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TTP death linked to elevated troponin and neurological signs
GLASGOW – , according to retrospective analysis of 475 patients from the United Kingdom TTP registry.
In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.
Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.
“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”
To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.
The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.
Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).
The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.
In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).
Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 109/L.
Median platelet count upon presentation was 15 x 109/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 109/L.
Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.
Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.
The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.
Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.
Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).
“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”
The investigators reported having no conflicts of interest.
GLASGOW – , according to retrospective analysis of 475 patients from the United Kingdom TTP registry.
In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.
Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.
“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”
To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.
The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.
Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).
The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.
In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).
Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 109/L.
Median platelet count upon presentation was 15 x 109/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 109/L.
Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.
Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.
The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.
Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.
Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).
“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”
The investigators reported having no conflicts of interest.
GLASGOW – , according to retrospective analysis of 475 patients from the United Kingdom TTP registry.
In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.
Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.
“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”
To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.
The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.
Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).
The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.
In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).
Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 109/L.
Median platelet count upon presentation was 15 x 109/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 109/L.
Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.
Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.
The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.
Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.
Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).
“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”
The investigators reported having no conflicts of interest.
REPORTING FROM BSH 2019
Key clinical point: Neurological abnormalities and elevated troponin predict mortality in patients with thrombotic thrombocytopenic purpura (TTP).
Major finding: ADAMTS13 IgG antibody level, elevated troponin, and neurological abnormalities were all linked to an increased mortality risk.
Study details: A retrospective analysis of 475 patients with clinically suspected thrombotic thrombocytopenic purpura (TTP) from the U.K. registry (2009-2018).
Disclosures: The investigators reported having no conflicts of interest.
High-dose MTX-based chemo is well tolerated in older PCNSL patients
GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.
For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.
Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.
Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.
“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”
This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.
The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.
The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.
The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.
The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.
Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).
Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.
A closer look at the data revealed some patterns, Dr. Poynton said.
“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.
Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.
Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.
Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”
He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.
“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”
Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.
GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.
For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.
Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.
Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.
“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”
This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.
The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.
The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.
The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.
The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.
Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).
Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.
A closer look at the data revealed some patterns, Dr. Poynton said.
“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.
Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.
Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.
Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”
He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.
“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”
Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.
GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.
For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.
Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.
Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.
“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”
This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.
The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.
The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.
The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.
The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.
Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).
Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.
A closer look at the data revealed some patterns, Dr. Poynton said.
“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.
Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.
Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.
Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”
He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.
“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”
Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.
REPORTING FROM BSH 2019
Monitoring, early intervention key to CAR T safety
GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.
As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.
“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”
Monitoring
Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.
“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”
Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.
“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”
At MD Anderson, these earlier interventions have decreased severity of adverse events.
“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.
Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.
“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”
Grading toxicity
In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.
“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”
She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.
To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.
“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.
With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.
“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”
Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.
Choosing therapy
When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.
“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”
According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.
“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.
Dr. Nastoupil concluded her presentation with an overview and look to the future.
“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”
Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”
Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.
GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.
As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.
“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”
Monitoring
Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.
“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”
Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.
“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”
At MD Anderson, these earlier interventions have decreased severity of adverse events.
“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.
Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.
“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”
Grading toxicity
In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.
“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”
She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.
To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.
“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.
With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.
“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”
Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.
Choosing therapy
When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.
“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”
According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.
“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.
Dr. Nastoupil concluded her presentation with an overview and look to the future.
“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”
Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”
Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.
GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.
As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.
“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”
Monitoring
Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.
“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”
Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.
“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”
At MD Anderson, these earlier interventions have decreased severity of adverse events.
“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.
Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.
“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”
Grading toxicity
In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.
“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”
She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.
To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.
“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.
With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.
“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”
Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.
Choosing therapy
When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.
“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”
According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.
“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.
Dr. Nastoupil concluded her presentation with an overview and look to the future.
“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”
Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”
Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.
EXPERT ANALYSIS FROM BSH 2019
Complementary medicine use common among patients on TKIs
GLASGOW – Many patients receiving tyrosine kinase inhibitors (TKIs) are taking complementary therapies or eating foods that interfere with TKI metabolism, based on results of a British survey of patients with chronic myeloid leukemia.
About one out of three patients with chronic myeloid leukemia (CML) reported taking complementary medicines, according to lead author David Sparksman, MD, of Norfolk and Norwich (England) University Hospital, and his colleagues.
Only a minority of patients were aware of the potential for dietary interactions with TKIs. However, even knowing the potential risk, about a quarter of patients still didn’t exclude these foods from their diets.
“These worrying results are unlikely to be confined to patients with CML,” the investigators wrote in an abstract presented at the annual meeting of the British Society for Haematology. “TKIs are used in the treatment of many other haematological malignancies.”
Because TKIs are metabolized by cytochrome P450 enzymes, inhibition of these enzymes by complementary therapies and foods may alter metabolism, and therefore, safety and efficacy of TKIs, according to the investigators.
“Use of complementary medicines and belief in their effectiveness is common,” the investigators wrote. “In a recent YouGov poll, 51% of those asked believed herbal medicine to be an effective treatment for illness.”
To investigate the prevalence of these beliefs and practices in a subset of cancer patients, the investigators identified 78 patients with CML undergoing follow-up at Norfolk and Norwich University Hospital. The median age of patients was 60 years. Eleven patients were excluded because they were not receiving a TKI and 6 patients declined to participate, leaving 61 patients in the final survey group.
Of these respondents, 41% had considered taking a complementary therapy and 34% were actively doing so. Further questioning revealed that about half of the patients taking a complementary medicine (52%) were taking a drug with known potential to interact with their TKI. Of these 11 patients, 5 were taking a complementary drug that would reduce serum concentrations of their TKI, potentially making it less effective. Conversely, six patients were taking a complementary drug that would increase serum concentrations, potentially increasing the risk of TKI side effects.
About 39% of respondents were aware of possible dietary interactions with TKIs, such as grapefruit. “Surprisingly,” the investigators said, 25% of patients with this knowledge still included such foods in their diet.
Dietary questioning revealed that among the patients who were unaware of food interactions, 67% were consuming foods that interact with TKIs.
Considering these results, the investigators offered some advice on patient communication and management.
“The use of complementary medicine should be discussed with all patients when starting TKIs and written information given to patients should highlight the potential dangers posed by substances which many patients currently regard as harmless,” thy wrote. “Since most patients will remain on treatment for many years, re-discussion about food and drug interactions should take place periodically to remind them of the potential risks.”
The investigators reported having no conflicts of interest.
GLASGOW – Many patients receiving tyrosine kinase inhibitors (TKIs) are taking complementary therapies or eating foods that interfere with TKI metabolism, based on results of a British survey of patients with chronic myeloid leukemia.
About one out of three patients with chronic myeloid leukemia (CML) reported taking complementary medicines, according to lead author David Sparksman, MD, of Norfolk and Norwich (England) University Hospital, and his colleagues.
Only a minority of patients were aware of the potential for dietary interactions with TKIs. However, even knowing the potential risk, about a quarter of patients still didn’t exclude these foods from their diets.
“These worrying results are unlikely to be confined to patients with CML,” the investigators wrote in an abstract presented at the annual meeting of the British Society for Haematology. “TKIs are used in the treatment of many other haematological malignancies.”
Because TKIs are metabolized by cytochrome P450 enzymes, inhibition of these enzymes by complementary therapies and foods may alter metabolism, and therefore, safety and efficacy of TKIs, according to the investigators.
“Use of complementary medicines and belief in their effectiveness is common,” the investigators wrote. “In a recent YouGov poll, 51% of those asked believed herbal medicine to be an effective treatment for illness.”
To investigate the prevalence of these beliefs and practices in a subset of cancer patients, the investigators identified 78 patients with CML undergoing follow-up at Norfolk and Norwich University Hospital. The median age of patients was 60 years. Eleven patients were excluded because they were not receiving a TKI and 6 patients declined to participate, leaving 61 patients in the final survey group.
Of these respondents, 41% had considered taking a complementary therapy and 34% were actively doing so. Further questioning revealed that about half of the patients taking a complementary medicine (52%) were taking a drug with known potential to interact with their TKI. Of these 11 patients, 5 were taking a complementary drug that would reduce serum concentrations of their TKI, potentially making it less effective. Conversely, six patients were taking a complementary drug that would increase serum concentrations, potentially increasing the risk of TKI side effects.
About 39% of respondents were aware of possible dietary interactions with TKIs, such as grapefruit. “Surprisingly,” the investigators said, 25% of patients with this knowledge still included such foods in their diet.
Dietary questioning revealed that among the patients who were unaware of food interactions, 67% were consuming foods that interact with TKIs.
Considering these results, the investigators offered some advice on patient communication and management.
“The use of complementary medicine should be discussed with all patients when starting TKIs and written information given to patients should highlight the potential dangers posed by substances which many patients currently regard as harmless,” thy wrote. “Since most patients will remain on treatment for many years, re-discussion about food and drug interactions should take place periodically to remind them of the potential risks.”
The investigators reported having no conflicts of interest.
GLASGOW – Many patients receiving tyrosine kinase inhibitors (TKIs) are taking complementary therapies or eating foods that interfere with TKI metabolism, based on results of a British survey of patients with chronic myeloid leukemia.
About one out of three patients with chronic myeloid leukemia (CML) reported taking complementary medicines, according to lead author David Sparksman, MD, of Norfolk and Norwich (England) University Hospital, and his colleagues.
Only a minority of patients were aware of the potential for dietary interactions with TKIs. However, even knowing the potential risk, about a quarter of patients still didn’t exclude these foods from their diets.
“These worrying results are unlikely to be confined to patients with CML,” the investigators wrote in an abstract presented at the annual meeting of the British Society for Haematology. “TKIs are used in the treatment of many other haematological malignancies.”
Because TKIs are metabolized by cytochrome P450 enzymes, inhibition of these enzymes by complementary therapies and foods may alter metabolism, and therefore, safety and efficacy of TKIs, according to the investigators.
“Use of complementary medicines and belief in their effectiveness is common,” the investigators wrote. “In a recent YouGov poll, 51% of those asked believed herbal medicine to be an effective treatment for illness.”
To investigate the prevalence of these beliefs and practices in a subset of cancer patients, the investigators identified 78 patients with CML undergoing follow-up at Norfolk and Norwich University Hospital. The median age of patients was 60 years. Eleven patients were excluded because they were not receiving a TKI and 6 patients declined to participate, leaving 61 patients in the final survey group.
Of these respondents, 41% had considered taking a complementary therapy and 34% were actively doing so. Further questioning revealed that about half of the patients taking a complementary medicine (52%) were taking a drug with known potential to interact with their TKI. Of these 11 patients, 5 were taking a complementary drug that would reduce serum concentrations of their TKI, potentially making it less effective. Conversely, six patients were taking a complementary drug that would increase serum concentrations, potentially increasing the risk of TKI side effects.
About 39% of respondents were aware of possible dietary interactions with TKIs, such as grapefruit. “Surprisingly,” the investigators said, 25% of patients with this knowledge still included such foods in their diet.
Dietary questioning revealed that among the patients who were unaware of food interactions, 67% were consuming foods that interact with TKIs.
Considering these results, the investigators offered some advice on patient communication and management.
“The use of complementary medicine should be discussed with all patients when starting TKIs and written information given to patients should highlight the potential dangers posed by substances which many patients currently regard as harmless,” thy wrote. “Since most patients will remain on treatment for many years, re-discussion about food and drug interactions should take place periodically to remind them of the potential risks.”
The investigators reported having no conflicts of interest.
REPORTING FROM BSH 2019
C3 inhibitor shows potential in PNH and AIHA
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
REPORTING FROM BSH 2019
Targeting parasitic histones may improve outcomes in cerebral malaria
GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.
A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.
“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”
In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”
Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).
These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).
During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.
“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”
Once in circulation, histones can make a bad situation even worse.
“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”
“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.
Based on this hypothesis, the investigators developed an anti-histone therapy.
“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”
Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said.
Concluding his presentation, he looked to the future.
“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.
“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.
The investigators declared no conflicts of interest.
SOURCE: Moxon et al. BSH 2019. Abstract OR-034.
GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.
A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.
“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”
In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”
Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).
These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).
During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.
“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”
Once in circulation, histones can make a bad situation even worse.
“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”
“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.
Based on this hypothesis, the investigators developed an anti-histone therapy.
“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”
Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said.
Concluding his presentation, he looked to the future.
“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.
“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.
The investigators declared no conflicts of interest.
SOURCE: Moxon et al. BSH 2019. Abstract OR-034.
GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.
A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.
“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”
In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”
Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).
These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).
During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.
“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”
Once in circulation, histones can make a bad situation even worse.
“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”
“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.
Based on this hypothesis, the investigators developed an anti-histone therapy.
“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”
Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said.
Concluding his presentation, he looked to the future.
“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.
“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.
The investigators declared no conflicts of interest.
SOURCE: Moxon et al. BSH 2019. Abstract OR-034.
REPORTING FROM BSH 2019
Early data support R-BAC for post-BTKi mantle cell lymphoma
GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.
Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.
This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.
Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.
Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.
All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m2 or 500 mg) on day 1, bendamustine 70 mg/m2 on days 1 and 2, and cytarabine 500 mg/m2 on days 1 through 3, given in a 28-day cycle.
Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.
Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.
Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.
For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).
The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.
The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.
Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”
During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.
“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”
The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.
In an interview, Dr. Rule added perspective to these findings.
“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”
However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.
Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.
He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”
With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.
The investigators reported having no conflicts of interest.
GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.
Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.
This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.
Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.
Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.
All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m2 or 500 mg) on day 1, bendamustine 70 mg/m2 on days 1 and 2, and cytarabine 500 mg/m2 on days 1 through 3, given in a 28-day cycle.
Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.
Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.
Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.
For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).
The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.
The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.
Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”
During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.
“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”
The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.
In an interview, Dr. Rule added perspective to these findings.
“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”
However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.
Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.
He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”
With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.
The investigators reported having no conflicts of interest.
GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.
Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.
This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.
Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.
Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.
All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m2 or 500 mg) on day 1, bendamustine 70 mg/m2 on days 1 and 2, and cytarabine 500 mg/m2 on days 1 through 3, given in a 28-day cycle.
Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.
Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.
Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.
For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).
The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.
The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.
Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”
During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.
“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”
The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.
In an interview, Dr. Rule added perspective to these findings.
“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”
However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.
Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.
He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”
With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.
The investigators reported having no conflicts of interest.
REPORTING FROM BSH 2019
Real world responses mirror TOURMALINE-MM1 data
Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.
Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).
Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”
This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.
“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.
In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.
The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.
About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).
Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.
Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.
Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.
Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.
“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”
When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.
However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.
“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.
The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.
SOURCE: Cook G et al. BSH 2019, Abstract OR-018.
Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.
Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).
Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”
This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.
“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.
In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.
The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.
About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).
Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.
Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.
Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.
Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.
“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”
When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.
However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.
“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.
The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.
SOURCE: Cook G et al. BSH 2019, Abstract OR-018.
Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.
Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).
Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”
This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.
“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.
In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.
The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.
About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).
Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.
Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.
Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.
Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.
“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”
When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.
However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.
“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.
The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.
SOURCE: Cook G et al. BSH 2019, Abstract OR-018.
Reporting from BSH 2019
Whole-genome sequencing demonstrates clinical relevance
GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.
A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.
Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.
“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.
The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.
Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.
Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.
“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”
Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.
Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.
“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”
Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.
“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.
Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”
The study was sponsored by NHS England. The investigators reported having no conflicts of interest.
SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.
GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.
A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.
Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.
“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.
The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.
Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.
Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.
“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”
Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.
Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.
“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”
Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.
“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.
Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”
The study was sponsored by NHS England. The investigators reported having no conflicts of interest.
SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.
GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.
A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.
Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.
“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.
The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.
Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.
Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.
“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”
Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.
Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.
“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”
Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.
“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.
Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”
The study was sponsored by NHS England. The investigators reported having no conflicts of interest.
SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.
REPORTING FROM BSH 2019