’re never going to be able to sort that out with a retrospective analysis.”
Specifically, Dr. Bianco noted that the findings did not include dose data. This is a key gap, he said, considering how often real-world datasets have shown that providers underdose DOACs for a number of unaccountable reasons, and how frequently patients exhibit poor adherence.
The study also lacked detail concerning the degree of renal dysfunction, which can determine drug eligibility, Dr. Bianco said. Furthermore, attempts to stratify patients based on thrombosis and bleeding risk were likely “insufficient,” he added.
Dr. Bianco also cautioned that the investigators defined valvular heart disease as any valve-related disease of any severity. In contrast, previous studies have generally restricted valvular heart disease to patients with mitral stenosis or prosthetic valves.
“This is definitely not the traditional definition of valvular heart disease, so the title is a little bit misleading in that sense, although they certainly do disclose that in the methods,” Dr. Bianco said.
On a more positive note, he highlighted the size of the patient population, and the real-world data, which included many patients who would be excluded from clinical trials.
More broadly, the study helps drive research forward, Dr. Bianco concluded; namely, by attracting financial support for a more powerful head-to-head trial that drug makers are unlikely to fund due to inherent market risk.
This study was supported by the National Institutes of Health. The investigators disclosed additional relationships with Takeda, Spark, Sanofi, and others. Dr. Bianco disclosed no conflicts of interest.
FROM ANNALS OF INTERNAL MEDICINE
I am not fine: The heavy toll cancer takes
PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”
Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.
She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session,
Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”
When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.
A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.
Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.
But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.
“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.
He was alive, just barely, Dr. Washington said.
“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.
But every time someone asked her whether she was okay, she replied: “I am fine.”
“A total lie,” she admitted.
Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”
Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.
Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.
The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.
Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.
Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.
“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
Are patients fine?
Like caregivers, patients often say they are fine when they are not.
The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.
The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.
Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.
Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.
To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
Are clinicians fine?
Nurses and physicians face challenges caring for patients with cancer.
Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.
Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.
Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.
Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.
It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.
Above all, “show that you care,” said Dr. Cardoso.
The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.
A version of this article first appeared on Medscape.com.
PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”
Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.
She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session,
Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”
When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.
A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.
Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.
But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.
“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.
He was alive, just barely, Dr. Washington said.
“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.
But every time someone asked her whether she was okay, she replied: “I am fine.”
“A total lie,” she admitted.
Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”
Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.
Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.
The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.
Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.
Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.
“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
Are patients fine?
Like caregivers, patients often say they are fine when they are not.
The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.
The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.
Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.
Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.
To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
Are clinicians fine?
Nurses and physicians face challenges caring for patients with cancer.
Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.
Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.
Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.
Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.
It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.
Above all, “show that you care,” said Dr. Cardoso.
The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.
A version of this article first appeared on Medscape.com.
PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”
Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.
She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session,
Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”
When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.
A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.
Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.
But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.
“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.
He was alive, just barely, Dr. Washington said.
“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.
But every time someone asked her whether she was okay, she replied: “I am fine.”
“A total lie,” she admitted.
Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”
Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.
Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.
The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.
Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.
Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.
“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
Are patients fine?
Like caregivers, patients often say they are fine when they are not.
The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.
The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.
Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.
Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.
To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
Are clinicians fine?
Nurses and physicians face challenges caring for patients with cancer.
Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.
Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.
Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.
Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.
It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.
Above all, “show that you care,” said Dr. Cardoso.
The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.
A version of this article first appeared on Medscape.com.
AT ESMO CONGRESS 2022
Worldwide trial seeks to revolutionize pediatric leukemia care
While great strides have been made in children’s leukemia care during the past 50 years, statistics have remained grim. For acute myeloid leukemia (AML), the most common type, 5-year survival rates were just 69% for children younger than 15 between 2009 and 2015. Patients who do survive past adolescence face high risks of future complications.
Specialists say the challenges hindering more progress include a lack of clinical research, an emphasis on competition over cooperation, and sparse insight into how best to adjust adult leukemia treatments to children.
“Our project aims to find better treatments, more targeted treatments, that will leave children with fewer long-term health problems as adults. We want them to not just survive but thrive,” Gwen Nichols, MD, chief medical officer of LLS, said in an interview. “What we’ve had was not working for anybody. So we have to try a different approach.”
The LLS Pediatric Acute Leukemia (PedAL) Master Trial launched in spring of 2022. Seventy-five study locations from Nova Scotia to Hawaii are now recruiting patients up to age 22 with known or suspected relapsed/refractory AML, mixed phenotype acute leukemia, or relapsed acute lymphoblastic leukemia (ALL).
The 5-year trial expects to recruit 960 participants in the United States and Canada. Clinics in Europe, Australia, and New Zealand also are taking part.
“Pediatric oncologists should know that PedAL, for the first time, is providing a cooperative, seamless way to interrogate [the genomics of] a child’s leukemia,” hematologist/oncologist Todd Cooper, DO, section chief of pediatric oncology at Seattle Children’s Cancer and Blood Disorders Center, said in an interview. “It is also providing a seamless and efficient way for children to be assigned to clinical trials that are going to be tailored towards a particular child’s leukemia. This is something that’s never been done.”
In North America, all trial participants with relapsed AML will undergo genetic sequencing for free as part of the screening process. Clinics “can’t always access genomic screening for their patients,” Dr. Nichols said. “We’re providing that even if they don’t participate in any other part of the trial, even if they go and get another available therapy or go on a different trial. We want them to know that this is available, and they will get the results. And if they’re looking for a trial when they get those results, we have trained oncology nurses who will help them navigate and find clinical trials.”
In PedAL itself, one subtrial is now in progress: An open-label phase 3 randomized multicenter analysis of whether the oral leukemia drug venetoclax combined with the intensive infused chemotherapy treatment FLA+GO (fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin) will improve overall survival compared to FLA+GO alone. Ninety-eight subjects are expected to join the 5-year subtrial.
“We expect within the next year to open three or four different subtrials of targeted therapies for specific groups of patients,” E. Anders Kolb, MD, chief of oncology and hematology at Nemours Children’s Health in Delaware and cochair of the PedAL trial, said in an interview. “Over the course of the next few years, we’re going to learn a lot about the natural history of relapsed leukemia – we don’t have a ton of data on that – and then how targeted therapies may alter some of those outcomes.”
Discussions with multiple drugmakers are in progress regarding the potential subtrials, he said.
The PedAL strategy addresses the lack of new drugs for children with AML, Seattle Children’s Dr. Cooper said. One main reason for the gap is that childhood leukemia is much less common than the adult form, he said, so a lot of drug development is geared toward adults. As a result, he said, new drugs “are geared towards adults whose leukemia is not as aggressive. Whereas in children, the acute leukemias, especially AML, are quite aggressive and need therapies that are often more intense.”
In addition, he said, “we have only recently become aware of how AML is biologically much different than in adults.”
In AML, Delaware’s Dr. Kolb explained, “there are many different phenotypes – ways that these cells can look and behave. But we treat them with a single regimen. What I like to tell families is that we’ve got a few tools in our toolbox, but they all happen to be sledgehammers. The key to the challenge in AML is that it is a molecular disease, but we’re treating it with therapies that were developed 40-50 years ago.”
In PedAL, the goal is to figure out the best ways to target therapy for the specific types that patients have. On this front, the genomic screening in the trial is crucial because it will identify which patients express certain targets and allow them to be assigned to appropriate sub-trials, Dr. Coooper said.
What’s next? “LLS has planned for this to be ongoing for the next 5 to 7 years, so that we can get a number of studies up and running,” Dr. Nichols said. “After that, those studies will continue. We will hope that most of them can be self-funded by then.”
As for cost, she noted that the PedAL trial is part of the society’s Dare to Dream Project, formerly known as the Children’s Initiative, which focuses on pediatric blood cancers. The project, with a fundraising goal of $175 million, focuses on research, patient services and survivorship.
”We have a whole range of services, travel assistance, copay programs and educational resources that doctors may want to use as a valid source of information,” she said. ‘When I was in practice, patients were always asking me, ‘Do you have anything I can read or take home to give my son something about his disease?’ LLS has good-quality, patient-level information for patients. We welcome people contacting us or going to our website and taking advantage of that for free.”
Dr. Nichols and Dr. Kolb report no disclosures. Dr. Cooper reports academic funding from LLS.
While great strides have been made in children’s leukemia care during the past 50 years, statistics have remained grim. For acute myeloid leukemia (AML), the most common type, 5-year survival rates were just 69% for children younger than 15 between 2009 and 2015. Patients who do survive past adolescence face high risks of future complications.
Specialists say the challenges hindering more progress include a lack of clinical research, an emphasis on competition over cooperation, and sparse insight into how best to adjust adult leukemia treatments to children.
“Our project aims to find better treatments, more targeted treatments, that will leave children with fewer long-term health problems as adults. We want them to not just survive but thrive,” Gwen Nichols, MD, chief medical officer of LLS, said in an interview. “What we’ve had was not working for anybody. So we have to try a different approach.”
The LLS Pediatric Acute Leukemia (PedAL) Master Trial launched in spring of 2022. Seventy-five study locations from Nova Scotia to Hawaii are now recruiting patients up to age 22 with known or suspected relapsed/refractory AML, mixed phenotype acute leukemia, or relapsed acute lymphoblastic leukemia (ALL).
The 5-year trial expects to recruit 960 participants in the United States and Canada. Clinics in Europe, Australia, and New Zealand also are taking part.
“Pediatric oncologists should know that PedAL, for the first time, is providing a cooperative, seamless way to interrogate [the genomics of] a child’s leukemia,” hematologist/oncologist Todd Cooper, DO, section chief of pediatric oncology at Seattle Children’s Cancer and Blood Disorders Center, said in an interview. “It is also providing a seamless and efficient way for children to be assigned to clinical trials that are going to be tailored towards a particular child’s leukemia. This is something that’s never been done.”
In North America, all trial participants with relapsed AML will undergo genetic sequencing for free as part of the screening process. Clinics “can’t always access genomic screening for their patients,” Dr. Nichols said. “We’re providing that even if they don’t participate in any other part of the trial, even if they go and get another available therapy or go on a different trial. We want them to know that this is available, and they will get the results. And if they’re looking for a trial when they get those results, we have trained oncology nurses who will help them navigate and find clinical trials.”
In PedAL itself, one subtrial is now in progress: An open-label phase 3 randomized multicenter analysis of whether the oral leukemia drug venetoclax combined with the intensive infused chemotherapy treatment FLA+GO (fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin) will improve overall survival compared to FLA+GO alone. Ninety-eight subjects are expected to join the 5-year subtrial.
“We expect within the next year to open three or four different subtrials of targeted therapies for specific groups of patients,” E. Anders Kolb, MD, chief of oncology and hematology at Nemours Children’s Health in Delaware and cochair of the PedAL trial, said in an interview. “Over the course of the next few years, we’re going to learn a lot about the natural history of relapsed leukemia – we don’t have a ton of data on that – and then how targeted therapies may alter some of those outcomes.”
Discussions with multiple drugmakers are in progress regarding the potential subtrials, he said.
The PedAL strategy addresses the lack of new drugs for children with AML, Seattle Children’s Dr. Cooper said. One main reason for the gap is that childhood leukemia is much less common than the adult form, he said, so a lot of drug development is geared toward adults. As a result, he said, new drugs “are geared towards adults whose leukemia is not as aggressive. Whereas in children, the acute leukemias, especially AML, are quite aggressive and need therapies that are often more intense.”
In addition, he said, “we have only recently become aware of how AML is biologically much different than in adults.”
In AML, Delaware’s Dr. Kolb explained, “there are many different phenotypes – ways that these cells can look and behave. But we treat them with a single regimen. What I like to tell families is that we’ve got a few tools in our toolbox, but they all happen to be sledgehammers. The key to the challenge in AML is that it is a molecular disease, but we’re treating it with therapies that were developed 40-50 years ago.”
In PedAL, the goal is to figure out the best ways to target therapy for the specific types that patients have. On this front, the genomic screening in the trial is crucial because it will identify which patients express certain targets and allow them to be assigned to appropriate sub-trials, Dr. Coooper said.
What’s next? “LLS has planned for this to be ongoing for the next 5 to 7 years, so that we can get a number of studies up and running,” Dr. Nichols said. “After that, those studies will continue. We will hope that most of them can be self-funded by then.”
As for cost, she noted that the PedAL trial is part of the society’s Dare to Dream Project, formerly known as the Children’s Initiative, which focuses on pediatric blood cancers. The project, with a fundraising goal of $175 million, focuses on research, patient services and survivorship.
”We have a whole range of services, travel assistance, copay programs and educational resources that doctors may want to use as a valid source of information,” she said. ‘When I was in practice, patients were always asking me, ‘Do you have anything I can read or take home to give my son something about his disease?’ LLS has good-quality, patient-level information for patients. We welcome people contacting us or going to our website and taking advantage of that for free.”
Dr. Nichols and Dr. Kolb report no disclosures. Dr. Cooper reports academic funding from LLS.
While great strides have been made in children’s leukemia care during the past 50 years, statistics have remained grim. For acute myeloid leukemia (AML), the most common type, 5-year survival rates were just 69% for children younger than 15 between 2009 and 2015. Patients who do survive past adolescence face high risks of future complications.
Specialists say the challenges hindering more progress include a lack of clinical research, an emphasis on competition over cooperation, and sparse insight into how best to adjust adult leukemia treatments to children.
“Our project aims to find better treatments, more targeted treatments, that will leave children with fewer long-term health problems as adults. We want them to not just survive but thrive,” Gwen Nichols, MD, chief medical officer of LLS, said in an interview. “What we’ve had was not working for anybody. So we have to try a different approach.”
The LLS Pediatric Acute Leukemia (PedAL) Master Trial launched in spring of 2022. Seventy-five study locations from Nova Scotia to Hawaii are now recruiting patients up to age 22 with known or suspected relapsed/refractory AML, mixed phenotype acute leukemia, or relapsed acute lymphoblastic leukemia (ALL).
The 5-year trial expects to recruit 960 participants in the United States and Canada. Clinics in Europe, Australia, and New Zealand also are taking part.
“Pediatric oncologists should know that PedAL, for the first time, is providing a cooperative, seamless way to interrogate [the genomics of] a child’s leukemia,” hematologist/oncologist Todd Cooper, DO, section chief of pediatric oncology at Seattle Children’s Cancer and Blood Disorders Center, said in an interview. “It is also providing a seamless and efficient way for children to be assigned to clinical trials that are going to be tailored towards a particular child’s leukemia. This is something that’s never been done.”
In North America, all trial participants with relapsed AML will undergo genetic sequencing for free as part of the screening process. Clinics “can’t always access genomic screening for their patients,” Dr. Nichols said. “We’re providing that even if they don’t participate in any other part of the trial, even if they go and get another available therapy or go on a different trial. We want them to know that this is available, and they will get the results. And if they’re looking for a trial when they get those results, we have trained oncology nurses who will help them navigate and find clinical trials.”
In PedAL itself, one subtrial is now in progress: An open-label phase 3 randomized multicenter analysis of whether the oral leukemia drug venetoclax combined with the intensive infused chemotherapy treatment FLA+GO (fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin) will improve overall survival compared to FLA+GO alone. Ninety-eight subjects are expected to join the 5-year subtrial.
“We expect within the next year to open three or four different subtrials of targeted therapies for specific groups of patients,” E. Anders Kolb, MD, chief of oncology and hematology at Nemours Children’s Health in Delaware and cochair of the PedAL trial, said in an interview. “Over the course of the next few years, we’re going to learn a lot about the natural history of relapsed leukemia – we don’t have a ton of data on that – and then how targeted therapies may alter some of those outcomes.”
Discussions with multiple drugmakers are in progress regarding the potential subtrials, he said.
The PedAL strategy addresses the lack of new drugs for children with AML, Seattle Children’s Dr. Cooper said. One main reason for the gap is that childhood leukemia is much less common than the adult form, he said, so a lot of drug development is geared toward adults. As a result, he said, new drugs “are geared towards adults whose leukemia is not as aggressive. Whereas in children, the acute leukemias, especially AML, are quite aggressive and need therapies that are often more intense.”
In addition, he said, “we have only recently become aware of how AML is biologically much different than in adults.”
In AML, Delaware’s Dr. Kolb explained, “there are many different phenotypes – ways that these cells can look and behave. But we treat them with a single regimen. What I like to tell families is that we’ve got a few tools in our toolbox, but they all happen to be sledgehammers. The key to the challenge in AML is that it is a molecular disease, but we’re treating it with therapies that were developed 40-50 years ago.”
In PedAL, the goal is to figure out the best ways to target therapy for the specific types that patients have. On this front, the genomic screening in the trial is crucial because it will identify which patients express certain targets and allow them to be assigned to appropriate sub-trials, Dr. Coooper said.
What’s next? “LLS has planned for this to be ongoing for the next 5 to 7 years, so that we can get a number of studies up and running,” Dr. Nichols said. “After that, those studies will continue. We will hope that most of them can be self-funded by then.”
As for cost, she noted that the PedAL trial is part of the society’s Dare to Dream Project, formerly known as the Children’s Initiative, which focuses on pediatric blood cancers. The project, with a fundraising goal of $175 million, focuses on research, patient services and survivorship.
”We have a whole range of services, travel assistance, copay programs and educational resources that doctors may want to use as a valid source of information,” she said. ‘When I was in practice, patients were always asking me, ‘Do you have anything I can read or take home to give my son something about his disease?’ LLS has good-quality, patient-level information for patients. We welcome people contacting us or going to our website and taking advantage of that for free.”
Dr. Nichols and Dr. Kolb report no disclosures. Dr. Cooper reports academic funding from LLS.