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‘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
‘Astonishing’ results: Skip salvage chemo, proceed to HSCT
NEW ORLEANS –
The results come from the phase 3 ASAP Trial and were presented at the annual meeting of the American Society of Hematology.
“We selected this to be in the plenary because it completely changes how we’ve traditionally thought about acute myeloid leukemia,” commented press briefing moderator Mikkael A. Sekeres, MD, from the University of Miami, who also serves as chair of the ASH Committee on Communications.
“When we have a patient who has relapsed or refractory AML, that person is in a very, very difficult situation, and the mortality among those sort of patients is incredibly high,” Dr. Sekeres commented. “So traditionally we’ve given them very high doses of chemotherapy to try to reduce the tumor burden – at least that’s been the theory – to then get them successfully to a transplant.”
This new finding “completely upends that, if these results hold,” he said. The clinical implication is that “we no longer have to hospitalize these patients and give them very aggressive chemotherapy ... [and] we don’t introduce all the morbidity from giving them very high dose chemotherapy, which can actually prevent a transplant from happening if they get sick enough, and we can get them to a transplant quicker.”
The ASAP trial was conducted in patients with an unfavorable risk AML who either had a poor response to first induction therapy or a relapse after first induction therapy.
They were randomly assigned to either a remission-induction strategy aiming for a better response prior to an allogeneic hematopoietic stem cell transplant (alloHCT), or a disease-control strategy consisting primarily of watchful waiting with low-dose cytarabine and single doses of mitoxantrone as needed, followed by sequential conditioning and alloHCT.
The results after 4 years of follow-up showed no differences in either leukemia-free survival or overall survival between patients who underwent additional chemotherapy with the remission-induction strategy and those who went straight to transplant, reported Johannes Schetelig, MD, MSc, from the Clinical Trials Unit at DKMS, Dresden, Germany.
“We expected non-inferiority – this was what we tested, and of course this was based on an assumption that we could get close or even somewhat better with respect to the primary endpoint, disease-free survival, after transplantation,” he said.
“What we did not expect is that the early success, [complete response] on day 56 after transplantation, also translates into equal long-term benefit, so this is what I was really astonished about,” Dr. Schetelig said at a press briefing prior to his presentation.
Less intensive approach
Dr. Schetelig explained that the rationale for the study was previous work by his group and others showing that alloHCT in patients with residual aplasia after first induction is feasible, with favorable outcomes, compared with standard of care. Additionally, the impetus for the research was evidence that sequential conditioning based on high-dose cytarabine or melphalan plus reduced-intensity conditioning and alloHCT resulted in long-term control for relapsed or refractory AML.
Dr. Schetelig also gave details of the two treatment arms of the ASAP trial. The remission-inducing arm consisted of cytarabine (3 g/m2 for younger patients or 1 g/m2 for patients over age 60) twice daily on days 1-3 plus 10 mitoxantrone mg/m2 on days 3-5 and subsequent alloHCT. In the other group – disease control prior to sequential conditioning and alloHCT – watchful waiting was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease control.
Although, as Dr. Schetelig noted, the statistical goal of the study was to show non-inferiority of the disease control arm, this less intensive strategy exceeded expectations for meeting the primary endpoint of disease-free survival (DFS; a maintained complete response) by day 56 after alloHCT.
In an intention-to-treat and per-protocol analysis, the respective rates of DFS at 56 days in the disease control group were 83.5% and 84.1%. In comparison, the respective rates in the remission-induction group were 81% and 81.3%.
Further, after a median follow-up from randomization of 37 months, there were no differences in either leukemia-free survival or overall survival out to 4 years after DFS at day 56.
The disease-control strategy was also associated with significantly fewer adverse events grade 3 or greater (23% vs. 64%, P < .001), and fewer days in hospital prior to transplant (mean 19 vs. 42, P < .001). There were no significant differences between the trial arms in either deaths within 28 days of randomization or time to discharge from hospital (28 days in each arm).
“These data support sequential conditioning and alloHCT without prior remission-induction chemotherapy whenever a stem cell donor is readily available,” the researchers concluded.
“These results underline the importance of facilitating alloHCT as [the] most effective anti-leukemic therapy in patients with [relapsed or refractory] AML and stress the need for starting donor search at diagnosis,” they added.
The study was sponsored by DKMS gemeinnützige GmbH. Dr. Schetelig disclosed honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Sekkeres reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
The results come from the phase 3 ASAP Trial and were presented at the annual meeting of the American Society of Hematology.
“We selected this to be in the plenary because it completely changes how we’ve traditionally thought about acute myeloid leukemia,” commented press briefing moderator Mikkael A. Sekeres, MD, from the University of Miami, who also serves as chair of the ASH Committee on Communications.
“When we have a patient who has relapsed or refractory AML, that person is in a very, very difficult situation, and the mortality among those sort of patients is incredibly high,” Dr. Sekeres commented. “So traditionally we’ve given them very high doses of chemotherapy to try to reduce the tumor burden – at least that’s been the theory – to then get them successfully to a transplant.”
This new finding “completely upends that, if these results hold,” he said. The clinical implication is that “we no longer have to hospitalize these patients and give them very aggressive chemotherapy ... [and] we don’t introduce all the morbidity from giving them very high dose chemotherapy, which can actually prevent a transplant from happening if they get sick enough, and we can get them to a transplant quicker.”
The ASAP trial was conducted in patients with an unfavorable risk AML who either had a poor response to first induction therapy or a relapse after first induction therapy.
They were randomly assigned to either a remission-induction strategy aiming for a better response prior to an allogeneic hematopoietic stem cell transplant (alloHCT), or a disease-control strategy consisting primarily of watchful waiting with low-dose cytarabine and single doses of mitoxantrone as needed, followed by sequential conditioning and alloHCT.
The results after 4 years of follow-up showed no differences in either leukemia-free survival or overall survival between patients who underwent additional chemotherapy with the remission-induction strategy and those who went straight to transplant, reported Johannes Schetelig, MD, MSc, from the Clinical Trials Unit at DKMS, Dresden, Germany.
“We expected non-inferiority – this was what we tested, and of course this was based on an assumption that we could get close or even somewhat better with respect to the primary endpoint, disease-free survival, after transplantation,” he said.
“What we did not expect is that the early success, [complete response] on day 56 after transplantation, also translates into equal long-term benefit, so this is what I was really astonished about,” Dr. Schetelig said at a press briefing prior to his presentation.
Less intensive approach
Dr. Schetelig explained that the rationale for the study was previous work by his group and others showing that alloHCT in patients with residual aplasia after first induction is feasible, with favorable outcomes, compared with standard of care. Additionally, the impetus for the research was evidence that sequential conditioning based on high-dose cytarabine or melphalan plus reduced-intensity conditioning and alloHCT resulted in long-term control for relapsed or refractory AML.
Dr. Schetelig also gave details of the two treatment arms of the ASAP trial. The remission-inducing arm consisted of cytarabine (3 g/m2 for younger patients or 1 g/m2 for patients over age 60) twice daily on days 1-3 plus 10 mitoxantrone mg/m2 on days 3-5 and subsequent alloHCT. In the other group – disease control prior to sequential conditioning and alloHCT – watchful waiting was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease control.
Although, as Dr. Schetelig noted, the statistical goal of the study was to show non-inferiority of the disease control arm, this less intensive strategy exceeded expectations for meeting the primary endpoint of disease-free survival (DFS; a maintained complete response) by day 56 after alloHCT.
In an intention-to-treat and per-protocol analysis, the respective rates of DFS at 56 days in the disease control group were 83.5% and 84.1%. In comparison, the respective rates in the remission-induction group were 81% and 81.3%.
Further, after a median follow-up from randomization of 37 months, there were no differences in either leukemia-free survival or overall survival out to 4 years after DFS at day 56.
The disease-control strategy was also associated with significantly fewer adverse events grade 3 or greater (23% vs. 64%, P < .001), and fewer days in hospital prior to transplant (mean 19 vs. 42, P < .001). There were no significant differences between the trial arms in either deaths within 28 days of randomization or time to discharge from hospital (28 days in each arm).
“These data support sequential conditioning and alloHCT without prior remission-induction chemotherapy whenever a stem cell donor is readily available,” the researchers concluded.
“These results underline the importance of facilitating alloHCT as [the] most effective anti-leukemic therapy in patients with [relapsed or refractory] AML and stress the need for starting donor search at diagnosis,” they added.
The study was sponsored by DKMS gemeinnützige GmbH. Dr. Schetelig disclosed honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Sekkeres reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
The results come from the phase 3 ASAP Trial and were presented at the annual meeting of the American Society of Hematology.
“We selected this to be in the plenary because it completely changes how we’ve traditionally thought about acute myeloid leukemia,” commented press briefing moderator Mikkael A. Sekeres, MD, from the University of Miami, who also serves as chair of the ASH Committee on Communications.
“When we have a patient who has relapsed or refractory AML, that person is in a very, very difficult situation, and the mortality among those sort of patients is incredibly high,” Dr. Sekeres commented. “So traditionally we’ve given them very high doses of chemotherapy to try to reduce the tumor burden – at least that’s been the theory – to then get them successfully to a transplant.”
This new finding “completely upends that, if these results hold,” he said. The clinical implication is that “we no longer have to hospitalize these patients and give them very aggressive chemotherapy ... [and] we don’t introduce all the morbidity from giving them very high dose chemotherapy, which can actually prevent a transplant from happening if they get sick enough, and we can get them to a transplant quicker.”
The ASAP trial was conducted in patients with an unfavorable risk AML who either had a poor response to first induction therapy or a relapse after first induction therapy.
They were randomly assigned to either a remission-induction strategy aiming for a better response prior to an allogeneic hematopoietic stem cell transplant (alloHCT), or a disease-control strategy consisting primarily of watchful waiting with low-dose cytarabine and single doses of mitoxantrone as needed, followed by sequential conditioning and alloHCT.
The results after 4 years of follow-up showed no differences in either leukemia-free survival or overall survival between patients who underwent additional chemotherapy with the remission-induction strategy and those who went straight to transplant, reported Johannes Schetelig, MD, MSc, from the Clinical Trials Unit at DKMS, Dresden, Germany.
“We expected non-inferiority – this was what we tested, and of course this was based on an assumption that we could get close or even somewhat better with respect to the primary endpoint, disease-free survival, after transplantation,” he said.
“What we did not expect is that the early success, [complete response] on day 56 after transplantation, also translates into equal long-term benefit, so this is what I was really astonished about,” Dr. Schetelig said at a press briefing prior to his presentation.
Less intensive approach
Dr. Schetelig explained that the rationale for the study was previous work by his group and others showing that alloHCT in patients with residual aplasia after first induction is feasible, with favorable outcomes, compared with standard of care. Additionally, the impetus for the research was evidence that sequential conditioning based on high-dose cytarabine or melphalan plus reduced-intensity conditioning and alloHCT resulted in long-term control for relapsed or refractory AML.
Dr. Schetelig also gave details of the two treatment arms of the ASAP trial. The remission-inducing arm consisted of cytarabine (3 g/m2 for younger patients or 1 g/m2 for patients over age 60) twice daily on days 1-3 plus 10 mitoxantrone mg/m2 on days 3-5 and subsequent alloHCT. In the other group – disease control prior to sequential conditioning and alloHCT – watchful waiting was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease control.
Although, as Dr. Schetelig noted, the statistical goal of the study was to show non-inferiority of the disease control arm, this less intensive strategy exceeded expectations for meeting the primary endpoint of disease-free survival (DFS; a maintained complete response) by day 56 after alloHCT.
In an intention-to-treat and per-protocol analysis, the respective rates of DFS at 56 days in the disease control group were 83.5% and 84.1%. In comparison, the respective rates in the remission-induction group were 81% and 81.3%.
Further, after a median follow-up from randomization of 37 months, there were no differences in either leukemia-free survival or overall survival out to 4 years after DFS at day 56.
The disease-control strategy was also associated with significantly fewer adverse events grade 3 or greater (23% vs. 64%, P < .001), and fewer days in hospital prior to transplant (mean 19 vs. 42, P < .001). There were no significant differences between the trial arms in either deaths within 28 days of randomization or time to discharge from hospital (28 days in each arm).
“These data support sequential conditioning and alloHCT without prior remission-induction chemotherapy whenever a stem cell donor is readily available,” the researchers concluded.
“These results underline the importance of facilitating alloHCT as [the] most effective anti-leukemic therapy in patients with [relapsed or refractory] AML and stress the need for starting donor search at diagnosis,” they added.
The study was sponsored by DKMS gemeinnützige GmbH. Dr. Schetelig disclosed honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Sekkeres reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASH 2022
Oral SERD camizestrant prolongs PFS vs. fulvestrant in breast cancer
SAN ANTONIO – compared with the first-generation SERD fulvestrant Faslodex, in the SERENA-2 trial, shows a study recently presented at the San Antonio Breast Cancer Symposium.
Among 180 postmenopausal women with ER+/HER2– breast cancers that had recurred or progressed following at least one line of endocrine therapy, the median progression-free survival (PFS) after a median follow-up of 16.6-17.4 months was 7.2 months for patients treated at a 75-mg dose of camizestrant and 7.7 months for those treated at a 150-mg dose, compared with 3.7 months for patients who received fulvestrant, reported Mafalda Oliveira, MD, PhD, from Vall d’Hebron University Hospital in Barcelona.
Oral agent
Camizestrant is a next-generation oral SERD and pure estrogen receptor antagonist that was shown in the SERENA-1 trial to be safe and to have clinical activity against ER+ breast cancers.
SERENA-2 pitted camizestrant at doses of 75 mg, 150 mg, or 300 mg against standard-dose fulvestrant, although the 300-mg dose was dropped in a protocol amendment after 20 patients had been assigned to that arm. (Currently planned studies with camizestrant will be conducted with the 75-mg dose.)
The investigators enrolled women with ER+/HER2– advanced breast cancer who had not previously received fulvestrant or an oral SERD. Eligible patients were limited to no more than one prior line of endocrine and one prior line of chemotherapy for advanced breast cancers. The study included patients with both measurable and unmeasurable disease.
The median patient age was about 60 years. Approximately 59% of patients in each arm had either lung or liver metastases. Patients with recurrence in bone only comprised 14.9%-19.4%.
Mutations in ESR1, a gene associated with hormonal resistance, were detectable in 29.7%-47.9% of patients.
Better PFS
As noted before, the primary endpoint of investigator-assessed median PFS favored camizestrant in both the 75-mg arm (7.2 months) and the 150-mg arm (7.7 months), with respective adjusted hazard ratios for progression versus fulvestrant of 0.58 (P = .0124) and 0.67 (P = .0161).
Camizestrant at the 75-mg dose was also superior to fulvestrant among patients who had previously received a cyclin-dependent kinase 4/6 inhibitor, with median PFS of 5.5 months and 3.8 months for the 75-mg and 150-mg doses, respectively, compared with 2.1 months.
The adjusted HR for progression with camizestrant with the 75-mg dose was 0.49, with a 90% confidence interval indicating significance. The 150-mg dose was not significantly superior to fulvestrant, however.
Both camizestrant doses were also superior for prolonging PFS versus fulvestrant among patients with lung and/or liver metastases, with median PFS of 7.2 months, 5.6 months, and 2.0 months, respectively.
The experimental SERD also outperformed fulvestrant in an analysis looking at PFS by ESR1 mutational status and ER-driven disease. Among patients with ESR1 wild type, however, median PFS rates with camizestrant 75 mg and fulvestrant were the same (7.2 months).
The 24-week objective response rates were 15.7% in the 75-mg camizestrant arm, 20% in the 150-mg arm, and 11.8% in the fulvestrant arm. The respective clinical benefit rates, including all patients with responses or stable disease, were 47.3%, 49.3%, and 38.4%. The camizestrant clinical benefit rates did not differ significantly from those with fulvestrant, however.
Treatment-related adverse events of grade 3 or greater occurred in only five patients, and only two patients, both in the 75-mg camizestrant arm, discontinued therapy because of adverse events. There were no treatment-related deaths.
Adverse events that occurred only with camizestrant included photopsia (flashing lights or floaters in the field of vision) and sinus bradycardia.
Promising, but early
Carlos Artega, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, who was not involved in the study, said the data look promising in comparison with fulvestrant.
“There is a clear suggestion that this might be better,” he said. “[Camizestrant] seems to be better at reducing the titer in plasma of the ESR1 mutation, and there is very strong basic science that supports that.”
He noted that the study numbers were relatively small, however.
Dr. Arteaga was speaking at a media briefing held immediately prior to the presentation of the data in an oral abstract session.
Fabrice Andre, MD, from Gustave Roussy in Villejuif, France, the invited discussant for the oral session, noted that, in patients with ESR1 wild type, where fulvestrant shows some efficacy, camizestrant appears to be equally effective, and that the latter agent may be more synergistic with targeted therapies than fulvestrant.
Given high patient dropout rates with currently available SERDs, there is a need for SERDs used in the adjuvant setting that are effective at minimally bioactive doses for patients who are predicted to poorly adherent, Dr. Andre said.
The study was funded by AstraZeneca. Dr. Oliveira has received personal funding from AstraZeneca, Guardant Health, Roche, Merck Sharp & Dohme, Pfizer, Seagen, iTeos Therapeutics, Eisai, Novartis, Relay Therapeutics, and Gilead. Dr. Arteaga is a scientific adviser to AstraZeneca and others, and has received grant support from Pfizer Lilly and Takeda. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.
SAN ANTONIO – compared with the first-generation SERD fulvestrant Faslodex, in the SERENA-2 trial, shows a study recently presented at the San Antonio Breast Cancer Symposium.
Among 180 postmenopausal women with ER+/HER2– breast cancers that had recurred or progressed following at least one line of endocrine therapy, the median progression-free survival (PFS) after a median follow-up of 16.6-17.4 months was 7.2 months for patients treated at a 75-mg dose of camizestrant and 7.7 months for those treated at a 150-mg dose, compared with 3.7 months for patients who received fulvestrant, reported Mafalda Oliveira, MD, PhD, from Vall d’Hebron University Hospital in Barcelona.
Oral agent
Camizestrant is a next-generation oral SERD and pure estrogen receptor antagonist that was shown in the SERENA-1 trial to be safe and to have clinical activity against ER+ breast cancers.
SERENA-2 pitted camizestrant at doses of 75 mg, 150 mg, or 300 mg against standard-dose fulvestrant, although the 300-mg dose was dropped in a protocol amendment after 20 patients had been assigned to that arm. (Currently planned studies with camizestrant will be conducted with the 75-mg dose.)
The investigators enrolled women with ER+/HER2– advanced breast cancer who had not previously received fulvestrant or an oral SERD. Eligible patients were limited to no more than one prior line of endocrine and one prior line of chemotherapy for advanced breast cancers. The study included patients with both measurable and unmeasurable disease.
The median patient age was about 60 years. Approximately 59% of patients in each arm had either lung or liver metastases. Patients with recurrence in bone only comprised 14.9%-19.4%.
Mutations in ESR1, a gene associated with hormonal resistance, were detectable in 29.7%-47.9% of patients.
Better PFS
As noted before, the primary endpoint of investigator-assessed median PFS favored camizestrant in both the 75-mg arm (7.2 months) and the 150-mg arm (7.7 months), with respective adjusted hazard ratios for progression versus fulvestrant of 0.58 (P = .0124) and 0.67 (P = .0161).
Camizestrant at the 75-mg dose was also superior to fulvestrant among patients who had previously received a cyclin-dependent kinase 4/6 inhibitor, with median PFS of 5.5 months and 3.8 months for the 75-mg and 150-mg doses, respectively, compared with 2.1 months.
The adjusted HR for progression with camizestrant with the 75-mg dose was 0.49, with a 90% confidence interval indicating significance. The 150-mg dose was not significantly superior to fulvestrant, however.
Both camizestrant doses were also superior for prolonging PFS versus fulvestrant among patients with lung and/or liver metastases, with median PFS of 7.2 months, 5.6 months, and 2.0 months, respectively.
The experimental SERD also outperformed fulvestrant in an analysis looking at PFS by ESR1 mutational status and ER-driven disease. Among patients with ESR1 wild type, however, median PFS rates with camizestrant 75 mg and fulvestrant were the same (7.2 months).
The 24-week objective response rates were 15.7% in the 75-mg camizestrant arm, 20% in the 150-mg arm, and 11.8% in the fulvestrant arm. The respective clinical benefit rates, including all patients with responses or stable disease, were 47.3%, 49.3%, and 38.4%. The camizestrant clinical benefit rates did not differ significantly from those with fulvestrant, however.
Treatment-related adverse events of grade 3 or greater occurred in only five patients, and only two patients, both in the 75-mg camizestrant arm, discontinued therapy because of adverse events. There were no treatment-related deaths.
Adverse events that occurred only with camizestrant included photopsia (flashing lights or floaters in the field of vision) and sinus bradycardia.
Promising, but early
Carlos Artega, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, who was not involved in the study, said the data look promising in comparison with fulvestrant.
“There is a clear suggestion that this might be better,” he said. “[Camizestrant] seems to be better at reducing the titer in plasma of the ESR1 mutation, and there is very strong basic science that supports that.”
He noted that the study numbers were relatively small, however.
Dr. Arteaga was speaking at a media briefing held immediately prior to the presentation of the data in an oral abstract session.
Fabrice Andre, MD, from Gustave Roussy in Villejuif, France, the invited discussant for the oral session, noted that, in patients with ESR1 wild type, where fulvestrant shows some efficacy, camizestrant appears to be equally effective, and that the latter agent may be more synergistic with targeted therapies than fulvestrant.
Given high patient dropout rates with currently available SERDs, there is a need for SERDs used in the adjuvant setting that are effective at minimally bioactive doses for patients who are predicted to poorly adherent, Dr. Andre said.
The study was funded by AstraZeneca. Dr. Oliveira has received personal funding from AstraZeneca, Guardant Health, Roche, Merck Sharp & Dohme, Pfizer, Seagen, iTeos Therapeutics, Eisai, Novartis, Relay Therapeutics, and Gilead. Dr. Arteaga is a scientific adviser to AstraZeneca and others, and has received grant support from Pfizer Lilly and Takeda. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.
SAN ANTONIO – compared with the first-generation SERD fulvestrant Faslodex, in the SERENA-2 trial, shows a study recently presented at the San Antonio Breast Cancer Symposium.
Among 180 postmenopausal women with ER+/HER2– breast cancers that had recurred or progressed following at least one line of endocrine therapy, the median progression-free survival (PFS) after a median follow-up of 16.6-17.4 months was 7.2 months for patients treated at a 75-mg dose of camizestrant and 7.7 months for those treated at a 150-mg dose, compared with 3.7 months for patients who received fulvestrant, reported Mafalda Oliveira, MD, PhD, from Vall d’Hebron University Hospital in Barcelona.
Oral agent
Camizestrant is a next-generation oral SERD and pure estrogen receptor antagonist that was shown in the SERENA-1 trial to be safe and to have clinical activity against ER+ breast cancers.
SERENA-2 pitted camizestrant at doses of 75 mg, 150 mg, or 300 mg against standard-dose fulvestrant, although the 300-mg dose was dropped in a protocol amendment after 20 patients had been assigned to that arm. (Currently planned studies with camizestrant will be conducted with the 75-mg dose.)
The investigators enrolled women with ER+/HER2– advanced breast cancer who had not previously received fulvestrant or an oral SERD. Eligible patients were limited to no more than one prior line of endocrine and one prior line of chemotherapy for advanced breast cancers. The study included patients with both measurable and unmeasurable disease.
The median patient age was about 60 years. Approximately 59% of patients in each arm had either lung or liver metastases. Patients with recurrence in bone only comprised 14.9%-19.4%.
Mutations in ESR1, a gene associated with hormonal resistance, were detectable in 29.7%-47.9% of patients.
Better PFS
As noted before, the primary endpoint of investigator-assessed median PFS favored camizestrant in both the 75-mg arm (7.2 months) and the 150-mg arm (7.7 months), with respective adjusted hazard ratios for progression versus fulvestrant of 0.58 (P = .0124) and 0.67 (P = .0161).
Camizestrant at the 75-mg dose was also superior to fulvestrant among patients who had previously received a cyclin-dependent kinase 4/6 inhibitor, with median PFS of 5.5 months and 3.8 months for the 75-mg and 150-mg doses, respectively, compared with 2.1 months.
The adjusted HR for progression with camizestrant with the 75-mg dose was 0.49, with a 90% confidence interval indicating significance. The 150-mg dose was not significantly superior to fulvestrant, however.
Both camizestrant doses were also superior for prolonging PFS versus fulvestrant among patients with lung and/or liver metastases, with median PFS of 7.2 months, 5.6 months, and 2.0 months, respectively.
The experimental SERD also outperformed fulvestrant in an analysis looking at PFS by ESR1 mutational status and ER-driven disease. Among patients with ESR1 wild type, however, median PFS rates with camizestrant 75 mg and fulvestrant were the same (7.2 months).
The 24-week objective response rates were 15.7% in the 75-mg camizestrant arm, 20% in the 150-mg arm, and 11.8% in the fulvestrant arm. The respective clinical benefit rates, including all patients with responses or stable disease, were 47.3%, 49.3%, and 38.4%. The camizestrant clinical benefit rates did not differ significantly from those with fulvestrant, however.
Treatment-related adverse events of grade 3 or greater occurred in only five patients, and only two patients, both in the 75-mg camizestrant arm, discontinued therapy because of adverse events. There were no treatment-related deaths.
Adverse events that occurred only with camizestrant included photopsia (flashing lights or floaters in the field of vision) and sinus bradycardia.
Promising, but early
Carlos Artega, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, who was not involved in the study, said the data look promising in comparison with fulvestrant.
“There is a clear suggestion that this might be better,” he said. “[Camizestrant] seems to be better at reducing the titer in plasma of the ESR1 mutation, and there is very strong basic science that supports that.”
He noted that the study numbers were relatively small, however.
Dr. Arteaga was speaking at a media briefing held immediately prior to the presentation of the data in an oral abstract session.
Fabrice Andre, MD, from Gustave Roussy in Villejuif, France, the invited discussant for the oral session, noted that, in patients with ESR1 wild type, where fulvestrant shows some efficacy, camizestrant appears to be equally effective, and that the latter agent may be more synergistic with targeted therapies than fulvestrant.
Given high patient dropout rates with currently available SERDs, there is a need for SERDs used in the adjuvant setting that are effective at minimally bioactive doses for patients who are predicted to poorly adherent, Dr. Andre said.
The study was funded by AstraZeneca. Dr. Oliveira has received personal funding from AstraZeneca, Guardant Health, Roche, Merck Sharp & Dohme, Pfizer, Seagen, iTeos Therapeutics, Eisai, Novartis, Relay Therapeutics, and Gilead. Dr. Arteaga is a scientific adviser to AstraZeneca and others, and has received grant support from Pfizer Lilly and Takeda. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.
AT SABCS 2022
Chemotherapy meets its match against aggressive ER+/HER2– breast cancers
SAN ANTONIO – Results of a study being hailed as practice changing showed that, for pre- or perimenopausal women with aggressive hormone receptor-positive, HER2-negative (HR+/HER2–) untreated breast cancers,
That’s according to investigators of the phase 2 RIGHT Choice study who found that first-line ribociclib, combined with either letrozole or anastrozole plus goserelin, was associated with a doubling of progression-free survival (PFS), compared with the investigator’s choice of combination chemotherapy, reported Yen-Shen Lu, MD, from National Taiwan University Hospital in Taipei, at the San Antonio Breast Cancer Symposium.
“These results from RIGHT Choice have now shown that first-line ribociclib plus endocrine therapy should be considered the preferred treatment option for this patient population,” he said.
Chemo loses its luster
“This is not time first time that we’ve looked at a CDK4/6 inhibitor compared to chemotherapy, but this is the first time that we’ve seen it compared to a combination chemotherapy,” commented Virginia Kaklamani, MD, from University of Texas Health, San Antonio, who moderated a media briefing held prior to Dr. Lu’s presentation of the data in an oral abstract session.
“I think with this study we’re finding that chemotherapy, at least in the early stages of [estrogen receptor]–positive breast cancer, is probably not appropriate for our patients,” she said.
Chemotherapy is the current standard of care for patients with advanced breast cancers with aggressive disease features that can include rapidly progressive disease, high symptom burden, and/or life-threatening visceral crises requiring rapid control of disease, Dr. Lu said.
Compared with single-agent chemotherapy, combination chemotherapy, for those who can tolerate it, is associated with higher overall response rates and longer PFS.
Although ribociclib plus endocrine therapy has been shown to offer significant PFS and overall survival (OS) benefits, compared with endocrine therapy alone, there have not been any head-to-head studies pitting these agents against combination chemotherapy.
Study details
To rectify this, Dr. Lu and colleagues enrolled 222 pre- or perimenopausal women with HR+/HER2– advanced breast cancers with aggressive features who had not yet received systemic therapy for advanced breast cancer.
After stratification for the presence or absence of liver metastases and by length of disease-free interval (time from complete resection of a primary tumor to documented recurrence), the patients were randomly assigned to receive either ribociclib 600 mg 3 weeks on, 1 week off) plus letrozole or anastrozole and goserelin, or the investigators choice of either docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine.
After a median follow-up of 24.1 months at the time of data cutoff in April 2022, median PFS, the primary endpoint, was 24 months in the ribociclib plus endocrine therapy arm versus 12.3 months in the chemotherapy arm.
This translated into a hazard ratio for progression on ribociclib plus endocrine therapy of 0.54 (P = .0007).
The benefit for the ribociclib combination, compared with combination chemotherapy, was consistent across most patient subgroups, Dr. Lu said.
The median time to treatment failure was also longer with ribociclib, at 18.6 months versus 8.5 months, respectively, translating into a HR of 0.45 favoring ribociclib, with a statistically significant confidence interval.
Overall response rates were similar between the groups, at 65.2% with ribociclib versus 60% with chemotherapy. The respective clinical benefit rates (including complete and partial responses plus stable disease) were 80.4% versus 72.7%.
The time to response was similar between the treatment arms, an important consideration for patients with rapidly progressive disease, Dr. Lu noted.
Adverse events that occurred more frequently with ribociclib were neutropenia and leukopenia. Events more common with chemotherapy included anemia, liver enzyme elevations, nausea, vomiting, diarrhea, alopecia, fatigue, and palmar-plantar erythrodysesthesia.
Confirmation
“These data are just confirming what we’ve already known, and that is that with ER-positive, HER2-negative breast cancer where you have metastatic disease and more aggressive characteristics, treating with a CDK4/6 inhibitor and endocrine therapy leads to high response rates,” breast cancer specialist Matthew P. Goetz, MD, from the Mayo Clinic in Rochester, Minn., said in an interview. Dr. Goetz was not involved in the study.
“What was surprising to me was the fact that the response rates with chemotherapy were not higher,” he said. “We sometime think that the more chemotherapy, the higher the response rates. It was nice to see a direct comparison with chemotherapy, and really to see that giving a target therapy actually led to very, very good results. That tells us that there should be very few situations where we would be prescribing chemotherapy over CDK4/6 inhibitor–based therapies.”
The study was funded by Novartis Pharma. Dr. Lu disclosed personal funding from Novartis and others. Dr. Goetz disclosed grants and other supports for work with the development of abemaciclib and palbociclib, and consulting for Pfizer and others. Dr. Kaklamani disclosed speakers bureau activity for Novartis and others, research support from Eisai, and consulting for other companies.
SAN ANTONIO – Results of a study being hailed as practice changing showed that, for pre- or perimenopausal women with aggressive hormone receptor-positive, HER2-negative (HR+/HER2–) untreated breast cancers,
That’s according to investigators of the phase 2 RIGHT Choice study who found that first-line ribociclib, combined with either letrozole or anastrozole plus goserelin, was associated with a doubling of progression-free survival (PFS), compared with the investigator’s choice of combination chemotherapy, reported Yen-Shen Lu, MD, from National Taiwan University Hospital in Taipei, at the San Antonio Breast Cancer Symposium.
“These results from RIGHT Choice have now shown that first-line ribociclib plus endocrine therapy should be considered the preferred treatment option for this patient population,” he said.
Chemo loses its luster
“This is not time first time that we’ve looked at a CDK4/6 inhibitor compared to chemotherapy, but this is the first time that we’ve seen it compared to a combination chemotherapy,” commented Virginia Kaklamani, MD, from University of Texas Health, San Antonio, who moderated a media briefing held prior to Dr. Lu’s presentation of the data in an oral abstract session.
“I think with this study we’re finding that chemotherapy, at least in the early stages of [estrogen receptor]–positive breast cancer, is probably not appropriate for our patients,” she said.
Chemotherapy is the current standard of care for patients with advanced breast cancers with aggressive disease features that can include rapidly progressive disease, high symptom burden, and/or life-threatening visceral crises requiring rapid control of disease, Dr. Lu said.
Compared with single-agent chemotherapy, combination chemotherapy, for those who can tolerate it, is associated with higher overall response rates and longer PFS.
Although ribociclib plus endocrine therapy has been shown to offer significant PFS and overall survival (OS) benefits, compared with endocrine therapy alone, there have not been any head-to-head studies pitting these agents against combination chemotherapy.
Study details
To rectify this, Dr. Lu and colleagues enrolled 222 pre- or perimenopausal women with HR+/HER2– advanced breast cancers with aggressive features who had not yet received systemic therapy for advanced breast cancer.
After stratification for the presence or absence of liver metastases and by length of disease-free interval (time from complete resection of a primary tumor to documented recurrence), the patients were randomly assigned to receive either ribociclib 600 mg 3 weeks on, 1 week off) plus letrozole or anastrozole and goserelin, or the investigators choice of either docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine.
After a median follow-up of 24.1 months at the time of data cutoff in April 2022, median PFS, the primary endpoint, was 24 months in the ribociclib plus endocrine therapy arm versus 12.3 months in the chemotherapy arm.
This translated into a hazard ratio for progression on ribociclib plus endocrine therapy of 0.54 (P = .0007).
The benefit for the ribociclib combination, compared with combination chemotherapy, was consistent across most patient subgroups, Dr. Lu said.
The median time to treatment failure was also longer with ribociclib, at 18.6 months versus 8.5 months, respectively, translating into a HR of 0.45 favoring ribociclib, with a statistically significant confidence interval.
Overall response rates were similar between the groups, at 65.2% with ribociclib versus 60% with chemotherapy. The respective clinical benefit rates (including complete and partial responses plus stable disease) were 80.4% versus 72.7%.
The time to response was similar between the treatment arms, an important consideration for patients with rapidly progressive disease, Dr. Lu noted.
Adverse events that occurred more frequently with ribociclib were neutropenia and leukopenia. Events more common with chemotherapy included anemia, liver enzyme elevations, nausea, vomiting, diarrhea, alopecia, fatigue, and palmar-plantar erythrodysesthesia.
Confirmation
“These data are just confirming what we’ve already known, and that is that with ER-positive, HER2-negative breast cancer where you have metastatic disease and more aggressive characteristics, treating with a CDK4/6 inhibitor and endocrine therapy leads to high response rates,” breast cancer specialist Matthew P. Goetz, MD, from the Mayo Clinic in Rochester, Minn., said in an interview. Dr. Goetz was not involved in the study.
“What was surprising to me was the fact that the response rates with chemotherapy were not higher,” he said. “We sometime think that the more chemotherapy, the higher the response rates. It was nice to see a direct comparison with chemotherapy, and really to see that giving a target therapy actually led to very, very good results. That tells us that there should be very few situations where we would be prescribing chemotherapy over CDK4/6 inhibitor–based therapies.”
The study was funded by Novartis Pharma. Dr. Lu disclosed personal funding from Novartis and others. Dr. Goetz disclosed grants and other supports for work with the development of abemaciclib and palbociclib, and consulting for Pfizer and others. Dr. Kaklamani disclosed speakers bureau activity for Novartis and others, research support from Eisai, and consulting for other companies.
SAN ANTONIO – Results of a study being hailed as practice changing showed that, for pre- or perimenopausal women with aggressive hormone receptor-positive, HER2-negative (HR+/HER2–) untreated breast cancers,
That’s according to investigators of the phase 2 RIGHT Choice study who found that first-line ribociclib, combined with either letrozole or anastrozole plus goserelin, was associated with a doubling of progression-free survival (PFS), compared with the investigator’s choice of combination chemotherapy, reported Yen-Shen Lu, MD, from National Taiwan University Hospital in Taipei, at the San Antonio Breast Cancer Symposium.
“These results from RIGHT Choice have now shown that first-line ribociclib plus endocrine therapy should be considered the preferred treatment option for this patient population,” he said.
Chemo loses its luster
“This is not time first time that we’ve looked at a CDK4/6 inhibitor compared to chemotherapy, but this is the first time that we’ve seen it compared to a combination chemotherapy,” commented Virginia Kaklamani, MD, from University of Texas Health, San Antonio, who moderated a media briefing held prior to Dr. Lu’s presentation of the data in an oral abstract session.
“I think with this study we’re finding that chemotherapy, at least in the early stages of [estrogen receptor]–positive breast cancer, is probably not appropriate for our patients,” she said.
Chemotherapy is the current standard of care for patients with advanced breast cancers with aggressive disease features that can include rapidly progressive disease, high symptom burden, and/or life-threatening visceral crises requiring rapid control of disease, Dr. Lu said.
Compared with single-agent chemotherapy, combination chemotherapy, for those who can tolerate it, is associated with higher overall response rates and longer PFS.
Although ribociclib plus endocrine therapy has been shown to offer significant PFS and overall survival (OS) benefits, compared with endocrine therapy alone, there have not been any head-to-head studies pitting these agents against combination chemotherapy.
Study details
To rectify this, Dr. Lu and colleagues enrolled 222 pre- or perimenopausal women with HR+/HER2– advanced breast cancers with aggressive features who had not yet received systemic therapy for advanced breast cancer.
After stratification for the presence or absence of liver metastases and by length of disease-free interval (time from complete resection of a primary tumor to documented recurrence), the patients were randomly assigned to receive either ribociclib 600 mg 3 weeks on, 1 week off) plus letrozole or anastrozole and goserelin, or the investigators choice of either docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine.
After a median follow-up of 24.1 months at the time of data cutoff in April 2022, median PFS, the primary endpoint, was 24 months in the ribociclib plus endocrine therapy arm versus 12.3 months in the chemotherapy arm.
This translated into a hazard ratio for progression on ribociclib plus endocrine therapy of 0.54 (P = .0007).
The benefit for the ribociclib combination, compared with combination chemotherapy, was consistent across most patient subgroups, Dr. Lu said.
The median time to treatment failure was also longer with ribociclib, at 18.6 months versus 8.5 months, respectively, translating into a HR of 0.45 favoring ribociclib, with a statistically significant confidence interval.
Overall response rates were similar between the groups, at 65.2% with ribociclib versus 60% with chemotherapy. The respective clinical benefit rates (including complete and partial responses plus stable disease) were 80.4% versus 72.7%.
The time to response was similar between the treatment arms, an important consideration for patients with rapidly progressive disease, Dr. Lu noted.
Adverse events that occurred more frequently with ribociclib were neutropenia and leukopenia. Events more common with chemotherapy included anemia, liver enzyme elevations, nausea, vomiting, diarrhea, alopecia, fatigue, and palmar-plantar erythrodysesthesia.
Confirmation
“These data are just confirming what we’ve already known, and that is that with ER-positive, HER2-negative breast cancer where you have metastatic disease and more aggressive characteristics, treating with a CDK4/6 inhibitor and endocrine therapy leads to high response rates,” breast cancer specialist Matthew P. Goetz, MD, from the Mayo Clinic in Rochester, Minn., said in an interview. Dr. Goetz was not involved in the study.
“What was surprising to me was the fact that the response rates with chemotherapy were not higher,” he said. “We sometime think that the more chemotherapy, the higher the response rates. It was nice to see a direct comparison with chemotherapy, and really to see that giving a target therapy actually led to very, very good results. That tells us that there should be very few situations where we would be prescribing chemotherapy over CDK4/6 inhibitor–based therapies.”
The study was funded by Novartis Pharma. Dr. Lu disclosed personal funding from Novartis and others. Dr. Goetz disclosed grants and other supports for work with the development of abemaciclib and palbociclib, and consulting for Pfizer and others. Dr. Kaklamani disclosed speakers bureau activity for Novartis and others, research support from Eisai, and consulting for other companies.
AT SABCS 2022
Potential cause of worse outcomes among Black breast cancer patients found
SAN ANTONIO – compared with White women, a discovery that may at least partially explain racial differences in breast cancer outcomes, investigators say.
The finding, which comes from a retrospective study comparing differences in tumor microenvironment of metastasis (TMEM) “doorways” between Black and White women suggest that tumors in Black women may have a stronger prometastatic response to neoadjuvant chemotherapy than tumors in White women, reported Maja H. Oktay, MD, PhD, of Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, New York, at the San Antonio Breast Cancer Symposium.
“Looking forward ... we propose to use TMEM doorway density as a prognostic marker for distant recurrence-free survival as a marker of dissemination, and also as a predictive marker of response to drugs that can block TMEM doorways,” she said at a briefing held prior to the presentation of data in an oral abstract session.
Entry points
As their name implies, TMEM doorways are transient entry points or portals that allow cancer cells to disseminate to distant sites. TMEM doorways are composed of tumor cells, macrophages, and endothelial cells that come into direct contact and together create temporary vascular openings that allow tumor cells to cross cell walls into circulation, where they can then hitch a ride and travel to distant organ sites.
Previous studies have shown that TMEM doorway density is a prognostic marker of metastasis in breast cancer patients treated with adjuvant chemotherapy. And as Dr. Oktay and colleagues showed in the current study, TMEM doorway density, as measured by a TMEM doorway score, is a prognostic marker for distant metastatic recurrence of ER+/HER2– breast cancer following neoadjuvant chemotherapy.
They also showed that neoadjuvant chemotherapy may increase the TMEM doorway score and lead to a pro–metastatic tumor microenvironment in some women.
Doorway scores
The investigators measured TMEM doorway scores from residual breast cancers in women who had undergone standard neoadjuvant chemotherapy. The cohort consisted of 96 Black women, 43 of whom had ER+/HER2– breast cancer and 37 of whom had triple-negative breast cancer (TNBC), and 87 White women, 50 with ER+/HER2– cancer and 22 with TNBC. The remaining patients had other breast cancer subtypes.
They found that TNBCs had higher TMEM doorway density score and higher macrophage density scores, which may explain why patients with TNBC often have early recurrence of disease.
They also found that, compared with White patients, Black patients with ER+/HER2– tumors, but not TNBC tumors, had higher TMEM doorway density scores. Similarly, Black patients with ER+/HER– cancers, but not TNBC, had higher macrophage levels than White women, a finding that may explain racial disparity in ER+/HER2– disease, Dr. Oktay said.
For the entire cohort, patients with high TMEM doorway density scores had significantly worse distant recurrence–free survival than patients with intermediate or low scores (P = .008), and there was a trend toward worse DRFS among all patients with ER+/HER2– who were in the highest third of scores, but this did not quite reach statistical significance.
High versus low TMEM doorway density score was also an independent prognostic factor for worse outcomes among the entire cohort (P = .01).
There was no significant difference in TMEM density scores among patients with TNBC.
Neither high macrophage counts nor microvascular density alone were significantly associated with inferior DRFS. TMEM doorway score was the only factor significantly prognostic for worse outcomes among patients in the entire cohort.
Hypothesis needs further testing
Invited discussant Lori Pierce, MD, a radiation oncologist with Michigan Medicine, University of Michigan, Ann Arbor, said it’s unclear whether TMEM doorway density changed following neoadjuvant chemotherapy as there were no prechemotherapy scores available in this study.
“But I think the key part is that, if we think neoadjuvant chemotherapy promotes metastasis, then there should be an inferior outcome compared to adjuvant chemotherapy, but that’s not what we see. Well-powered randomized trials show equivalent outcomes with neoadjuvant chemotherapy as well as adjuvant,” she said.
She noted that a 2018 meta-analysis of individual patient data from 10 randomized trials comparing neoadjuvant with adjuvant chemotherapy in early breast cancer showed no differences in long-term distant recurrences, breast cancer–specific mortality, or all-cause mortality between the two modalities.
“While I think these data are very provocative, I certainly wouldn’t want Black women or any women who need neoadjuvant therapy to be discouraged because of these data. We need these data to be tested rigorously, so I look forward to the clinical trials that will test this question and can really give us more information about this very interesting hypothesis,” Dr. Pierce said.
The study was funded by the National Institutes of Health, New York State Department of Health Peter T. Rowley Breast Cancer Scientific Research Projects, Helen & Irving Spatz Family Foundation, Evelyn Gruss Lipper Charitable Foundation, and the Gruss-Lipper Biophotonics Center and the integrated imaging program at the Albert Einstein College of Medicine. Dr. Oktay reported no conflicts of interests.
SAN ANTONIO – compared with White women, a discovery that may at least partially explain racial differences in breast cancer outcomes, investigators say.
The finding, which comes from a retrospective study comparing differences in tumor microenvironment of metastasis (TMEM) “doorways” between Black and White women suggest that tumors in Black women may have a stronger prometastatic response to neoadjuvant chemotherapy than tumors in White women, reported Maja H. Oktay, MD, PhD, of Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, New York, at the San Antonio Breast Cancer Symposium.
“Looking forward ... we propose to use TMEM doorway density as a prognostic marker for distant recurrence-free survival as a marker of dissemination, and also as a predictive marker of response to drugs that can block TMEM doorways,” she said at a briefing held prior to the presentation of data in an oral abstract session.
Entry points
As their name implies, TMEM doorways are transient entry points or portals that allow cancer cells to disseminate to distant sites. TMEM doorways are composed of tumor cells, macrophages, and endothelial cells that come into direct contact and together create temporary vascular openings that allow tumor cells to cross cell walls into circulation, where they can then hitch a ride and travel to distant organ sites.
Previous studies have shown that TMEM doorway density is a prognostic marker of metastasis in breast cancer patients treated with adjuvant chemotherapy. And as Dr. Oktay and colleagues showed in the current study, TMEM doorway density, as measured by a TMEM doorway score, is a prognostic marker for distant metastatic recurrence of ER+/HER2– breast cancer following neoadjuvant chemotherapy.
They also showed that neoadjuvant chemotherapy may increase the TMEM doorway score and lead to a pro–metastatic tumor microenvironment in some women.
Doorway scores
The investigators measured TMEM doorway scores from residual breast cancers in women who had undergone standard neoadjuvant chemotherapy. The cohort consisted of 96 Black women, 43 of whom had ER+/HER2– breast cancer and 37 of whom had triple-negative breast cancer (TNBC), and 87 White women, 50 with ER+/HER2– cancer and 22 with TNBC. The remaining patients had other breast cancer subtypes.
They found that TNBCs had higher TMEM doorway density score and higher macrophage density scores, which may explain why patients with TNBC often have early recurrence of disease.
They also found that, compared with White patients, Black patients with ER+/HER2– tumors, but not TNBC tumors, had higher TMEM doorway density scores. Similarly, Black patients with ER+/HER– cancers, but not TNBC, had higher macrophage levels than White women, a finding that may explain racial disparity in ER+/HER2– disease, Dr. Oktay said.
For the entire cohort, patients with high TMEM doorway density scores had significantly worse distant recurrence–free survival than patients with intermediate or low scores (P = .008), and there was a trend toward worse DRFS among all patients with ER+/HER2– who were in the highest third of scores, but this did not quite reach statistical significance.
High versus low TMEM doorway density score was also an independent prognostic factor for worse outcomes among the entire cohort (P = .01).
There was no significant difference in TMEM density scores among patients with TNBC.
Neither high macrophage counts nor microvascular density alone were significantly associated with inferior DRFS. TMEM doorway score was the only factor significantly prognostic for worse outcomes among patients in the entire cohort.
Hypothesis needs further testing
Invited discussant Lori Pierce, MD, a radiation oncologist with Michigan Medicine, University of Michigan, Ann Arbor, said it’s unclear whether TMEM doorway density changed following neoadjuvant chemotherapy as there were no prechemotherapy scores available in this study.
“But I think the key part is that, if we think neoadjuvant chemotherapy promotes metastasis, then there should be an inferior outcome compared to adjuvant chemotherapy, but that’s not what we see. Well-powered randomized trials show equivalent outcomes with neoadjuvant chemotherapy as well as adjuvant,” she said.
She noted that a 2018 meta-analysis of individual patient data from 10 randomized trials comparing neoadjuvant with adjuvant chemotherapy in early breast cancer showed no differences in long-term distant recurrences, breast cancer–specific mortality, or all-cause mortality between the two modalities.
“While I think these data are very provocative, I certainly wouldn’t want Black women or any women who need neoadjuvant therapy to be discouraged because of these data. We need these data to be tested rigorously, so I look forward to the clinical trials that will test this question and can really give us more information about this very interesting hypothesis,” Dr. Pierce said.
The study was funded by the National Institutes of Health, New York State Department of Health Peter T. Rowley Breast Cancer Scientific Research Projects, Helen & Irving Spatz Family Foundation, Evelyn Gruss Lipper Charitable Foundation, and the Gruss-Lipper Biophotonics Center and the integrated imaging program at the Albert Einstein College of Medicine. Dr. Oktay reported no conflicts of interests.
SAN ANTONIO – compared with White women, a discovery that may at least partially explain racial differences in breast cancer outcomes, investigators say.
The finding, which comes from a retrospective study comparing differences in tumor microenvironment of metastasis (TMEM) “doorways” between Black and White women suggest that tumors in Black women may have a stronger prometastatic response to neoadjuvant chemotherapy than tumors in White women, reported Maja H. Oktay, MD, PhD, of Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, New York, at the San Antonio Breast Cancer Symposium.
“Looking forward ... we propose to use TMEM doorway density as a prognostic marker for distant recurrence-free survival as a marker of dissemination, and also as a predictive marker of response to drugs that can block TMEM doorways,” she said at a briefing held prior to the presentation of data in an oral abstract session.
Entry points
As their name implies, TMEM doorways are transient entry points or portals that allow cancer cells to disseminate to distant sites. TMEM doorways are composed of tumor cells, macrophages, and endothelial cells that come into direct contact and together create temporary vascular openings that allow tumor cells to cross cell walls into circulation, where they can then hitch a ride and travel to distant organ sites.
Previous studies have shown that TMEM doorway density is a prognostic marker of metastasis in breast cancer patients treated with adjuvant chemotherapy. And as Dr. Oktay and colleagues showed in the current study, TMEM doorway density, as measured by a TMEM doorway score, is a prognostic marker for distant metastatic recurrence of ER+/HER2– breast cancer following neoadjuvant chemotherapy.
They also showed that neoadjuvant chemotherapy may increase the TMEM doorway score and lead to a pro–metastatic tumor microenvironment in some women.
Doorway scores
The investigators measured TMEM doorway scores from residual breast cancers in women who had undergone standard neoadjuvant chemotherapy. The cohort consisted of 96 Black women, 43 of whom had ER+/HER2– breast cancer and 37 of whom had triple-negative breast cancer (TNBC), and 87 White women, 50 with ER+/HER2– cancer and 22 with TNBC. The remaining patients had other breast cancer subtypes.
They found that TNBCs had higher TMEM doorway density score and higher macrophage density scores, which may explain why patients with TNBC often have early recurrence of disease.
They also found that, compared with White patients, Black patients with ER+/HER2– tumors, but not TNBC tumors, had higher TMEM doorway density scores. Similarly, Black patients with ER+/HER– cancers, but not TNBC, had higher macrophage levels than White women, a finding that may explain racial disparity in ER+/HER2– disease, Dr. Oktay said.
For the entire cohort, patients with high TMEM doorway density scores had significantly worse distant recurrence–free survival than patients with intermediate or low scores (P = .008), and there was a trend toward worse DRFS among all patients with ER+/HER2– who were in the highest third of scores, but this did not quite reach statistical significance.
High versus low TMEM doorway density score was also an independent prognostic factor for worse outcomes among the entire cohort (P = .01).
There was no significant difference in TMEM density scores among patients with TNBC.
Neither high macrophage counts nor microvascular density alone were significantly associated with inferior DRFS. TMEM doorway score was the only factor significantly prognostic for worse outcomes among patients in the entire cohort.
Hypothesis needs further testing
Invited discussant Lori Pierce, MD, a radiation oncologist with Michigan Medicine, University of Michigan, Ann Arbor, said it’s unclear whether TMEM doorway density changed following neoadjuvant chemotherapy as there were no prechemotherapy scores available in this study.
“But I think the key part is that, if we think neoadjuvant chemotherapy promotes metastasis, then there should be an inferior outcome compared to adjuvant chemotherapy, but that’s not what we see. Well-powered randomized trials show equivalent outcomes with neoadjuvant chemotherapy as well as adjuvant,” she said.
She noted that a 2018 meta-analysis of individual patient data from 10 randomized trials comparing neoadjuvant with adjuvant chemotherapy in early breast cancer showed no differences in long-term distant recurrences, breast cancer–specific mortality, or all-cause mortality between the two modalities.
“While I think these data are very provocative, I certainly wouldn’t want Black women or any women who need neoadjuvant therapy to be discouraged because of these data. We need these data to be tested rigorously, so I look forward to the clinical trials that will test this question and can really give us more information about this very interesting hypothesis,” Dr. Pierce said.
The study was funded by the National Institutes of Health, New York State Department of Health Peter T. Rowley Breast Cancer Scientific Research Projects, Helen & Irving Spatz Family Foundation, Evelyn Gruss Lipper Charitable Foundation, and the Gruss-Lipper Biophotonics Center and the integrated imaging program at the Albert Einstein College of Medicine. Dr. Oktay reported no conflicts of interests.
AT SABCS 2022
ASH 2022: New clinical data challenge long-held assumptions
The conference starts in New Orleans on Saturday, Dec. 10, , but a sample of what is to come was given last week in a preview media briefing, moderated by Mikkael A. Sekeres, MD, from the University of Miami. Dr. Sekeres, who recently authored a book on the FDA and how it regulates drug approvals, also serves as chair of the ASH Committee on Communications.
“Feeding Our Patients Gruel”
Dr. Sekeres expressed particular excitement about a multicenter randomized trial done in Italy. It showed that patients who have neutropenia after a stem cell transplant need not be required to eat a bland diet (Abstract 169).
“We for years have been essentially feeding our patients gruel in the hospital, and these are folks who have to be hospitalized for a stem cell transplant or in my case – I’m a leukemia specialist – for acute leukemia, for 4-6 weeks. The neutropenic diet consists of the blandest food you can imagine, with nothing to really spice it up.”
He noted that a neutropenic diet is so unpalatable that family members often sneak food into patient rooms, and “for years we’ve never seen adverse outcomes in any of those folks who instead of having mashed potatoes and oatmeal ate a corned beef sandwich for dinner.”
Now, the results from this trial “actually give us license to finally allow patients to eat whatever they want,” Dr. Sekeres said.
Practice-changing data
ASH experts pointed to two more presentations that are expected to change clinical practice. These include the finding that high-dose methotrexate does not reduce the risk for central nervous system relapse in children with acute lymphoblastic leukemia and lymphoblastic lymphoma (Abstract 214).
Another new study that seems to defy conventional wisdom showed that in adults with relapsed or refractory acute myeloid leukemia, intensive chemotherapy in an effort to achieve remission before a stem cell transplant did not result in better outcomes, compared with sequential conditioning and immediate transplant (Abstract 4).
Premature aging in HL survivors
ASH President Jane N. Winter, MD, from Northwestern University, Chicago, who also spoke at the briefing, highlighted a study that followed adult survivors of pediatric Hodgkin lymphoma. This study, from St. Jude Children’s Research Hospital in Memphis and the Wilmot Cancer Institute at the University of Rochester (N.Y), found that these adult survivors are at significantly elevated risk for epigenetic age acceleration accompanied by neurocognitive deficits when compared with controls (Abstract 902).
“This is an area that is very near and dear to my heart,” she said. “Much of my career has focused on reducing the therapy to reduce the long-term consequences of treatments. Pediatricians have been very much wedded to very intensive therapies and tend to incorporate radiation more commonly in their treatment strategies for children than we do in adults.”
Dr. Winter noted that, although clinicians focus primarily on the link between mediastinal radiation and long-term adverse events such as breast cancer, “now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated. Being able to screen for this impact of our treatment, and perhaps then develop strategies to deal with it or prevent it, will have very wide-ranging impact.”
Inherited thrombophilia and miscarriage
Cynthia E. Dunbar, MD, chief of the translational stem cell biology branch at the National Heart, Lung, and Blood Institute in Bethesda, Md., who also spoke at the briefing, said that one of the abstracts most important to her practice is a study concerning pregnancy. It showed that low-molecular-weight heparin did not prevent miscarriage in pregnant women with confirmed inherited thrombophilia who had two or more prior pregnancy losses, compared with standard surveillance (Abstract LBA-5).
“This is not my field at all; on the other hand, as a hematologist and a woman, that’s what my emails in the middle of the night and my panicked phone calls are often about. Once somebody has one miscarriage, especially if they feel like they’re already over 30 and the clock is ticking, there’s a huge emphasis and a huge amount of pressure on obstetricians to basically work up for everything, kind of a shotgun [approach],” she said.
Those workups may reveal genetic mutations that are associated with mild elevations in risk for clotting. As a result, some pregnant women are put on anticoagulation therapy, which can cause complications for both pregnancy and delivery. These study findings don’t solve the problem of spontaneous pregnancy loss, but they at least rule out inherited thrombophilia as a preventable cause of miscarriages, Dr. Dunbar said.
Another potentially practice-changing abstract is a study showing that, in younger adults with mantle cell lymphoma, the addition of the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) to induction therapy and as maintenance with or without autologous stem cell transplant had strong efficacy and acceptable toxicity (Abstract 1).
“The results show that the ibrutinib-containing regimen without transplant is at least as good as the current standard of care with transplant.” Dr. Winter said. “Additional follow-up will be required to show definitively that an autotransplant is unnecessary if ibrutinib is included in this treatment regimen.”
A version of this article first appeared on Medscape.com.
The conference starts in New Orleans on Saturday, Dec. 10, , but a sample of what is to come was given last week in a preview media briefing, moderated by Mikkael A. Sekeres, MD, from the University of Miami. Dr. Sekeres, who recently authored a book on the FDA and how it regulates drug approvals, also serves as chair of the ASH Committee on Communications.
“Feeding Our Patients Gruel”
Dr. Sekeres expressed particular excitement about a multicenter randomized trial done in Italy. It showed that patients who have neutropenia after a stem cell transplant need not be required to eat a bland diet (Abstract 169).
“We for years have been essentially feeding our patients gruel in the hospital, and these are folks who have to be hospitalized for a stem cell transplant or in my case – I’m a leukemia specialist – for acute leukemia, for 4-6 weeks. The neutropenic diet consists of the blandest food you can imagine, with nothing to really spice it up.”
He noted that a neutropenic diet is so unpalatable that family members often sneak food into patient rooms, and “for years we’ve never seen adverse outcomes in any of those folks who instead of having mashed potatoes and oatmeal ate a corned beef sandwich for dinner.”
Now, the results from this trial “actually give us license to finally allow patients to eat whatever they want,” Dr. Sekeres said.
Practice-changing data
ASH experts pointed to two more presentations that are expected to change clinical practice. These include the finding that high-dose methotrexate does not reduce the risk for central nervous system relapse in children with acute lymphoblastic leukemia and lymphoblastic lymphoma (Abstract 214).
Another new study that seems to defy conventional wisdom showed that in adults with relapsed or refractory acute myeloid leukemia, intensive chemotherapy in an effort to achieve remission before a stem cell transplant did not result in better outcomes, compared with sequential conditioning and immediate transplant (Abstract 4).
Premature aging in HL survivors
ASH President Jane N. Winter, MD, from Northwestern University, Chicago, who also spoke at the briefing, highlighted a study that followed adult survivors of pediatric Hodgkin lymphoma. This study, from St. Jude Children’s Research Hospital in Memphis and the Wilmot Cancer Institute at the University of Rochester (N.Y), found that these adult survivors are at significantly elevated risk for epigenetic age acceleration accompanied by neurocognitive deficits when compared with controls (Abstract 902).
“This is an area that is very near and dear to my heart,” she said. “Much of my career has focused on reducing the therapy to reduce the long-term consequences of treatments. Pediatricians have been very much wedded to very intensive therapies and tend to incorporate radiation more commonly in their treatment strategies for children than we do in adults.”
Dr. Winter noted that, although clinicians focus primarily on the link between mediastinal radiation and long-term adverse events such as breast cancer, “now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated. Being able to screen for this impact of our treatment, and perhaps then develop strategies to deal with it or prevent it, will have very wide-ranging impact.”
Inherited thrombophilia and miscarriage
Cynthia E. Dunbar, MD, chief of the translational stem cell biology branch at the National Heart, Lung, and Blood Institute in Bethesda, Md., who also spoke at the briefing, said that one of the abstracts most important to her practice is a study concerning pregnancy. It showed that low-molecular-weight heparin did not prevent miscarriage in pregnant women with confirmed inherited thrombophilia who had two or more prior pregnancy losses, compared with standard surveillance (Abstract LBA-5).
“This is not my field at all; on the other hand, as a hematologist and a woman, that’s what my emails in the middle of the night and my panicked phone calls are often about. Once somebody has one miscarriage, especially if they feel like they’re already over 30 and the clock is ticking, there’s a huge emphasis and a huge amount of pressure on obstetricians to basically work up for everything, kind of a shotgun [approach],” she said.
Those workups may reveal genetic mutations that are associated with mild elevations in risk for clotting. As a result, some pregnant women are put on anticoagulation therapy, which can cause complications for both pregnancy and delivery. These study findings don’t solve the problem of spontaneous pregnancy loss, but they at least rule out inherited thrombophilia as a preventable cause of miscarriages, Dr. Dunbar said.
Another potentially practice-changing abstract is a study showing that, in younger adults with mantle cell lymphoma, the addition of the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) to induction therapy and as maintenance with or without autologous stem cell transplant had strong efficacy and acceptable toxicity (Abstract 1).
“The results show that the ibrutinib-containing regimen without transplant is at least as good as the current standard of care with transplant.” Dr. Winter said. “Additional follow-up will be required to show definitively that an autotransplant is unnecessary if ibrutinib is included in this treatment regimen.”
A version of this article first appeared on Medscape.com.
The conference starts in New Orleans on Saturday, Dec. 10, , but a sample of what is to come was given last week in a preview media briefing, moderated by Mikkael A. Sekeres, MD, from the University of Miami. Dr. Sekeres, who recently authored a book on the FDA and how it regulates drug approvals, also serves as chair of the ASH Committee on Communications.
“Feeding Our Patients Gruel”
Dr. Sekeres expressed particular excitement about a multicenter randomized trial done in Italy. It showed that patients who have neutropenia after a stem cell transplant need not be required to eat a bland diet (Abstract 169).
“We for years have been essentially feeding our patients gruel in the hospital, and these are folks who have to be hospitalized for a stem cell transplant or in my case – I’m a leukemia specialist – for acute leukemia, for 4-6 weeks. The neutropenic diet consists of the blandest food you can imagine, with nothing to really spice it up.”
He noted that a neutropenic diet is so unpalatable that family members often sneak food into patient rooms, and “for years we’ve never seen adverse outcomes in any of those folks who instead of having mashed potatoes and oatmeal ate a corned beef sandwich for dinner.”
Now, the results from this trial “actually give us license to finally allow patients to eat whatever they want,” Dr. Sekeres said.
Practice-changing data
ASH experts pointed to two more presentations that are expected to change clinical practice. These include the finding that high-dose methotrexate does not reduce the risk for central nervous system relapse in children with acute lymphoblastic leukemia and lymphoblastic lymphoma (Abstract 214).
Another new study that seems to defy conventional wisdom showed that in adults with relapsed or refractory acute myeloid leukemia, intensive chemotherapy in an effort to achieve remission before a stem cell transplant did not result in better outcomes, compared with sequential conditioning and immediate transplant (Abstract 4).
Premature aging in HL survivors
ASH President Jane N. Winter, MD, from Northwestern University, Chicago, who also spoke at the briefing, highlighted a study that followed adult survivors of pediatric Hodgkin lymphoma. This study, from St. Jude Children’s Research Hospital in Memphis and the Wilmot Cancer Institute at the University of Rochester (N.Y), found that these adult survivors are at significantly elevated risk for epigenetic age acceleration accompanied by neurocognitive deficits when compared with controls (Abstract 902).
“This is an area that is very near and dear to my heart,” she said. “Much of my career has focused on reducing the therapy to reduce the long-term consequences of treatments. Pediatricians have been very much wedded to very intensive therapies and tend to incorporate radiation more commonly in their treatment strategies for children than we do in adults.”
Dr. Winter noted that, although clinicians focus primarily on the link between mediastinal radiation and long-term adverse events such as breast cancer, “now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated. Being able to screen for this impact of our treatment, and perhaps then develop strategies to deal with it or prevent it, will have very wide-ranging impact.”
Inherited thrombophilia and miscarriage
Cynthia E. Dunbar, MD, chief of the translational stem cell biology branch at the National Heart, Lung, and Blood Institute in Bethesda, Md., who also spoke at the briefing, said that one of the abstracts most important to her practice is a study concerning pregnancy. It showed that low-molecular-weight heparin did not prevent miscarriage in pregnant women with confirmed inherited thrombophilia who had two or more prior pregnancy losses, compared with standard surveillance (Abstract LBA-5).
“This is not my field at all; on the other hand, as a hematologist and a woman, that’s what my emails in the middle of the night and my panicked phone calls are often about. Once somebody has one miscarriage, especially if they feel like they’re already over 30 and the clock is ticking, there’s a huge emphasis and a huge amount of pressure on obstetricians to basically work up for everything, kind of a shotgun [approach],” she said.
Those workups may reveal genetic mutations that are associated with mild elevations in risk for clotting. As a result, some pregnant women are put on anticoagulation therapy, which can cause complications for both pregnancy and delivery. These study findings don’t solve the problem of spontaneous pregnancy loss, but they at least rule out inherited thrombophilia as a preventable cause of miscarriages, Dr. Dunbar said.
Another potentially practice-changing abstract is a study showing that, in younger adults with mantle cell lymphoma, the addition of the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) to induction therapy and as maintenance with or without autologous stem cell transplant had strong efficacy and acceptable toxicity (Abstract 1).
“The results show that the ibrutinib-containing regimen without transplant is at least as good as the current standard of care with transplant.” Dr. Winter said. “Additional follow-up will be required to show definitively that an autotransplant is unnecessary if ibrutinib is included in this treatment regimen.”
A version of this article first appeared on Medscape.com.
FROM ASH 2022
Poor NAFLD outcomes with increased VCTE-measured liver stiffness
according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.
Although previous retrospective studies have suggested that increased liver stiffness, as measured by VCTE (FibroScan), is associated with increases in liver-related events, there is a paucity of prospective data, reported Samer Gawrieh, MD, from Indiana University, Carmel and Indianapolis. VCTE is a noninvasive measure of cirrhosis progression.
In their prospective cohort study of patients representing the entire spectrum of NAFLD, the progression to LSM-defined cirrhosis was independently associated with the risk for a composite clinical outcome of death, decompensation, hepatocellular carcinoma, or a Model for End Stage Liver Disease (MELD) score of greater than 15, he said.
Their findings show that “progression to LSM-defined cirrhosis by VCTE is strongly associated with poor clinical outcomes,” Dr. Gawrieh said.
Study findings
Investigators looked at prospective data on 894 patients with biopsy-proven NAFLD in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network database. The sample included patients with a minimum of two LSM readings taken from 2014 through 2022.
They defined LSM-defined cirrhosis as reaching LSM of greater than 14.9 kPa (90% specificity cutoff) among patients without cirrhosis on the baseline VCTE (a 90% sensitivity cutoff of LSM less than 12.1 kPa).
They also performed a histology-based subanalysis, including data only from those patients who had LSM within 6 months of a liver biopsy.
The median patient age was 60 years, 37% were male, and 80.9% were White and 11.5% were Hispanic/Latino. The median body mass index (BMI) was 32.
Out of all the patients, 119 (13.3%) had progression to LSM-defined cirrhosis.
At a median follow-up of 3.69 years for the 775 patients without LSM progression, 79 (10.2%) had one or more of the events in the composite clinical outcome.
In contrast, after a median 5.48 years of follow-up, 31 of the 119 patients with progression (26.1%) had one or more of the composite events (P < .0001).
The median rates of progression to LSM-defined cirrhosis in the overall cohort were 2% at 1 year, 11% at 3 years, and 16% at 5 years.
Researchers found a correlation between progression to LSM-defined cirrhosis and baseline histological fibrosis stage on biopsy, with a rate of 7% among those with no baseline fibrosis, 9% each for patients with stage I A-C or stage II fibrosis, 24% of those with baseline bridging fibrosis, and 25% of those with baseline cirrhosis.
A comparison of the time to a composite clinical outcome event between patients with progression to LSM-defined cirrhosis and those without progression showed that LSM-defined progression was associated with near doubling in risk, with a hazard ratio of 1.84 (P = .0039).
In a multivariate Cox regression analysis controlling for age, sex, race, BMI, diabetes status, and baseline LSM, only LSM-defined progression (HR, 1.93; P < .01) and age (HR, 1.03; P < .01) were significant predictors.
Dr. Gawrieh noted that while age was a statistically significant factor, it was only weakly associated.
“These data suggest that development of cirrhosis LSM criteria is a promising surrogate for clinical outcomes in patients with NAFLD,” Dr. Gawrieh concluded.
Progression definition questioned
Following the presentation, Nezam Afdhal, MD, chief of the division of gastroenterology, hepatology, and nutrition at Beth Israel Deaconess Hospital in Boston, questioned how 25% of patients who had biopsy-proven cirrhosis could progress to LSM-defined cirrhosis.
Dr. Gawrieh said that, according to inclusion criteria, the patients could not have LSM-defined cirrhosis with the sensitivity cutoff of 12.1 kPa, and that of the 10 patients with baseline cirrhosis in the cohort, all had LSM of less than 12.1 kPa. However, he admitted that because those 10 patients were technically not progressors to cirrhosis, they should have been removed from the analysis for clinical outcomes.
Mark Hartman, MD, a clinical researcher at Eli Lilly and Company in Indianapolis, said the study is valuable but noted that those patients who progressed tended to have higher LSM at baseline as well as a higher [fibrosis-4 score].
Dr. Gawrieh added that the investigators are exploring variables that might explain progression to cirrhosis among patients without high baseline liver stiffness, such as alcohol use or drug-induced liver injury.
The study was supported by the National Institutes of Health and the NASH Clinical Research Network institutions. Dr. Gawrieh disclosed research grants from NIH, Zydus, Viking, and Sonic Incytes, and consulting for TransMedics and Pfizer. Dr. Afdhal and Dr. Hartman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.
Although previous retrospective studies have suggested that increased liver stiffness, as measured by VCTE (FibroScan), is associated with increases in liver-related events, there is a paucity of prospective data, reported Samer Gawrieh, MD, from Indiana University, Carmel and Indianapolis. VCTE is a noninvasive measure of cirrhosis progression.
In their prospective cohort study of patients representing the entire spectrum of NAFLD, the progression to LSM-defined cirrhosis was independently associated with the risk for a composite clinical outcome of death, decompensation, hepatocellular carcinoma, or a Model for End Stage Liver Disease (MELD) score of greater than 15, he said.
Their findings show that “progression to LSM-defined cirrhosis by VCTE is strongly associated with poor clinical outcomes,” Dr. Gawrieh said.
Study findings
Investigators looked at prospective data on 894 patients with biopsy-proven NAFLD in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network database. The sample included patients with a minimum of two LSM readings taken from 2014 through 2022.
They defined LSM-defined cirrhosis as reaching LSM of greater than 14.9 kPa (90% specificity cutoff) among patients without cirrhosis on the baseline VCTE (a 90% sensitivity cutoff of LSM less than 12.1 kPa).
They also performed a histology-based subanalysis, including data only from those patients who had LSM within 6 months of a liver biopsy.
The median patient age was 60 years, 37% were male, and 80.9% were White and 11.5% were Hispanic/Latino. The median body mass index (BMI) was 32.
Out of all the patients, 119 (13.3%) had progression to LSM-defined cirrhosis.
At a median follow-up of 3.69 years for the 775 patients without LSM progression, 79 (10.2%) had one or more of the events in the composite clinical outcome.
In contrast, after a median 5.48 years of follow-up, 31 of the 119 patients with progression (26.1%) had one or more of the composite events (P < .0001).
The median rates of progression to LSM-defined cirrhosis in the overall cohort were 2% at 1 year, 11% at 3 years, and 16% at 5 years.
Researchers found a correlation between progression to LSM-defined cirrhosis and baseline histological fibrosis stage on biopsy, with a rate of 7% among those with no baseline fibrosis, 9% each for patients with stage I A-C or stage II fibrosis, 24% of those with baseline bridging fibrosis, and 25% of those with baseline cirrhosis.
A comparison of the time to a composite clinical outcome event between patients with progression to LSM-defined cirrhosis and those without progression showed that LSM-defined progression was associated with near doubling in risk, with a hazard ratio of 1.84 (P = .0039).
In a multivariate Cox regression analysis controlling for age, sex, race, BMI, diabetes status, and baseline LSM, only LSM-defined progression (HR, 1.93; P < .01) and age (HR, 1.03; P < .01) were significant predictors.
Dr. Gawrieh noted that while age was a statistically significant factor, it was only weakly associated.
“These data suggest that development of cirrhosis LSM criteria is a promising surrogate for clinical outcomes in patients with NAFLD,” Dr. Gawrieh concluded.
Progression definition questioned
Following the presentation, Nezam Afdhal, MD, chief of the division of gastroenterology, hepatology, and nutrition at Beth Israel Deaconess Hospital in Boston, questioned how 25% of patients who had biopsy-proven cirrhosis could progress to LSM-defined cirrhosis.
Dr. Gawrieh said that, according to inclusion criteria, the patients could not have LSM-defined cirrhosis with the sensitivity cutoff of 12.1 kPa, and that of the 10 patients with baseline cirrhosis in the cohort, all had LSM of less than 12.1 kPa. However, he admitted that because those 10 patients were technically not progressors to cirrhosis, they should have been removed from the analysis for clinical outcomes.
Mark Hartman, MD, a clinical researcher at Eli Lilly and Company in Indianapolis, said the study is valuable but noted that those patients who progressed tended to have higher LSM at baseline as well as a higher [fibrosis-4 score].
Dr. Gawrieh added that the investigators are exploring variables that might explain progression to cirrhosis among patients without high baseline liver stiffness, such as alcohol use or drug-induced liver injury.
The study was supported by the National Institutes of Health and the NASH Clinical Research Network institutions. Dr. Gawrieh disclosed research grants from NIH, Zydus, Viking, and Sonic Incytes, and consulting for TransMedics and Pfizer. Dr. Afdhal and Dr. Hartman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.
Although previous retrospective studies have suggested that increased liver stiffness, as measured by VCTE (FibroScan), is associated with increases in liver-related events, there is a paucity of prospective data, reported Samer Gawrieh, MD, from Indiana University, Carmel and Indianapolis. VCTE is a noninvasive measure of cirrhosis progression.
In their prospective cohort study of patients representing the entire spectrum of NAFLD, the progression to LSM-defined cirrhosis was independently associated with the risk for a composite clinical outcome of death, decompensation, hepatocellular carcinoma, or a Model for End Stage Liver Disease (MELD) score of greater than 15, he said.
Their findings show that “progression to LSM-defined cirrhosis by VCTE is strongly associated with poor clinical outcomes,” Dr. Gawrieh said.
Study findings
Investigators looked at prospective data on 894 patients with biopsy-proven NAFLD in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network database. The sample included patients with a minimum of two LSM readings taken from 2014 through 2022.
They defined LSM-defined cirrhosis as reaching LSM of greater than 14.9 kPa (90% specificity cutoff) among patients without cirrhosis on the baseline VCTE (a 90% sensitivity cutoff of LSM less than 12.1 kPa).
They also performed a histology-based subanalysis, including data only from those patients who had LSM within 6 months of a liver biopsy.
The median patient age was 60 years, 37% were male, and 80.9% were White and 11.5% were Hispanic/Latino. The median body mass index (BMI) was 32.
Out of all the patients, 119 (13.3%) had progression to LSM-defined cirrhosis.
At a median follow-up of 3.69 years for the 775 patients without LSM progression, 79 (10.2%) had one or more of the events in the composite clinical outcome.
In contrast, after a median 5.48 years of follow-up, 31 of the 119 patients with progression (26.1%) had one or more of the composite events (P < .0001).
The median rates of progression to LSM-defined cirrhosis in the overall cohort were 2% at 1 year, 11% at 3 years, and 16% at 5 years.
Researchers found a correlation between progression to LSM-defined cirrhosis and baseline histological fibrosis stage on biopsy, with a rate of 7% among those with no baseline fibrosis, 9% each for patients with stage I A-C or stage II fibrosis, 24% of those with baseline bridging fibrosis, and 25% of those with baseline cirrhosis.
A comparison of the time to a composite clinical outcome event between patients with progression to LSM-defined cirrhosis and those without progression showed that LSM-defined progression was associated with near doubling in risk, with a hazard ratio of 1.84 (P = .0039).
In a multivariate Cox regression analysis controlling for age, sex, race, BMI, diabetes status, and baseline LSM, only LSM-defined progression (HR, 1.93; P < .01) and age (HR, 1.03; P < .01) were significant predictors.
Dr. Gawrieh noted that while age was a statistically significant factor, it was only weakly associated.
“These data suggest that development of cirrhosis LSM criteria is a promising surrogate for clinical outcomes in patients with NAFLD,” Dr. Gawrieh concluded.
Progression definition questioned
Following the presentation, Nezam Afdhal, MD, chief of the division of gastroenterology, hepatology, and nutrition at Beth Israel Deaconess Hospital in Boston, questioned how 25% of patients who had biopsy-proven cirrhosis could progress to LSM-defined cirrhosis.
Dr. Gawrieh said that, according to inclusion criteria, the patients could not have LSM-defined cirrhosis with the sensitivity cutoff of 12.1 kPa, and that of the 10 patients with baseline cirrhosis in the cohort, all had LSM of less than 12.1 kPa. However, he admitted that because those 10 patients were technically not progressors to cirrhosis, they should have been removed from the analysis for clinical outcomes.
Mark Hartman, MD, a clinical researcher at Eli Lilly and Company in Indianapolis, said the study is valuable but noted that those patients who progressed tended to have higher LSM at baseline as well as a higher [fibrosis-4 score].
Dr. Gawrieh added that the investigators are exploring variables that might explain progression to cirrhosis among patients without high baseline liver stiffness, such as alcohol use or drug-induced liver injury.
The study was supported by the National Institutes of Health and the NASH Clinical Research Network institutions. Dr. Gawrieh disclosed research grants from NIH, Zydus, Viking, and Sonic Incytes, and consulting for TransMedics and Pfizer. Dr. Afdhal and Dr. Hartman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LIVER MEETING
New ACR vaccination guideline: Take your best shot
PHILADELPHIA – The new American College of Rheumatology Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal Diseases (RMDs) emphasizes that both adult and pediatric patients should receive recommended vaccinations whenever possible.
But the guideline, currently in press, also offers recommendations about whether and when to withhold vaccines from patients with RMDs, such as avoiding the use of live attenuated virus vaccines in patients who are on immunosuppressive drug regimens, such as conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, or targeted synthetic DMARDs.
The new consensus guideline was formulated with the understanding that patients with RMDs are at increased risk for vaccine-preventable infections and more serious complications from infections, compared with the general population.
However, the guideline also acknowledges that the immunogenicity and safety of vaccines may differ among patients with RMDs, and that, depending on the patient age and disease state, individuals may benefit from modified vaccine indications, schedules, or modified medication schedules, said guideline panel member Anne Bass, MD, a rheumatologist at Hospital for Special Surgery and a professor of clinical medicine at Weill Cornell Medicine in New York, who presented the guideline with other panel members in a session outlining the recommendations at the annual meeting of the ACR.
“In addition, vaccination recommendations – since much of it relates to medications – really applies across diseases, and so the ACR felt that, rather than having vaccine recommendations tacked onto the end of treatment guidelines for each individual disease, that the topic should be discussed or tackled as a whole,” she said.
The guideline does not cover vaccinations in patients taking nonsteroidal anti-inflammatory drugs because this class of agents has minimal or no impact on antibody responses to vaccines. The guideline also does not address vaccinations against COVID-19 infections since the rapidly changing formulations would make the recommendations obsolete before they were even published, and because the U.S. Centers for Disease Control and Prevention provides up-to-date guidance on COVID-19 vaccinations in patients with compromised immunity, she said.
Guiding principles
The overarching principles of the guideline are to give indicated vaccines to patients with RMD whenever possible and that any decision to hold medications before or after vaccination consider the dosage used, RMD disease activity, and the patient’s risk for vaccine-preventable infection.
The guideline also states that “shared decision-making with patients is a key component of any vaccination strategy.”
Panel member Clifton O. Bingham III, MD, professor of medicine at Johns Hopkins University in Baltimore, outlined expanded indications for vaccinations against influenza, pneumococcal infections, varicella zoster virus (VZV) and human papillomavirus (HPV).
Influenza
The guideline conditionally recommends that patients with RMD aged 65 years and older and adults older than age 18 years who are on immunosuppressive medications should receive either high-dose or adjuvanted influenza vaccination rather than regular-dose vaccines.
“It’s recognized that the high-dose or adjuvanted vaccinations may be unavailable for patients when they’re seen in your practice,” Dr. Bingham said,” and we came out with two additional statements within the guidelines that said that any flu vaccine is recommended over no flu vaccinations, because we do know that responses are elicited, and a flu vaccination today is preferred over a flu vaccination delay.”
Pneumococcal vaccination
The panelists strongly recommended that patients with RMD younger than age 65 years who are on immunosuppressive medication receive pneumococcal vaccinations.
The ACR guideline is in sync with those issued by the CDC’s Advisory Committee on Immunization Practices, Dr. Bingham said. He urged audience members to visit a CDC-ACIP web page for more information on who should receive pneumococcal vaccination and when.
Recombinant varicella zoster
The recommendations strongly support that patients aged 18 years and over who are on immunosuppressive therapies should receive the recombinant VZV vaccine (Shingrix).
HPV
A less robust, conditional recommendation is for patients with RMDs who are between the ages of 26 and 45 years and on immunosuppressive medications to receive the HPV vaccine (if they have not already received the vaccine).
Non-live attenuated vaccines
Kevin Winthrop, MD, MPH, professor of infectious diseases and public health at Oregon Health & Science University, Portland, summarized the recommendations for managing immunosuppressive therapies in patients scheduled to receive vaccinations using killed or nonactive antigens.
“In influenza season, don’t pass up the opportunity to vaccinate,” he said, adding, “if you can wait on rituximab dosing, do it, and if you can’t, go ahead and vaccinate.”
The guidelines also recommend a 2-week methotrexate hold at the time of influenza vaccination; other DMARD dosing changes are likely not necessary at the time of vaccination, “but this is an area of fervent study, and I think in a year or two we’ll have more experimental hold data with regard to other DMARDs,” Dr. Winthrop said.
For other nonlive attenuated vaccinations, recommendations are similar to those for influenza, except with more flexible timing because these vaccinations are not seasonal. When and how to hold methotrexate is still up in the air, he said.
Additionally, it’s recommended that vaccinations be delayed in patients on high-dose prednisone until the drug is tapered to below 20 mg per day, and ideally to less than 10 mg per day, he said.
Live-attenuated vaccines
The guideline conditionally recommends deferring live-attenuated vaccines in patients on immunosuppressive drugs. It also recommends holding these medications “for an appropriate period before” vaccination and for 4 weeks afterward.
“Although the evidence around conventional synthetic DMARDs and TNF inhibitors is reassuring in terms of their safety at the time of live attenuated vaccines, as you can see the number of studies is quite small, and so the voting panel conditionally recommend against administering live-attenuated virus vaccines to patients who are on conventional synthetics, biologic, or targeted DMARDs,” Dr. Bass said.
In utero exposures
Most women with RMD who have recently given birth will consult their general pediatricians rather than rheumatologists for infant vaccinations, but pediatricians may not be aware of the affect that in utero exposures to biologic DMARDs can have on vaccine safety and immunogenicity in infants, Dr, Bass said.
“It’s important that you, as a provider, give your recommendations regarding infant rotavirus vaccination after in utero exposure to the pregnant rheumatic disease patient prior to delivery, and let that patient know that this is something that they should share with their pediatrician to be,” she advised audience members.
Getting the message out
In an interview, session moderator and guidelines panelist Lisa F. Imundo, MD, director of the center for adolescent rheumatology at Columbia University in New York, noted that rheumatologists don’t usually have the full schedule of pediatric vaccinations in stock and often leave the decisions about what to give – and when – to general practitioners.
“Pediatric rheumatologists sometimes will give patients flu vaccinations because they’re a high-risk population of patients, and we want to make sure that they’re getting it in a timely manner,” she said.
In addition, because pneumococcal polysaccharide vaccines are not indicated in the general pediatric population, children on biologic DMARDs who have completed their standard series of pneumococcal conjugate vaccines (PCV13 or PVC15) are recommended to get a 23-valent pneumococcal polysaccharide vaccine, Dr. Imundo said.
She also noted that communication between pediatric rheumatologists and general practitioners about vaccine recommendations can be challenging.
“It’s a huge issue, figuring out how we’re going to communicate all of this information to our pediatric colleagues,” she said. “With individual patients, we may sometimes remind doctors, especially with our younger patients who haven’t gotten their live vaccines, that they really shouldn’t get live vaccines until they’re off medication or until we arrange holding medication for some period of time.”
She said that ACR vaccine committee members are working with infectious disease specialists and guideline developers for the American Academy of Pediatrics to ensure guidelines include the most important vaccination recommendations for pediatric patients with RMDs.
The development process for the guidelines was supported by the ACR. Dr. Bass reported no relevant disclosures, Dr. Bingham disclosed consulting activities, grant/research support, and royalties from various corporate entities. Dr. Winthrop disclosed consulting activities for and research funding from various companies. Dr. Imundo reported no relevant financial relationships.
PHILADELPHIA – The new American College of Rheumatology Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal Diseases (RMDs) emphasizes that both adult and pediatric patients should receive recommended vaccinations whenever possible.
But the guideline, currently in press, also offers recommendations about whether and when to withhold vaccines from patients with RMDs, such as avoiding the use of live attenuated virus vaccines in patients who are on immunosuppressive drug regimens, such as conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, or targeted synthetic DMARDs.
The new consensus guideline was formulated with the understanding that patients with RMDs are at increased risk for vaccine-preventable infections and more serious complications from infections, compared with the general population.
However, the guideline also acknowledges that the immunogenicity and safety of vaccines may differ among patients with RMDs, and that, depending on the patient age and disease state, individuals may benefit from modified vaccine indications, schedules, or modified medication schedules, said guideline panel member Anne Bass, MD, a rheumatologist at Hospital for Special Surgery and a professor of clinical medicine at Weill Cornell Medicine in New York, who presented the guideline with other panel members in a session outlining the recommendations at the annual meeting of the ACR.
“In addition, vaccination recommendations – since much of it relates to medications – really applies across diseases, and so the ACR felt that, rather than having vaccine recommendations tacked onto the end of treatment guidelines for each individual disease, that the topic should be discussed or tackled as a whole,” she said.
The guideline does not cover vaccinations in patients taking nonsteroidal anti-inflammatory drugs because this class of agents has minimal or no impact on antibody responses to vaccines. The guideline also does not address vaccinations against COVID-19 infections since the rapidly changing formulations would make the recommendations obsolete before they were even published, and because the U.S. Centers for Disease Control and Prevention provides up-to-date guidance on COVID-19 vaccinations in patients with compromised immunity, she said.
Guiding principles
The overarching principles of the guideline are to give indicated vaccines to patients with RMD whenever possible and that any decision to hold medications before or after vaccination consider the dosage used, RMD disease activity, and the patient’s risk for vaccine-preventable infection.
The guideline also states that “shared decision-making with patients is a key component of any vaccination strategy.”
Panel member Clifton O. Bingham III, MD, professor of medicine at Johns Hopkins University in Baltimore, outlined expanded indications for vaccinations against influenza, pneumococcal infections, varicella zoster virus (VZV) and human papillomavirus (HPV).
Influenza
The guideline conditionally recommends that patients with RMD aged 65 years and older and adults older than age 18 years who are on immunosuppressive medications should receive either high-dose or adjuvanted influenza vaccination rather than regular-dose vaccines.
“It’s recognized that the high-dose or adjuvanted vaccinations may be unavailable for patients when they’re seen in your practice,” Dr. Bingham said,” and we came out with two additional statements within the guidelines that said that any flu vaccine is recommended over no flu vaccinations, because we do know that responses are elicited, and a flu vaccination today is preferred over a flu vaccination delay.”
Pneumococcal vaccination
The panelists strongly recommended that patients with RMD younger than age 65 years who are on immunosuppressive medication receive pneumococcal vaccinations.
The ACR guideline is in sync with those issued by the CDC’s Advisory Committee on Immunization Practices, Dr. Bingham said. He urged audience members to visit a CDC-ACIP web page for more information on who should receive pneumococcal vaccination and when.
Recombinant varicella zoster
The recommendations strongly support that patients aged 18 years and over who are on immunosuppressive therapies should receive the recombinant VZV vaccine (Shingrix).
HPV
A less robust, conditional recommendation is for patients with RMDs who are between the ages of 26 and 45 years and on immunosuppressive medications to receive the HPV vaccine (if they have not already received the vaccine).
Non-live attenuated vaccines
Kevin Winthrop, MD, MPH, professor of infectious diseases and public health at Oregon Health & Science University, Portland, summarized the recommendations for managing immunosuppressive therapies in patients scheduled to receive vaccinations using killed or nonactive antigens.
“In influenza season, don’t pass up the opportunity to vaccinate,” he said, adding, “if you can wait on rituximab dosing, do it, and if you can’t, go ahead and vaccinate.”
The guidelines also recommend a 2-week methotrexate hold at the time of influenza vaccination; other DMARD dosing changes are likely not necessary at the time of vaccination, “but this is an area of fervent study, and I think in a year or two we’ll have more experimental hold data with regard to other DMARDs,” Dr. Winthrop said.
For other nonlive attenuated vaccinations, recommendations are similar to those for influenza, except with more flexible timing because these vaccinations are not seasonal. When and how to hold methotrexate is still up in the air, he said.
Additionally, it’s recommended that vaccinations be delayed in patients on high-dose prednisone until the drug is tapered to below 20 mg per day, and ideally to less than 10 mg per day, he said.
Live-attenuated vaccines
The guideline conditionally recommends deferring live-attenuated vaccines in patients on immunosuppressive drugs. It also recommends holding these medications “for an appropriate period before” vaccination and for 4 weeks afterward.
“Although the evidence around conventional synthetic DMARDs and TNF inhibitors is reassuring in terms of their safety at the time of live attenuated vaccines, as you can see the number of studies is quite small, and so the voting panel conditionally recommend against administering live-attenuated virus vaccines to patients who are on conventional synthetics, biologic, or targeted DMARDs,” Dr. Bass said.
In utero exposures
Most women with RMD who have recently given birth will consult their general pediatricians rather than rheumatologists for infant vaccinations, but pediatricians may not be aware of the affect that in utero exposures to biologic DMARDs can have on vaccine safety and immunogenicity in infants, Dr, Bass said.
“It’s important that you, as a provider, give your recommendations regarding infant rotavirus vaccination after in utero exposure to the pregnant rheumatic disease patient prior to delivery, and let that patient know that this is something that they should share with their pediatrician to be,” she advised audience members.
Getting the message out
In an interview, session moderator and guidelines panelist Lisa F. Imundo, MD, director of the center for adolescent rheumatology at Columbia University in New York, noted that rheumatologists don’t usually have the full schedule of pediatric vaccinations in stock and often leave the decisions about what to give – and when – to general practitioners.
“Pediatric rheumatologists sometimes will give patients flu vaccinations because they’re a high-risk population of patients, and we want to make sure that they’re getting it in a timely manner,” she said.
In addition, because pneumococcal polysaccharide vaccines are not indicated in the general pediatric population, children on biologic DMARDs who have completed their standard series of pneumococcal conjugate vaccines (PCV13 or PVC15) are recommended to get a 23-valent pneumococcal polysaccharide vaccine, Dr. Imundo said.
She also noted that communication between pediatric rheumatologists and general practitioners about vaccine recommendations can be challenging.
“It’s a huge issue, figuring out how we’re going to communicate all of this information to our pediatric colleagues,” she said. “With individual patients, we may sometimes remind doctors, especially with our younger patients who haven’t gotten their live vaccines, that they really shouldn’t get live vaccines until they’re off medication or until we arrange holding medication for some period of time.”
She said that ACR vaccine committee members are working with infectious disease specialists and guideline developers for the American Academy of Pediatrics to ensure guidelines include the most important vaccination recommendations for pediatric patients with RMDs.
The development process for the guidelines was supported by the ACR. Dr. Bass reported no relevant disclosures, Dr. Bingham disclosed consulting activities, grant/research support, and royalties from various corporate entities. Dr. Winthrop disclosed consulting activities for and research funding from various companies. Dr. Imundo reported no relevant financial relationships.
PHILADELPHIA – The new American College of Rheumatology Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal Diseases (RMDs) emphasizes that both adult and pediatric patients should receive recommended vaccinations whenever possible.
But the guideline, currently in press, also offers recommendations about whether and when to withhold vaccines from patients with RMDs, such as avoiding the use of live attenuated virus vaccines in patients who are on immunosuppressive drug regimens, such as conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, or targeted synthetic DMARDs.
The new consensus guideline was formulated with the understanding that patients with RMDs are at increased risk for vaccine-preventable infections and more serious complications from infections, compared with the general population.
However, the guideline also acknowledges that the immunogenicity and safety of vaccines may differ among patients with RMDs, and that, depending on the patient age and disease state, individuals may benefit from modified vaccine indications, schedules, or modified medication schedules, said guideline panel member Anne Bass, MD, a rheumatologist at Hospital for Special Surgery and a professor of clinical medicine at Weill Cornell Medicine in New York, who presented the guideline with other panel members in a session outlining the recommendations at the annual meeting of the ACR.
“In addition, vaccination recommendations – since much of it relates to medications – really applies across diseases, and so the ACR felt that, rather than having vaccine recommendations tacked onto the end of treatment guidelines for each individual disease, that the topic should be discussed or tackled as a whole,” she said.
The guideline does not cover vaccinations in patients taking nonsteroidal anti-inflammatory drugs because this class of agents has minimal or no impact on antibody responses to vaccines. The guideline also does not address vaccinations against COVID-19 infections since the rapidly changing formulations would make the recommendations obsolete before they were even published, and because the U.S. Centers for Disease Control and Prevention provides up-to-date guidance on COVID-19 vaccinations in patients with compromised immunity, she said.
Guiding principles
The overarching principles of the guideline are to give indicated vaccines to patients with RMD whenever possible and that any decision to hold medications before or after vaccination consider the dosage used, RMD disease activity, and the patient’s risk for vaccine-preventable infection.
The guideline also states that “shared decision-making with patients is a key component of any vaccination strategy.”
Panel member Clifton O. Bingham III, MD, professor of medicine at Johns Hopkins University in Baltimore, outlined expanded indications for vaccinations against influenza, pneumococcal infections, varicella zoster virus (VZV) and human papillomavirus (HPV).
Influenza
The guideline conditionally recommends that patients with RMD aged 65 years and older and adults older than age 18 years who are on immunosuppressive medications should receive either high-dose or adjuvanted influenza vaccination rather than regular-dose vaccines.
“It’s recognized that the high-dose or adjuvanted vaccinations may be unavailable for patients when they’re seen in your practice,” Dr. Bingham said,” and we came out with two additional statements within the guidelines that said that any flu vaccine is recommended over no flu vaccinations, because we do know that responses are elicited, and a flu vaccination today is preferred over a flu vaccination delay.”
Pneumococcal vaccination
The panelists strongly recommended that patients with RMD younger than age 65 years who are on immunosuppressive medication receive pneumococcal vaccinations.
The ACR guideline is in sync with those issued by the CDC’s Advisory Committee on Immunization Practices, Dr. Bingham said. He urged audience members to visit a CDC-ACIP web page for more information on who should receive pneumococcal vaccination and when.
Recombinant varicella zoster
The recommendations strongly support that patients aged 18 years and over who are on immunosuppressive therapies should receive the recombinant VZV vaccine (Shingrix).
HPV
A less robust, conditional recommendation is for patients with RMDs who are between the ages of 26 and 45 years and on immunosuppressive medications to receive the HPV vaccine (if they have not already received the vaccine).
Non-live attenuated vaccines
Kevin Winthrop, MD, MPH, professor of infectious diseases and public health at Oregon Health & Science University, Portland, summarized the recommendations for managing immunosuppressive therapies in patients scheduled to receive vaccinations using killed or nonactive antigens.
“In influenza season, don’t pass up the opportunity to vaccinate,” he said, adding, “if you can wait on rituximab dosing, do it, and if you can’t, go ahead and vaccinate.”
The guidelines also recommend a 2-week methotrexate hold at the time of influenza vaccination; other DMARD dosing changes are likely not necessary at the time of vaccination, “but this is an area of fervent study, and I think in a year or two we’ll have more experimental hold data with regard to other DMARDs,” Dr. Winthrop said.
For other nonlive attenuated vaccinations, recommendations are similar to those for influenza, except with more flexible timing because these vaccinations are not seasonal. When and how to hold methotrexate is still up in the air, he said.
Additionally, it’s recommended that vaccinations be delayed in patients on high-dose prednisone until the drug is tapered to below 20 mg per day, and ideally to less than 10 mg per day, he said.
Live-attenuated vaccines
The guideline conditionally recommends deferring live-attenuated vaccines in patients on immunosuppressive drugs. It also recommends holding these medications “for an appropriate period before” vaccination and for 4 weeks afterward.
“Although the evidence around conventional synthetic DMARDs and TNF inhibitors is reassuring in terms of their safety at the time of live attenuated vaccines, as you can see the number of studies is quite small, and so the voting panel conditionally recommend against administering live-attenuated virus vaccines to patients who are on conventional synthetics, biologic, or targeted DMARDs,” Dr. Bass said.
In utero exposures
Most women with RMD who have recently given birth will consult their general pediatricians rather than rheumatologists for infant vaccinations, but pediatricians may not be aware of the affect that in utero exposures to biologic DMARDs can have on vaccine safety and immunogenicity in infants, Dr, Bass said.
“It’s important that you, as a provider, give your recommendations regarding infant rotavirus vaccination after in utero exposure to the pregnant rheumatic disease patient prior to delivery, and let that patient know that this is something that they should share with their pediatrician to be,” she advised audience members.
Getting the message out
In an interview, session moderator and guidelines panelist Lisa F. Imundo, MD, director of the center for adolescent rheumatology at Columbia University in New York, noted that rheumatologists don’t usually have the full schedule of pediatric vaccinations in stock and often leave the decisions about what to give – and when – to general practitioners.
“Pediatric rheumatologists sometimes will give patients flu vaccinations because they’re a high-risk population of patients, and we want to make sure that they’re getting it in a timely manner,” she said.
In addition, because pneumococcal polysaccharide vaccines are not indicated in the general pediatric population, children on biologic DMARDs who have completed their standard series of pneumococcal conjugate vaccines (PCV13 or PVC15) are recommended to get a 23-valent pneumococcal polysaccharide vaccine, Dr. Imundo said.
She also noted that communication between pediatric rheumatologists and general practitioners about vaccine recommendations can be challenging.
“It’s a huge issue, figuring out how we’re going to communicate all of this information to our pediatric colleagues,” she said. “With individual patients, we may sometimes remind doctors, especially with our younger patients who haven’t gotten their live vaccines, that they really shouldn’t get live vaccines until they’re off medication or until we arrange holding medication for some period of time.”
She said that ACR vaccine committee members are working with infectious disease specialists and guideline developers for the American Academy of Pediatrics to ensure guidelines include the most important vaccination recommendations for pediatric patients with RMDs.
The development process for the guidelines was supported by the ACR. Dr. Bass reported no relevant disclosures, Dr. Bingham disclosed consulting activities, grant/research support, and royalties from various corporate entities. Dr. Winthrop disclosed consulting activities for and research funding from various companies. Dr. Imundo reported no relevant financial relationships.
AT ACR 2022
Midodrine may be comparable to albumin for PICD prevention in ACLF
WASHINGTON – , according to the results of a randomized controlled trial.
Albumin protected 80% of patients from PICD 6 days after paracentesis, whereas midodrine protected 84%, a difference that was not statistically significant. However, albumin was associated with a slightly higher incidence of adverse events and higher costs, said Mithun Sharma, MD, during his presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Midodrine may be a safer and cost-effective option for these patients, said Dr. Sharma, of the department of hepatology and liver transplantation, AIG Hospitals, Hyderabad, India.
But he cautioned that given the small size of the open-label study, with only 25 patients in each arm, the results should be considered as proof of concept and need to be validated in larger studies.
PICD common in ACLF
PICD is caused by fluid shift during paracentesis, leading to a decrease in effective circulating blood volume.
The incidence of PICD after large-volume paracentesis in patients receiving albumin ranges from 12% to 20%, Dr. Sharma noted.
Albumin has been shown in several trials to be effective at reducing the incidence of PICD in patients undergoing paracentesis, but this agent requires IV infusion and is comparatively costly, he said.
In contrast, midodrine, a selective alpha-adrenergic agonist usually prescribed for orthostatic hypotension, may help to prevent PICD through its mechanism of action, maintaining mean arterial pressure (MAP).
In two small studies comparing albumin infusion in patients undergoing paracentesis with 8 liters of fluid removal, midodrine was either inferior to albumin or had no beneficial effect, Dr. Sharma said.
Patients with ACLF, however, have paracentesis with much lower fluid volumes, typically with less than 5 liters removed, and may be good candidates for midodrine.
Study details
Dr. Sharma and colleagues tested their hypothesis that in patients with ACLF undergoing modest-volume paracentesis, with fluid removal below 5 liters, midodrine could prevent PICD by increasing MAP, with an efficacy similar to that of intravenous 20% human albumin infusions.
They enrolled 50 patients with ACLF defined by Asian Pacific Association for the Study of the Liver criteria who were undergoing paracentesis with 3- to 4-liter fluid volumes.
They defined PICD as at least a 50% increase in plasma renin activity (PRA) over baseline on the 6th day following paracentesis.
The patients were randomly assigned to receive either intravenous 20% human albumin infusions toward the end of paracentesis or midodrine-hydrochloride 7.5 mg three times daily starting 2 hours before paracentesis. Because of the difference in drug delivery methods, the study could not be blinded to treatment type.
Patients’ mean arterial pressures were recorded daily, renal parameters and serum electrolytes were monitored on days 3 and 6, and blood samples were tested for PRA on day 1 and day 6.
The most common acute and chronic hepatic insults and baseline characteristics of the patients were similar between the groups, with alcohol-related liver disease the most common underlying etiology of cirrhosis.
The incidence of PICD at day 6, the primary endpoint, did not differ significantly between the groups, although mean PRA levels on day 6 were numerically higher in the midodrine group. There was a significant rise in the absolute PRA volume from baseline (P = .006), but this rise did not meet the PICD definition.
Researchers found no significant differences between the two groups in absolute change in PRA, and no significant changes in either group in MAP, creatinine, or sodium levels.
Complications and costs
PICD developed in four patients assigned to the albumin group and five patients assigned to the midodrine group; however, this difference was not significant. Fluid overload occurred in only one patient, in the albumin group.
No cases of hypertension or urinary retention arose in either group.
Grade I/II hepatic encephalopathy occurred 2-3 days after paracentesis in three patients on albumin and in two patients on midodrine.
Acute kidney injury was seen in three patients on albumin and in one patient on midodrine.
At 28 days after paracentesis, three patients in the albumin group had died, all from sepsis and multiorgan failure, while four patients in the midodrine group had died, three from sepsis and multiorgan failure and one from an upper gastrointestinal bleed.
Two patients in the albumin group and one patient in the midodrine group underwent liver transplant 1 month after paracentesis.
A cost-effectiveness analysis showed that the mean cost of albumin infusions was about sixfold higher than that of oral midodrine.
More data needed
Session moderator Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences in New Delhi, India, who was not involved in the study, commented that while midodrine is a good drug and generally safe, he would wait to use it in patients who needed modest-volume paracentesis until more data are published.
Dr. Sarin also emphasized that albumin is “mandatory” for protecting patients who require large-volume paracentesis, and that it would be “unethical” not to use it in that clinical situation.
The study was internally supported. Dr. Sharma and Dr. Sarin have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WASHINGTON – , according to the results of a randomized controlled trial.
Albumin protected 80% of patients from PICD 6 days after paracentesis, whereas midodrine protected 84%, a difference that was not statistically significant. However, albumin was associated with a slightly higher incidence of adverse events and higher costs, said Mithun Sharma, MD, during his presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Midodrine may be a safer and cost-effective option for these patients, said Dr. Sharma, of the department of hepatology and liver transplantation, AIG Hospitals, Hyderabad, India.
But he cautioned that given the small size of the open-label study, with only 25 patients in each arm, the results should be considered as proof of concept and need to be validated in larger studies.
PICD common in ACLF
PICD is caused by fluid shift during paracentesis, leading to a decrease in effective circulating blood volume.
The incidence of PICD after large-volume paracentesis in patients receiving albumin ranges from 12% to 20%, Dr. Sharma noted.
Albumin has been shown in several trials to be effective at reducing the incidence of PICD in patients undergoing paracentesis, but this agent requires IV infusion and is comparatively costly, he said.
In contrast, midodrine, a selective alpha-adrenergic agonist usually prescribed for orthostatic hypotension, may help to prevent PICD through its mechanism of action, maintaining mean arterial pressure (MAP).
In two small studies comparing albumin infusion in patients undergoing paracentesis with 8 liters of fluid removal, midodrine was either inferior to albumin or had no beneficial effect, Dr. Sharma said.
Patients with ACLF, however, have paracentesis with much lower fluid volumes, typically with less than 5 liters removed, and may be good candidates for midodrine.
Study details
Dr. Sharma and colleagues tested their hypothesis that in patients with ACLF undergoing modest-volume paracentesis, with fluid removal below 5 liters, midodrine could prevent PICD by increasing MAP, with an efficacy similar to that of intravenous 20% human albumin infusions.
They enrolled 50 patients with ACLF defined by Asian Pacific Association for the Study of the Liver criteria who were undergoing paracentesis with 3- to 4-liter fluid volumes.
They defined PICD as at least a 50% increase in plasma renin activity (PRA) over baseline on the 6th day following paracentesis.
The patients were randomly assigned to receive either intravenous 20% human albumin infusions toward the end of paracentesis or midodrine-hydrochloride 7.5 mg three times daily starting 2 hours before paracentesis. Because of the difference in drug delivery methods, the study could not be blinded to treatment type.
Patients’ mean arterial pressures were recorded daily, renal parameters and serum electrolytes were monitored on days 3 and 6, and blood samples were tested for PRA on day 1 and day 6.
The most common acute and chronic hepatic insults and baseline characteristics of the patients were similar between the groups, with alcohol-related liver disease the most common underlying etiology of cirrhosis.
The incidence of PICD at day 6, the primary endpoint, did not differ significantly between the groups, although mean PRA levels on day 6 were numerically higher in the midodrine group. There was a significant rise in the absolute PRA volume from baseline (P = .006), but this rise did not meet the PICD definition.
Researchers found no significant differences between the two groups in absolute change in PRA, and no significant changes in either group in MAP, creatinine, or sodium levels.
Complications and costs
PICD developed in four patients assigned to the albumin group and five patients assigned to the midodrine group; however, this difference was not significant. Fluid overload occurred in only one patient, in the albumin group.
No cases of hypertension or urinary retention arose in either group.
Grade I/II hepatic encephalopathy occurred 2-3 days after paracentesis in three patients on albumin and in two patients on midodrine.
Acute kidney injury was seen in three patients on albumin and in one patient on midodrine.
At 28 days after paracentesis, three patients in the albumin group had died, all from sepsis and multiorgan failure, while four patients in the midodrine group had died, three from sepsis and multiorgan failure and one from an upper gastrointestinal bleed.
Two patients in the albumin group and one patient in the midodrine group underwent liver transplant 1 month after paracentesis.
A cost-effectiveness analysis showed that the mean cost of albumin infusions was about sixfold higher than that of oral midodrine.
More data needed
Session moderator Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences in New Delhi, India, who was not involved in the study, commented that while midodrine is a good drug and generally safe, he would wait to use it in patients who needed modest-volume paracentesis until more data are published.
Dr. Sarin also emphasized that albumin is “mandatory” for protecting patients who require large-volume paracentesis, and that it would be “unethical” not to use it in that clinical situation.
The study was internally supported. Dr. Sharma and Dr. Sarin have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WASHINGTON – , according to the results of a randomized controlled trial.
Albumin protected 80% of patients from PICD 6 days after paracentesis, whereas midodrine protected 84%, a difference that was not statistically significant. However, albumin was associated with a slightly higher incidence of adverse events and higher costs, said Mithun Sharma, MD, during his presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Midodrine may be a safer and cost-effective option for these patients, said Dr. Sharma, of the department of hepatology and liver transplantation, AIG Hospitals, Hyderabad, India.
But he cautioned that given the small size of the open-label study, with only 25 patients in each arm, the results should be considered as proof of concept and need to be validated in larger studies.
PICD common in ACLF
PICD is caused by fluid shift during paracentesis, leading to a decrease in effective circulating blood volume.
The incidence of PICD after large-volume paracentesis in patients receiving albumin ranges from 12% to 20%, Dr. Sharma noted.
Albumin has been shown in several trials to be effective at reducing the incidence of PICD in patients undergoing paracentesis, but this agent requires IV infusion and is comparatively costly, he said.
In contrast, midodrine, a selective alpha-adrenergic agonist usually prescribed for orthostatic hypotension, may help to prevent PICD through its mechanism of action, maintaining mean arterial pressure (MAP).
In two small studies comparing albumin infusion in patients undergoing paracentesis with 8 liters of fluid removal, midodrine was either inferior to albumin or had no beneficial effect, Dr. Sharma said.
Patients with ACLF, however, have paracentesis with much lower fluid volumes, typically with less than 5 liters removed, and may be good candidates for midodrine.
Study details
Dr. Sharma and colleagues tested their hypothesis that in patients with ACLF undergoing modest-volume paracentesis, with fluid removal below 5 liters, midodrine could prevent PICD by increasing MAP, with an efficacy similar to that of intravenous 20% human albumin infusions.
They enrolled 50 patients with ACLF defined by Asian Pacific Association for the Study of the Liver criteria who were undergoing paracentesis with 3- to 4-liter fluid volumes.
They defined PICD as at least a 50% increase in plasma renin activity (PRA) over baseline on the 6th day following paracentesis.
The patients were randomly assigned to receive either intravenous 20% human albumin infusions toward the end of paracentesis or midodrine-hydrochloride 7.5 mg three times daily starting 2 hours before paracentesis. Because of the difference in drug delivery methods, the study could not be blinded to treatment type.
Patients’ mean arterial pressures were recorded daily, renal parameters and serum electrolytes were monitored on days 3 and 6, and blood samples were tested for PRA on day 1 and day 6.
The most common acute and chronic hepatic insults and baseline characteristics of the patients were similar between the groups, with alcohol-related liver disease the most common underlying etiology of cirrhosis.
The incidence of PICD at day 6, the primary endpoint, did not differ significantly between the groups, although mean PRA levels on day 6 were numerically higher in the midodrine group. There was a significant rise in the absolute PRA volume from baseline (P = .006), but this rise did not meet the PICD definition.
Researchers found no significant differences between the two groups in absolute change in PRA, and no significant changes in either group in MAP, creatinine, or sodium levels.
Complications and costs
PICD developed in four patients assigned to the albumin group and five patients assigned to the midodrine group; however, this difference was not significant. Fluid overload occurred in only one patient, in the albumin group.
No cases of hypertension or urinary retention arose in either group.
Grade I/II hepatic encephalopathy occurred 2-3 days after paracentesis in three patients on albumin and in two patients on midodrine.
Acute kidney injury was seen in three patients on albumin and in one patient on midodrine.
At 28 days after paracentesis, three patients in the albumin group had died, all from sepsis and multiorgan failure, while four patients in the midodrine group had died, three from sepsis and multiorgan failure and one from an upper gastrointestinal bleed.
Two patients in the albumin group and one patient in the midodrine group underwent liver transplant 1 month after paracentesis.
A cost-effectiveness analysis showed that the mean cost of albumin infusions was about sixfold higher than that of oral midodrine.
More data needed
Session moderator Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences in New Delhi, India, who was not involved in the study, commented that while midodrine is a good drug and generally safe, he would wait to use it in patients who needed modest-volume paracentesis until more data are published.
Dr. Sarin also emphasized that albumin is “mandatory” for protecting patients who require large-volume paracentesis, and that it would be “unethical” not to use it in that clinical situation.
The study was internally supported. Dr. Sharma and Dr. Sarin have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LIVER MEETING
Randomized trial finds community-based weight-loss programs ease knee OA pain
PHILADELPHIA – What works in the clinic can also work in community settings: Patients who are overweight or obese with knee osteoarthritis can find relief from pain through diet and exercise programs conducted in recreation centers, local gyms, fitness centers, and other places close to home, according to investigators in a pragmatic randomized trial.
The Weight Loss and Exercise for Communities With Arthritis in North Carolina (WE-CAN) study was modeled after the successful Intensive Diet and Exercise for Arthritis trial, which showed that adults randomized to 18 months of either a diet and exercise program or diet alone had more weight loss and larger reductions in levels of the inflammatory cytokine interleukin-6 than patients randomized to exercise alone, and that diet alone was associated with greater reductions in knee compressive force than exercise alone.
That study was conducted by Stephen P. Messier, PhD, and colleagues at Wake Forest University, Winston-Salem, N.C.. As previously reported, the investigators also saw continued benefits for participants years after the original trial.
With the WE-CAN trial, results of which were reported at the annual meeting of the American College of Rheumatology, Dr. Messier and colleagues took the intervention one step further, randomizing 823 community-dwelling adults who were overweight or obese (body mass index [BMI], ≥ 27 kg/m2) with knee OA to either an 18-month diet and exercise intervention or attention control group consisting of five 1-hour face-to-face meetings over 18 months, plus information packets and phone sessions during alternate months.
“Compared to the control group, diet plus exercise had a statistically significant but modest reduction in pain. Diet plus exercise was 20% more likely to attain a clinically important 2-point improvement in pain,” Dr. Messier said in an oral abstract session at ACR.
Real-world setting
The primary goal of WE-CAN was to “determine whether adaptation of a diet and exercise academic center–based efficacy trial to community settings results in a statistically significant reduction in pain relative to an attention control.”
A total of 3,751 potential candidates were screened, and 823 were randomized and assigned to either a diet and exercise arm (414) or attention control arm (409). Of the patients randomized, 336 in the diet/exercise arm and 322 in the control arm attended the final 18-month follow-up visit.
The exercise component consisted of a 15-minute walking period, followed by a 20-minute weight-training period, and ending with a second 15-minute walking period. The diet goal was 10% or greater weight loss, aided by a distribution of low-calorie recipes to produce a reduced-calorie diet of the patient’s choice, with the option to include nutritional powder to make low-calories shakes as meal replacements, one or two per day for the first 6 months, with the option of one per day for the remaining months.
The pragmatic components included the use of established community facilities in both urban and rural counties in North Carolina, broad inclusion criteria, patient-centered outcomes, use of community-based staff to deliver the treatment, nonphysicians trained by study physicians to perform knee exams, and various means of communication, Dr. Messier said.
Participants in each arm were closely matched by demographic and clinical characteristics, with a mean age of 64.5 years in the diet/exercise group and 64.7 years in the attention control group, respective mean weight of 100.7 kg and 101.1 kg, and respective BMI of 36.7 and 36.9. Women comprised about 77% of participants in each group.
Endpoints met
The trial met its primary endpoint of a significantly greater reduction in pain at 18 months in the diet and exercise group as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and scored on a scale of 0 (no pain) to 20 (worst pain).
In an analysis adjusted for sex, BMI, and baseline values, there was a 32% reduction in pain scores from baseline in the active intervention arm versus 24% in the control arm (P = .02).
In all, 60.2% of participants assigned to diet and exercise had a minimum reduction in pain scores of at least 2 points at 18 months, compared with 49.7% of participants assigned to the attention control group. This translated into a relative risk for achieving at least a 2-point improvement with diet and exercise was 1.20 (P = .01).
Among participants who remained in the study for the entire 18 months, there were significant improvements in the diet and exercise group compared with controls in the prespecified secondary endpoints of weight change (–8 kg vs. –2 kg), waist circumference, WOMAC function, 6-minute walk distance, and mean Short Form–36 health-related quality of life subscale (P < .001 for all comparisons).
Dr. Messier acknowledged that the diagnosis of knee OA was based only on ACR clinical criteria and was not confirmed with imaging. In addition, offering patients the option of free meal replacement limited the pragmatic nature of the intervention.
He also noted that the 24% reduction in pain seen in the control group suggests that interacting with patients can improve clinical outcomes.
‘Tour de force’
In the question-and-answer session following Dr. Messier’s presentation, David T. Felson, MD, a rheumatologist at Boston Medical Center, called in and said the study was “a tour de force” and congratulated Dr. Messier and colleagues on “a lovely study.”
Dr. Felson asked whether the investigators had conducted a mediation analysis to determine what proportion of the improvement was attributable to weight loss, and whether patients assigned to exercise were sticking with it throughout the study.
Dr. Messier replied that they had not yet done a mediation analysis but were continuing to examine the data. Regarding the exercise question, he noted that “the adherence was over 80% for 6 months and over 70% for the whole 18 months, so they did a really nice job.”
In an interview, session moderator Anne Davidson, MBBS, director of the rheumatology program at Northwell Health in Manhasset, N.Y., commented that the investigators managed to accomplish a very challenging task.
“In terms of recruitment of patients with engagement of community facilities and quality of data, I would say that, as far as an osteoarthritis study goes, this was really a tremendous effort on the part of all people involved,” she said.
She noted that, while the WE-CAN program may work in North Carolina, there may be barriers to implementing it elsewhere, such as large suburban areas where some patients experience food insecurity and others have difficulty with transportation and access to treatment facilities.
“The question here that remains is, as Dr. Felson asked, what is the contribution of weight loss and what is the contribution of exercise? Because if it’s just weight loss, we have a whole lot of new things coming to help with that,” she said.
The WE-CAN study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier disclosed that GNC, a health food and nutrition chain, donated the meal replacements used by patients. Dr. Davidson reported no relevant conflicts of interest.
PHILADELPHIA – What works in the clinic can also work in community settings: Patients who are overweight or obese with knee osteoarthritis can find relief from pain through diet and exercise programs conducted in recreation centers, local gyms, fitness centers, and other places close to home, according to investigators in a pragmatic randomized trial.
The Weight Loss and Exercise for Communities With Arthritis in North Carolina (WE-CAN) study was modeled after the successful Intensive Diet and Exercise for Arthritis trial, which showed that adults randomized to 18 months of either a diet and exercise program or diet alone had more weight loss and larger reductions in levels of the inflammatory cytokine interleukin-6 than patients randomized to exercise alone, and that diet alone was associated with greater reductions in knee compressive force than exercise alone.
That study was conducted by Stephen P. Messier, PhD, and colleagues at Wake Forest University, Winston-Salem, N.C.. As previously reported, the investigators also saw continued benefits for participants years after the original trial.
With the WE-CAN trial, results of which were reported at the annual meeting of the American College of Rheumatology, Dr. Messier and colleagues took the intervention one step further, randomizing 823 community-dwelling adults who were overweight or obese (body mass index [BMI], ≥ 27 kg/m2) with knee OA to either an 18-month diet and exercise intervention or attention control group consisting of five 1-hour face-to-face meetings over 18 months, plus information packets and phone sessions during alternate months.
“Compared to the control group, diet plus exercise had a statistically significant but modest reduction in pain. Diet plus exercise was 20% more likely to attain a clinically important 2-point improvement in pain,” Dr. Messier said in an oral abstract session at ACR.
Real-world setting
The primary goal of WE-CAN was to “determine whether adaptation of a diet and exercise academic center–based efficacy trial to community settings results in a statistically significant reduction in pain relative to an attention control.”
A total of 3,751 potential candidates were screened, and 823 were randomized and assigned to either a diet and exercise arm (414) or attention control arm (409). Of the patients randomized, 336 in the diet/exercise arm and 322 in the control arm attended the final 18-month follow-up visit.
The exercise component consisted of a 15-minute walking period, followed by a 20-minute weight-training period, and ending with a second 15-minute walking period. The diet goal was 10% or greater weight loss, aided by a distribution of low-calorie recipes to produce a reduced-calorie diet of the patient’s choice, with the option to include nutritional powder to make low-calories shakes as meal replacements, one or two per day for the first 6 months, with the option of one per day for the remaining months.
The pragmatic components included the use of established community facilities in both urban and rural counties in North Carolina, broad inclusion criteria, patient-centered outcomes, use of community-based staff to deliver the treatment, nonphysicians trained by study physicians to perform knee exams, and various means of communication, Dr. Messier said.
Participants in each arm were closely matched by demographic and clinical characteristics, with a mean age of 64.5 years in the diet/exercise group and 64.7 years in the attention control group, respective mean weight of 100.7 kg and 101.1 kg, and respective BMI of 36.7 and 36.9. Women comprised about 77% of participants in each group.
Endpoints met
The trial met its primary endpoint of a significantly greater reduction in pain at 18 months in the diet and exercise group as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and scored on a scale of 0 (no pain) to 20 (worst pain).
In an analysis adjusted for sex, BMI, and baseline values, there was a 32% reduction in pain scores from baseline in the active intervention arm versus 24% in the control arm (P = .02).
In all, 60.2% of participants assigned to diet and exercise had a minimum reduction in pain scores of at least 2 points at 18 months, compared with 49.7% of participants assigned to the attention control group. This translated into a relative risk for achieving at least a 2-point improvement with diet and exercise was 1.20 (P = .01).
Among participants who remained in the study for the entire 18 months, there were significant improvements in the diet and exercise group compared with controls in the prespecified secondary endpoints of weight change (–8 kg vs. –2 kg), waist circumference, WOMAC function, 6-minute walk distance, and mean Short Form–36 health-related quality of life subscale (P < .001 for all comparisons).
Dr. Messier acknowledged that the diagnosis of knee OA was based only on ACR clinical criteria and was not confirmed with imaging. In addition, offering patients the option of free meal replacement limited the pragmatic nature of the intervention.
He also noted that the 24% reduction in pain seen in the control group suggests that interacting with patients can improve clinical outcomes.
‘Tour de force’
In the question-and-answer session following Dr. Messier’s presentation, David T. Felson, MD, a rheumatologist at Boston Medical Center, called in and said the study was “a tour de force” and congratulated Dr. Messier and colleagues on “a lovely study.”
Dr. Felson asked whether the investigators had conducted a mediation analysis to determine what proportion of the improvement was attributable to weight loss, and whether patients assigned to exercise were sticking with it throughout the study.
Dr. Messier replied that they had not yet done a mediation analysis but were continuing to examine the data. Regarding the exercise question, he noted that “the adherence was over 80% for 6 months and over 70% for the whole 18 months, so they did a really nice job.”
In an interview, session moderator Anne Davidson, MBBS, director of the rheumatology program at Northwell Health in Manhasset, N.Y., commented that the investigators managed to accomplish a very challenging task.
“In terms of recruitment of patients with engagement of community facilities and quality of data, I would say that, as far as an osteoarthritis study goes, this was really a tremendous effort on the part of all people involved,” she said.
She noted that, while the WE-CAN program may work in North Carolina, there may be barriers to implementing it elsewhere, such as large suburban areas where some patients experience food insecurity and others have difficulty with transportation and access to treatment facilities.
“The question here that remains is, as Dr. Felson asked, what is the contribution of weight loss and what is the contribution of exercise? Because if it’s just weight loss, we have a whole lot of new things coming to help with that,” she said.
The WE-CAN study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier disclosed that GNC, a health food and nutrition chain, donated the meal replacements used by patients. Dr. Davidson reported no relevant conflicts of interest.
PHILADELPHIA – What works in the clinic can also work in community settings: Patients who are overweight or obese with knee osteoarthritis can find relief from pain through diet and exercise programs conducted in recreation centers, local gyms, fitness centers, and other places close to home, according to investigators in a pragmatic randomized trial.
The Weight Loss and Exercise for Communities With Arthritis in North Carolina (WE-CAN) study was modeled after the successful Intensive Diet and Exercise for Arthritis trial, which showed that adults randomized to 18 months of either a diet and exercise program or diet alone had more weight loss and larger reductions in levels of the inflammatory cytokine interleukin-6 than patients randomized to exercise alone, and that diet alone was associated with greater reductions in knee compressive force than exercise alone.
That study was conducted by Stephen P. Messier, PhD, and colleagues at Wake Forest University, Winston-Salem, N.C.. As previously reported, the investigators also saw continued benefits for participants years after the original trial.
With the WE-CAN trial, results of which were reported at the annual meeting of the American College of Rheumatology, Dr. Messier and colleagues took the intervention one step further, randomizing 823 community-dwelling adults who were overweight or obese (body mass index [BMI], ≥ 27 kg/m2) with knee OA to either an 18-month diet and exercise intervention or attention control group consisting of five 1-hour face-to-face meetings over 18 months, plus information packets and phone sessions during alternate months.
“Compared to the control group, diet plus exercise had a statistically significant but modest reduction in pain. Diet plus exercise was 20% more likely to attain a clinically important 2-point improvement in pain,” Dr. Messier said in an oral abstract session at ACR.
Real-world setting
The primary goal of WE-CAN was to “determine whether adaptation of a diet and exercise academic center–based efficacy trial to community settings results in a statistically significant reduction in pain relative to an attention control.”
A total of 3,751 potential candidates were screened, and 823 were randomized and assigned to either a diet and exercise arm (414) or attention control arm (409). Of the patients randomized, 336 in the diet/exercise arm and 322 in the control arm attended the final 18-month follow-up visit.
The exercise component consisted of a 15-minute walking period, followed by a 20-minute weight-training period, and ending with a second 15-minute walking period. The diet goal was 10% or greater weight loss, aided by a distribution of low-calorie recipes to produce a reduced-calorie diet of the patient’s choice, with the option to include nutritional powder to make low-calories shakes as meal replacements, one or two per day for the first 6 months, with the option of one per day for the remaining months.
The pragmatic components included the use of established community facilities in both urban and rural counties in North Carolina, broad inclusion criteria, patient-centered outcomes, use of community-based staff to deliver the treatment, nonphysicians trained by study physicians to perform knee exams, and various means of communication, Dr. Messier said.
Participants in each arm were closely matched by demographic and clinical characteristics, with a mean age of 64.5 years in the diet/exercise group and 64.7 years in the attention control group, respective mean weight of 100.7 kg and 101.1 kg, and respective BMI of 36.7 and 36.9. Women comprised about 77% of participants in each group.
Endpoints met
The trial met its primary endpoint of a significantly greater reduction in pain at 18 months in the diet and exercise group as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and scored on a scale of 0 (no pain) to 20 (worst pain).
In an analysis adjusted for sex, BMI, and baseline values, there was a 32% reduction in pain scores from baseline in the active intervention arm versus 24% in the control arm (P = .02).
In all, 60.2% of participants assigned to diet and exercise had a minimum reduction in pain scores of at least 2 points at 18 months, compared with 49.7% of participants assigned to the attention control group. This translated into a relative risk for achieving at least a 2-point improvement with diet and exercise was 1.20 (P = .01).
Among participants who remained in the study for the entire 18 months, there were significant improvements in the diet and exercise group compared with controls in the prespecified secondary endpoints of weight change (–8 kg vs. –2 kg), waist circumference, WOMAC function, 6-minute walk distance, and mean Short Form–36 health-related quality of life subscale (P < .001 for all comparisons).
Dr. Messier acknowledged that the diagnosis of knee OA was based only on ACR clinical criteria and was not confirmed with imaging. In addition, offering patients the option of free meal replacement limited the pragmatic nature of the intervention.
He also noted that the 24% reduction in pain seen in the control group suggests that interacting with patients can improve clinical outcomes.
‘Tour de force’
In the question-and-answer session following Dr. Messier’s presentation, David T. Felson, MD, a rheumatologist at Boston Medical Center, called in and said the study was “a tour de force” and congratulated Dr. Messier and colleagues on “a lovely study.”
Dr. Felson asked whether the investigators had conducted a mediation analysis to determine what proportion of the improvement was attributable to weight loss, and whether patients assigned to exercise were sticking with it throughout the study.
Dr. Messier replied that they had not yet done a mediation analysis but were continuing to examine the data. Regarding the exercise question, he noted that “the adherence was over 80% for 6 months and over 70% for the whole 18 months, so they did a really nice job.”
In an interview, session moderator Anne Davidson, MBBS, director of the rheumatology program at Northwell Health in Manhasset, N.Y., commented that the investigators managed to accomplish a very challenging task.
“In terms of recruitment of patients with engagement of community facilities and quality of data, I would say that, as far as an osteoarthritis study goes, this was really a tremendous effort on the part of all people involved,” she said.
She noted that, while the WE-CAN program may work in North Carolina, there may be barriers to implementing it elsewhere, such as large suburban areas where some patients experience food insecurity and others have difficulty with transportation and access to treatment facilities.
“The question here that remains is, as Dr. Felson asked, what is the contribution of weight loss and what is the contribution of exercise? Because if it’s just weight loss, we have a whole lot of new things coming to help with that,” she said.
The WE-CAN study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier disclosed that GNC, a health food and nutrition chain, donated the meal replacements used by patients. Dr. Davidson reported no relevant conflicts of interest.
AT ACR 2022