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Majority of AML patients do not receive recommended molecular genetic testing
CHICAGO—While 67% of newly diagnosed patients with acute myeloid leukemia (AML) receive some genetic testing, only 9% receive all 7 of the genetic tests recommended by the National Comprehensive Cancer Network (NCCN), according to new research.
The data comes from the CONNECT MDS/AML Disease Registry, which collects treatment and outcome statistics from 86 sites across the United States, both academic medical centers and community settings. The findings reflect data gathered from 2013 to 2016.
Previously, data on genetic testing in AML patients came primarily from clinical trials, where adherence to guidelines is very high. The current analysis evaluated adherence to genetic testing guidelines in AML treated outside the clinic trial setting.
Daniel A. Pollyea, MD, of the University of Colorado Comprehensive Cancer Center in Aurora, presented the findings on behalf of the CONNECT MDS/AML Disease Registry Scientific Steering Committee (abstract 7022).
The CONNECT registry is a US prospective, observational cohort study of patients with newly diagnosed AML or myelodysplastic syndromes (MDS) aged 55 years or older. Enrollment is ongoing and study clinicians make all clinical decisions.
NCCN guidelines recommend testing AML patients for NPM1, FLT3-ITD, CEBPA, IDH1, IDH2, DNMT3A, and KIT mutations.
“We now know a tremendous amount about the genetic underpinnings of the disease,” Dr Pollyea said.
“We can test for these genetic changes in the clinic to see what’s making a patient’s disease tick. And often there are targeted therapies that can be matched with these genetic changes," he added. "But there’s a disconnect between what can be done, what should be done, and what is being done.”
The current analysis evaluated genetic testing in 259 AML patients, 173 (67%) of whom had some genetic testing.
The likelihood of patients getting tested varied by type of treatment center, age, karyotype, and insurance.
Patients treated at academic medical centers had higher rates of testing than those treated at community clinics (76% and 62%, respectively), P= 0.018
Patients younger than 65 years more often were tested than older patients (83% and 60%, respectively), P= 0.0003.
Patients with non-Medicare insurance were more often tested than those with Medicare (74% and 61%, respectively), P= .025.
And patients with normal karyotype were more often tested than those with abnormal karyotype (77% and 59%, respectively), P= 0.006.
Of the 173 patients who had some genetic testing, only 15 (9%) had all the molecular tests recommended by NCCN.
Of the 7 recommended tests, NPM1 (77%) and FLT3-ITD (76%) were most often reported and DNMT3A least often (16%).
Dr Pollyea attributed the lack of adherence to the guidelines in part to willingness of insurance companies to pay for testing.
He also suggested the guidelines themselves might need adjustment, given the low adherence rate.
Nevertheless, he affirmed the guidelines are well founded. “I think the guidelines are pretty solid and, in my opinion, I would say they don’t go far enough in recommending genetic testing.”
“We’re in our infancy with this testing, and even earlier than infancy in seeing how we’re doing on testing. But now with this registry we at least have the infrastructure available to ask these kinds of questions,” Dr Pollyea added. 
CHICAGO—While 67% of newly diagnosed patients with acute myeloid leukemia (AML) receive some genetic testing, only 9% receive all 7 of the genetic tests recommended by the National Comprehensive Cancer Network (NCCN), according to new research.
The data comes from the CONNECT MDS/AML Disease Registry, which collects treatment and outcome statistics from 86 sites across the United States, both academic medical centers and community settings. The findings reflect data gathered from 2013 to 2016.
Previously, data on genetic testing in AML patients came primarily from clinical trials, where adherence to guidelines is very high. The current analysis evaluated adherence to genetic testing guidelines in AML treated outside the clinic trial setting.
Daniel A. Pollyea, MD, of the University of Colorado Comprehensive Cancer Center in Aurora, presented the findings on behalf of the CONNECT MDS/AML Disease Registry Scientific Steering Committee (abstract 7022).
The CONNECT registry is a US prospective, observational cohort study of patients with newly diagnosed AML or myelodysplastic syndromes (MDS) aged 55 years or older. Enrollment is ongoing and study clinicians make all clinical decisions.
NCCN guidelines recommend testing AML patients for NPM1, FLT3-ITD, CEBPA, IDH1, IDH2, DNMT3A, and KIT mutations.
“We now know a tremendous amount about the genetic underpinnings of the disease,” Dr Pollyea said.
“We can test for these genetic changes in the clinic to see what’s making a patient’s disease tick. And often there are targeted therapies that can be matched with these genetic changes," he added. "But there’s a disconnect between what can be done, what should be done, and what is being done.”
The current analysis evaluated genetic testing in 259 AML patients, 173 (67%) of whom had some genetic testing.
The likelihood of patients getting tested varied by type of treatment center, age, karyotype, and insurance.
Patients treated at academic medical centers had higher rates of testing than those treated at community clinics (76% and 62%, respectively), P= 0.018
Patients younger than 65 years more often were tested than older patients (83% and 60%, respectively), P= 0.0003.
Patients with non-Medicare insurance were more often tested than those with Medicare (74% and 61%, respectively), P= .025.
And patients with normal karyotype were more often tested than those with abnormal karyotype (77% and 59%, respectively), P= 0.006.
Of the 173 patients who had some genetic testing, only 15 (9%) had all the molecular tests recommended by NCCN.
Of the 7 recommended tests, NPM1 (77%) and FLT3-ITD (76%) were most often reported and DNMT3A least often (16%).
Dr Pollyea attributed the lack of adherence to the guidelines in part to willingness of insurance companies to pay for testing.
He also suggested the guidelines themselves might need adjustment, given the low adherence rate.
Nevertheless, he affirmed the guidelines are well founded. “I think the guidelines are pretty solid and, in my opinion, I would say they don’t go far enough in recommending genetic testing.”
“We’re in our infancy with this testing, and even earlier than infancy in seeing how we’re doing on testing. But now with this registry we at least have the infrastructure available to ask these kinds of questions,” Dr Pollyea added.
CHICAGO—While 67% of newly diagnosed patients with acute myeloid leukemia (AML) receive some genetic testing, only 9% receive all 7 of the genetic tests recommended by the National Comprehensive Cancer Network (NCCN), according to new research.
The data comes from the CONNECT MDS/AML Disease Registry, which collects treatment and outcome statistics from 86 sites across the United States, both academic medical centers and community settings. The findings reflect data gathered from 2013 to 2016.
Previously, data on genetic testing in AML patients came primarily from clinical trials, where adherence to guidelines is very high. The current analysis evaluated adherence to genetic testing guidelines in AML treated outside the clinic trial setting.
Daniel A. Pollyea, MD, of the University of Colorado Comprehensive Cancer Center in Aurora, presented the findings on behalf of the CONNECT MDS/AML Disease Registry Scientific Steering Committee (abstract 7022).
The CONNECT registry is a US prospective, observational cohort study of patients with newly diagnosed AML or myelodysplastic syndromes (MDS) aged 55 years or older. Enrollment is ongoing and study clinicians make all clinical decisions.
NCCN guidelines recommend testing AML patients for NPM1, FLT3-ITD, CEBPA, IDH1, IDH2, DNMT3A, and KIT mutations.
“We now know a tremendous amount about the genetic underpinnings of the disease,” Dr Pollyea said.
“We can test for these genetic changes in the clinic to see what’s making a patient’s disease tick. And often there are targeted therapies that can be matched with these genetic changes," he added. "But there’s a disconnect between what can be done, what should be done, and what is being done.”
The current analysis evaluated genetic testing in 259 AML patients, 173 (67%) of whom had some genetic testing.
The likelihood of patients getting tested varied by type of treatment center, age, karyotype, and insurance.
Patients treated at academic medical centers had higher rates of testing than those treated at community clinics (76% and 62%, respectively), P= 0.018
Patients younger than 65 years more often were tested than older patients (83% and 60%, respectively), P= 0.0003.
Patients with non-Medicare insurance were more often tested than those with Medicare (74% and 61%, respectively), P= .025.
And patients with normal karyotype were more often tested than those with abnormal karyotype (77% and 59%, respectively), P= 0.006.
Of the 173 patients who had some genetic testing, only 15 (9%) had all the molecular tests recommended by NCCN.
Of the 7 recommended tests, NPM1 (77%) and FLT3-ITD (76%) were most often reported and DNMT3A least often (16%).
Dr Pollyea attributed the lack of adherence to the guidelines in part to willingness of insurance companies to pay for testing.
He also suggested the guidelines themselves might need adjustment, given the low adherence rate.
Nevertheless, he affirmed the guidelines are well founded. “I think the guidelines are pretty solid and, in my opinion, I would say they don’t go far enough in recommending genetic testing.”
“We’re in our infancy with this testing, and even earlier than infancy in seeing how we’re doing on testing. But now with this registry we at least have the infrastructure available to ask these kinds of questions,” Dr Pollyea added.
Researchers design new, safer antiplatelet drug based on snake venom
Researchers say they have designed an antiplatelet drug based on snake venom protein that stimulates platelets to form blood clots by latching onto glycoprotein VI (GPVI), which is safer than some currently available antiplatelet drugs that target glycoproteins IIb/IIIa.
Earlier studies have shown that platelets missing GPVI do not form clots and do not lead to severe bleeding.
The researchers, therefore, designed a drug to interact with the protein glycoprotein VI.
They used trowaglerix, a protein in the venom of the Tropidolaemus wagleri snake, to block GPVI activity.
An earlier study by the team found that trowaglerix worked through GPVI antagonism.
Some currently available antiplatelet drugs are also based on protein found in snake venom but target GPIIa/IIIb instead, which leads to the side effect of bleeding.
“[W]hy that target leads to the bleeding side effect is not fully understood,” said lead co-author Tur-Fu Huang, PhD, of the National Taiwan University in Taipei.
Specifically, the team sequenced trowaglerix and found an alpha subunit that specifically targeted GPVI snaclec, which is snake venom C-type lectin protein.
They then used computational peptide design to create a series of Troα6/Troα10 peptides—a hexapeptide and decapeptide, respectively—which were derived from trowaglerix.
Mice administered this new drug, researchers report, had slower blood clot formation compared to untreated mice. In addition, the treated mice did not bleed longer than the untreated mice.
The team believes their research supports the concept that these hexa/decapeptides have therapeutic potential and can be a template for a new, safer class of antiplatelet drug with a limited bleeding side effect.
“In general, this type of molecule design does not last long in the body,” said co-author Jane Tseng, PhD, also of the National Taiwan University, “so techniques like formulation or delivery system are likely needed to extend the exposure time in the human body.”
She also indicated that the design needs to be optimized, “to ensure that the molecule only interacts with GPVI and not other proteins which can cause unintended reactions.”
The research team reported its findings in Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association journal.
The National Science Council of Taiwan supported the study. 
Researchers say they have designed an antiplatelet drug based on snake venom protein that stimulates platelets to form blood clots by latching onto glycoprotein VI (GPVI), which is safer than some currently available antiplatelet drugs that target glycoproteins IIb/IIIa.
Earlier studies have shown that platelets missing GPVI do not form clots and do not lead to severe bleeding.
The researchers, therefore, designed a drug to interact with the protein glycoprotein VI.
They used trowaglerix, a protein in the venom of the Tropidolaemus wagleri snake, to block GPVI activity.
An earlier study by the team found that trowaglerix worked through GPVI antagonism.
Some currently available antiplatelet drugs are also based on protein found in snake venom but target GPIIa/IIIb instead, which leads to the side effect of bleeding.
“[W]hy that target leads to the bleeding side effect is not fully understood,” said lead co-author Tur-Fu Huang, PhD, of the National Taiwan University in Taipei.
Specifically, the team sequenced trowaglerix and found an alpha subunit that specifically targeted GPVI snaclec, which is snake venom C-type lectin protein.
They then used computational peptide design to create a series of Troα6/Troα10 peptides—a hexapeptide and decapeptide, respectively—which were derived from trowaglerix.
Mice administered this new drug, researchers report, had slower blood clot formation compared to untreated mice. In addition, the treated mice did not bleed longer than the untreated mice.
The team believes their research supports the concept that these hexa/decapeptides have therapeutic potential and can be a template for a new, safer class of antiplatelet drug with a limited bleeding side effect.
“In general, this type of molecule design does not last long in the body,” said co-author Jane Tseng, PhD, also of the National Taiwan University, “so techniques like formulation or delivery system are likely needed to extend the exposure time in the human body.”
She also indicated that the design needs to be optimized, “to ensure that the molecule only interacts with GPVI and not other proteins which can cause unintended reactions.”
The research team reported its findings in Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association journal.
The National Science Council of Taiwan supported the study.
Researchers say they have designed an antiplatelet drug based on snake venom protein that stimulates platelets to form blood clots by latching onto glycoprotein VI (GPVI), which is safer than some currently available antiplatelet drugs that target glycoproteins IIb/IIIa.
Earlier studies have shown that platelets missing GPVI do not form clots and do not lead to severe bleeding.
The researchers, therefore, designed a drug to interact with the protein glycoprotein VI.
They used trowaglerix, a protein in the venom of the Tropidolaemus wagleri snake, to block GPVI activity.
An earlier study by the team found that trowaglerix worked through GPVI antagonism.
Some currently available antiplatelet drugs are also based on protein found in snake venom but target GPIIa/IIIb instead, which leads to the side effect of bleeding.
“[W]hy that target leads to the bleeding side effect is not fully understood,” said lead co-author Tur-Fu Huang, PhD, of the National Taiwan University in Taipei.
Specifically, the team sequenced trowaglerix and found an alpha subunit that specifically targeted GPVI snaclec, which is snake venom C-type lectin protein.
They then used computational peptide design to create a series of Troα6/Troα10 peptides—a hexapeptide and decapeptide, respectively—which were derived from trowaglerix.
Mice administered this new drug, researchers report, had slower blood clot formation compared to untreated mice. In addition, the treated mice did not bleed longer than the untreated mice.
The team believes their research supports the concept that these hexa/decapeptides have therapeutic potential and can be a template for a new, safer class of antiplatelet drug with a limited bleeding side effect.
“In general, this type of molecule design does not last long in the body,” said co-author Jane Tseng, PhD, also of the National Taiwan University, “so techniques like formulation or delivery system are likely needed to extend the exposure time in the human body.”
She also indicated that the design needs to be optimized, “to ensure that the molecule only interacts with GPVI and not other proteins which can cause unintended reactions.”
The research team reported its findings in Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association journal.
The National Science Council of Taiwan supported the study.
EU label for nilotinib now includes info on stopping therapy
The European Commission has approved the inclusion of treatment-free remission (TFR) data in the European Union (EU) product information for nilotinib (Tasigna®).
TFR is the ability to maintain molecular response after stopping tyrosine kinase inhibitor (TKI) therapy in patients with Ph+ chronic myeloid leukemia in chronic phase (CML-CP).
Nilotinib is approved for the treatment of CML-CP in adults resistant or intolerant to at least one prior therapy, including imatinib, and for the treatment of adults with newly diagnosed Ph+ CML.
Nilotinib is the first and only TKI to include TFR data in its product information in the EU, according to Novartis, developer of the drug.
Two large international Ph+ CML trials assessing nilotinib discontinuation—ENESTfreedom and ENESTop—formed the basis of the decision.
The two open-label trials showed that half of Ph+ CML-CP patients who met rigorous predefined response criteria maintained TFR after stopping nilotinib, both in the frontline setting and after switching from imatinib.
Both trials included regular and frequent molecular monitoring of BCR-ABL levels with an assay that could measure transcript levels down to a molecular response (MR) of 4.5. Frequent monitoring after discontinuation helped determine loss of MR 4.0 and major molecular response, indicating the need to re-initiate treatment.
This phase 2 trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Following REsponsE in De nOvo CML-CP Patients) involved 215 patients with Ph+ CML-CP treated at 132 sites across 19 countries.
The trial evaluated whether treatment could be stopped in 190 of the patients after they had achieved a response of MR 4.5 and a sustained deep molecular response for 1 year as first-line treatment.
The results showed that 51.6% of the patients in the trial could discontinue therapy and remain in TFR at the 48-week analysis.
However, ENESTfreedom did not meet its primary endpoint of 50% or more of patients in MMR at 48 weeks in the TFR phase. The median treatment duration was 3.6 years.
Adverse events in the trial included musculoskeletal pain (24.7%) during the first years of the TFR phase compared with 16.3% in those still on nilotinib.
No patient progressed to advanced phase/blast crisis.
This phase 2 trial (Evaluating Nilotinib Efficacy and Safety Trial) involved 163 patients with Ph+ CML-CP treated at 63 sites across 18 countries. Investigators evaluated 126 patients who had been treated with imatinib and then switched to nilotinib and had achieved a sustained deep molecular response for 1 year while on nilotinib.
The trial demonstrated that 57.9% of patients maintained a molecular resonse at 48 weeks after stopping treatment. The trial met its primary endpoint—the proportion of patients who did not lose MR 4.0 or MMR within 48 weeks of discontinuing nilotinib in the TFR phase.
Again, the rates of musuloskeletal pain were higher in the first year of TFR than in patients still on nilotinib in the consolidation phase, 42.1% and 14.3%, respectively.
Results of the EURO-SKI trial also support the idea that certain CML patients can safely stop TKI therapy.
For full prescribing information, see the product insert.
The European Commission has approved the inclusion of treatment-free remission (TFR) data in the European Union (EU) product information for nilotinib (Tasigna®).
TFR is the ability to maintain molecular response after stopping tyrosine kinase inhibitor (TKI) therapy in patients with Ph+ chronic myeloid leukemia in chronic phase (CML-CP).
Nilotinib is approved for the treatment of CML-CP in adults resistant or intolerant to at least one prior therapy, including imatinib, and for the treatment of adults with newly diagnosed Ph+ CML.
Nilotinib is the first and only TKI to include TFR data in its product information in the EU, according to Novartis, developer of the drug.
Two large international Ph+ CML trials assessing nilotinib discontinuation—ENESTfreedom and ENESTop—formed the basis of the decision.
The two open-label trials showed that half of Ph+ CML-CP patients who met rigorous predefined response criteria maintained TFR after stopping nilotinib, both in the frontline setting and after switching from imatinib.
Both trials included regular and frequent molecular monitoring of BCR-ABL levels with an assay that could measure transcript levels down to a molecular response (MR) of 4.5. Frequent monitoring after discontinuation helped determine loss of MR 4.0 and major molecular response, indicating the need to re-initiate treatment.
This phase 2 trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Following REsponsE in De nOvo CML-CP Patients) involved 215 patients with Ph+ CML-CP treated at 132 sites across 19 countries.
The trial evaluated whether treatment could be stopped in 190 of the patients after they had achieved a response of MR 4.5 and a sustained deep molecular response for 1 year as first-line treatment.
The results showed that 51.6% of the patients in the trial could discontinue therapy and remain in TFR at the 48-week analysis.
However, ENESTfreedom did not meet its primary endpoint of 50% or more of patients in MMR at 48 weeks in the TFR phase. The median treatment duration was 3.6 years.
Adverse events in the trial included musculoskeletal pain (24.7%) during the first years of the TFR phase compared with 16.3% in those still on nilotinib.
No patient progressed to advanced phase/blast crisis.
This phase 2 trial (Evaluating Nilotinib Efficacy and Safety Trial) involved 163 patients with Ph+ CML-CP treated at 63 sites across 18 countries. Investigators evaluated 126 patients who had been treated with imatinib and then switched to nilotinib and had achieved a sustained deep molecular response for 1 year while on nilotinib.
The trial demonstrated that 57.9% of patients maintained a molecular resonse at 48 weeks after stopping treatment. The trial met its primary endpoint—the proportion of patients who did not lose MR 4.0 or MMR within 48 weeks of discontinuing nilotinib in the TFR phase.
Again, the rates of musuloskeletal pain were higher in the first year of TFR than in patients still on nilotinib in the consolidation phase, 42.1% and 14.3%, respectively.
Results of the EURO-SKI trial also support the idea that certain CML patients can safely stop TKI therapy.
For full prescribing information, see the product insert.
The European Commission has approved the inclusion of treatment-free remission (TFR) data in the European Union (EU) product information for nilotinib (Tasigna®).
TFR is the ability to maintain molecular response after stopping tyrosine kinase inhibitor (TKI) therapy in patients with Ph+ chronic myeloid leukemia in chronic phase (CML-CP).
Nilotinib is approved for the treatment of CML-CP in adults resistant or intolerant to at least one prior therapy, including imatinib, and for the treatment of adults with newly diagnosed Ph+ CML.
Nilotinib is the first and only TKI to include TFR data in its product information in the EU, according to Novartis, developer of the drug.
Two large international Ph+ CML trials assessing nilotinib discontinuation—ENESTfreedom and ENESTop—formed the basis of the decision.
The two open-label trials showed that half of Ph+ CML-CP patients who met rigorous predefined response criteria maintained TFR after stopping nilotinib, both in the frontline setting and after switching from imatinib.
Both trials included regular and frequent molecular monitoring of BCR-ABL levels with an assay that could measure transcript levels down to a molecular response (MR) of 4.5. Frequent monitoring after discontinuation helped determine loss of MR 4.0 and major molecular response, indicating the need to re-initiate treatment.
This phase 2 trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Following REsponsE in De nOvo CML-CP Patients) involved 215 patients with Ph+ CML-CP treated at 132 sites across 19 countries.
The trial evaluated whether treatment could be stopped in 190 of the patients after they had achieved a response of MR 4.5 and a sustained deep molecular response for 1 year as first-line treatment.
The results showed that 51.6% of the patients in the trial could discontinue therapy and remain in TFR at the 48-week analysis.
However, ENESTfreedom did not meet its primary endpoint of 50% or more of patients in MMR at 48 weeks in the TFR phase. The median treatment duration was 3.6 years.
Adverse events in the trial included musculoskeletal pain (24.7%) during the first years of the TFR phase compared with 16.3% in those still on nilotinib.
No patient progressed to advanced phase/blast crisis.
This phase 2 trial (Evaluating Nilotinib Efficacy and Safety Trial) involved 163 patients with Ph+ CML-CP treated at 63 sites across 18 countries. Investigators evaluated 126 patients who had been treated with imatinib and then switched to nilotinib and had achieved a sustained deep molecular response for 1 year while on nilotinib.
The trial demonstrated that 57.9% of patients maintained a molecular resonse at 48 weeks after stopping treatment. The trial met its primary endpoint—the proportion of patients who did not lose MR 4.0 or MMR within 48 weeks of discontinuing nilotinib in the TFR phase.
Again, the rates of musuloskeletal pain were higher in the first year of TFR than in patients still on nilotinib in the consolidation phase, 42.1% and 14.3%, respectively.
Results of the EURO-SKI trial also support the idea that certain CML patients can safely stop TKI therapy.
For full prescribing information, see the product insert.
Dasatinib potentially a new SOC for children with CML-CP
CHICAGO—The largest ongoing and prospective trial of pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP), according to the best knowledge of the investigators, has found dasatinib to be safe and effective as first- or second-line therapy for these children.
Patients refractory to or intolerant of imatinib had a major cytogenetic response (MCyR) by 3 months and responses at 12 and 24 months exceeded 90%.
Newly diagnosed patients had a complete cytogenetic response (CCyR) by 6 months.
“We believe our data suggests that dasatinib could be considered as a new standard of care (SOC) for children with CML in chronic phase,” said study author Lia Gore, MD, of the University of Colorado School of Medicine/Children’s Hospital Colorado in Aurora.
She presented the findings of the study at the ASCO 2017 Annual Meeting (abstract 10511).
Study design
CA 180-226 is a phase 2, open-label, nonrandomized, prospective study conducted in 18 countries. Patients younger than 18 years with newly diagnosed CML-CP, or imatinib-resistant/intolerant (R/I) CML-CP, or CML in accelerated phase, or Ph+ acute lymphoblastic leukemia (ALL) were enrolled on the study between March 2009 and September 2014.
Dr Gore’s presentation focused on the CML-CP patients in the study, both the newly diagnosed and the imatinib-R/I patients.
The imatinib-R/I patients received dasatinib 60 mg/m2 tablets once daily, and the newly diagnosed patients received the same tablet dosage daily or a powdered formulation for oral suspension (PFOS) of dasatinib at 72 mg/m2 daily.
Dr Gore noted the different dosage in the oral suspension formulation is based on bioavailability studies performed in adults, which was determined to be equivalent to the 60 mg/m2 tablet formulation.
Once accrual was reached in the tablet cohort, newly diagnosed patients were accrued to the PFOS cohort. The patients on PFOS could switch to tablets after a year or more on the oral suspension.
Patients remained on treatment until disease progression, unacceptable toxicity occurred, or the patient/physician preference.
All patients had a minimum follow-up of 2 years. The longest follow-up was more than 90 months.
Primary objectives of the study were MCyR greater than 30% for imatinib-R/I patients and complete CCyR greater than 55% for newly diagnosed patients.
Secondary objectives included time to and duration of response, major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety.
Baseline patient characteristics
One hundred thirteen patients were treated across the 3 cohorts—29 in the imatinib-R/I receiving tablets, 51 newly diagnosed patients receiving tablets, and 33 newly diagnosed patients in the PFOS arm. A total of 84 patients had newly diagnosed disease.
Of the 29 imatinib-R/I patients, 25 were resistant, 2 intolerant, and 2 undetermined. And 6 of the 25 resistant patients had defined imatinib-resistance mutations.
Median age was 13.8 years in the imatinib-R/I cohort, 12.9 years in the newly diagnosed on tablets, and 11.7 years in the PFOS group. Other baseline characteristics were similar among the cohorts.
“Importantly, there were 3 patients less than 2 years of age, and a substantial proportion of patients were actually less than 12 years of age,” Dr Gore pointed out.
Dasatinib exposure
The median duration of therapy was 50 months and 42 months in the R/I and newly diagnosed cohorts, respectively.
Forty-eight percent of the imatinib-R/I patients and 73% of the newly diagnosed patients are still on treatment. A relatively small number of patients discontinued therapy.
The median duration of therapy was shorter in the PFOS cohort because they were enrolled only after accrual to the tablet cohort. However, they were also followed up for more than 2 years.
Of the 33 patients on PFOS, 22 eventually switched to tablet formulation.
Results
The primary endpoint for imatinib-R/I patients—MCyR greater than 30%—was reached by 3 months, and MCyR at 12 and 24 months exceeded 90%. The median time to response was 3.1 months (range, 2.8 – 4.1), and median duration of response was not yet reached (range, 54.9 – not estimable).
For newly diagnosed patients, the preset defined rate of interest of 55% for CCyR was reached as early as 6 months, and exceeded 90% by 12 and 24 months.
Dr Gore pointed out that intolerant patients also reached CCyR relatively quickly, although it was not a specified endpoint.
Data indicate that responses occurred relatively quickly and continued to increase over time of follow-up.
MMR also continued to increase over time and showed no difference between formulation and response rate.
Median PFS has not been reached, as only 7 patients in each cohort had disease progression.
One imatinib-R/I patient died 1 year after stopping treatment. The patient, who had a GI bleed unrelated to dasatinib, had discontinued therapy for progressive disease with loss of MCyR.
Safety
Overall safety was very similar to the dasatinib exposure and experience in adults, Dr Gore said, and there were no differences in events between PFOS and tablets.
One patient in the PFOS cohort had a dasatinib-related grade 3 hypersensitivity reaction, which resolved after discontinuation of dasatinib.
“What’s important here,” she said, “is that there were almost no adverse events of severity in either cohort, only 1 in the imatinib refractory and intolerant and 1 in the newly diagnosed cohorts.”
“Most importantly for those of us with a lot of experience in this field,” she added, “there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, pulmonary hypertension, or any vascular occlusive events in patients noted on this trial.”
“Additionally, for pediatricians, we care a lot about what happens to growth in these patients and prospectively we collected a lot of data related to growth parameters in bone growth and development."
Of the dasatinib-related adverse events occurring in 10% or more of patients, there were only 5 growth and development events noted out of the 113 patients treated and all were grade 1 or 2 events, Dr Gore pointed out.
In the R/I cohort, one patient had osteopenia and gynecomastia. At the time of data analysis, this event had resolved even though the patient continued on dasatinib.
“We believe our data suggests that dasatinib could be considered as a new standard of care for children with CML in chronic phase,” she said.
“It includes the advantage of a liquid formulation as well as the advantages of once daily dosing and administration without regard to fed or fasting state,” she added, “which for all of us who treat children know could be quite important.”
The study was funded by Bristol-Myers Squibb.
CHICAGO—The largest ongoing and prospective trial of pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP), according to the best knowledge of the investigators, has found dasatinib to be safe and effective as first- or second-line therapy for these children.
Patients refractory to or intolerant of imatinib had a major cytogenetic response (MCyR) by 3 months and responses at 12 and 24 months exceeded 90%.
Newly diagnosed patients had a complete cytogenetic response (CCyR) by 6 months.
“We believe our data suggests that dasatinib could be considered as a new standard of care (SOC) for children with CML in chronic phase,” said study author Lia Gore, MD, of the University of Colorado School of Medicine/Children’s Hospital Colorado in Aurora.
She presented the findings of the study at the ASCO 2017 Annual Meeting (abstract 10511).
Study design
CA 180-226 is a phase 2, open-label, nonrandomized, prospective study conducted in 18 countries. Patients younger than 18 years with newly diagnosed CML-CP, or imatinib-resistant/intolerant (R/I) CML-CP, or CML in accelerated phase, or Ph+ acute lymphoblastic leukemia (ALL) were enrolled on the study between March 2009 and September 2014.
Dr Gore’s presentation focused on the CML-CP patients in the study, both the newly diagnosed and the imatinib-R/I patients.
The imatinib-R/I patients received dasatinib 60 mg/m2 tablets once daily, and the newly diagnosed patients received the same tablet dosage daily or a powdered formulation for oral suspension (PFOS) of dasatinib at 72 mg/m2 daily.
Dr Gore noted the different dosage in the oral suspension formulation is based on bioavailability studies performed in adults, which was determined to be equivalent to the 60 mg/m2 tablet formulation.
Once accrual was reached in the tablet cohort, newly diagnosed patients were accrued to the PFOS cohort. The patients on PFOS could switch to tablets after a year or more on the oral suspension.
Patients remained on treatment until disease progression, unacceptable toxicity occurred, or the patient/physician preference.
All patients had a minimum follow-up of 2 years. The longest follow-up was more than 90 months.
Primary objectives of the study were MCyR greater than 30% for imatinib-R/I patients and complete CCyR greater than 55% for newly diagnosed patients.
Secondary objectives included time to and duration of response, major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety.
Baseline patient characteristics
One hundred thirteen patients were treated across the 3 cohorts—29 in the imatinib-R/I receiving tablets, 51 newly diagnosed patients receiving tablets, and 33 newly diagnosed patients in the PFOS arm. A total of 84 patients had newly diagnosed disease.
Of the 29 imatinib-R/I patients, 25 were resistant, 2 intolerant, and 2 undetermined. And 6 of the 25 resistant patients had defined imatinib-resistance mutations.
Median age was 13.8 years in the imatinib-R/I cohort, 12.9 years in the newly diagnosed on tablets, and 11.7 years in the PFOS group. Other baseline characteristics were similar among the cohorts.
“Importantly, there were 3 patients less than 2 years of age, and a substantial proportion of patients were actually less than 12 years of age,” Dr Gore pointed out.
Dasatinib exposure
The median duration of therapy was 50 months and 42 months in the R/I and newly diagnosed cohorts, respectively.
Forty-eight percent of the imatinib-R/I patients and 73% of the newly diagnosed patients are still on treatment. A relatively small number of patients discontinued therapy.
The median duration of therapy was shorter in the PFOS cohort because they were enrolled only after accrual to the tablet cohort. However, they were also followed up for more than 2 years.
Of the 33 patients on PFOS, 22 eventually switched to tablet formulation.
Results
The primary endpoint for imatinib-R/I patients—MCyR greater than 30%—was reached by 3 months, and MCyR at 12 and 24 months exceeded 90%. The median time to response was 3.1 months (range, 2.8 – 4.1), and median duration of response was not yet reached (range, 54.9 – not estimable).
For newly diagnosed patients, the preset defined rate of interest of 55% for CCyR was reached as early as 6 months, and exceeded 90% by 12 and 24 months.
Dr Gore pointed out that intolerant patients also reached CCyR relatively quickly, although it was not a specified endpoint.
Data indicate that responses occurred relatively quickly and continued to increase over time of follow-up.
MMR also continued to increase over time and showed no difference between formulation and response rate.
Median PFS has not been reached, as only 7 patients in each cohort had disease progression.
One imatinib-R/I patient died 1 year after stopping treatment. The patient, who had a GI bleed unrelated to dasatinib, had discontinued therapy for progressive disease with loss of MCyR.
Safety
Overall safety was very similar to the dasatinib exposure and experience in adults, Dr Gore said, and there were no differences in events between PFOS and tablets.
One patient in the PFOS cohort had a dasatinib-related grade 3 hypersensitivity reaction, which resolved after discontinuation of dasatinib.
“What’s important here,” she said, “is that there were almost no adverse events of severity in either cohort, only 1 in the imatinib refractory and intolerant and 1 in the newly diagnosed cohorts.”
“Most importantly for those of us with a lot of experience in this field,” she added, “there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, pulmonary hypertension, or any vascular occlusive events in patients noted on this trial.”
“Additionally, for pediatricians, we care a lot about what happens to growth in these patients and prospectively we collected a lot of data related to growth parameters in bone growth and development."
Of the dasatinib-related adverse events occurring in 10% or more of patients, there were only 5 growth and development events noted out of the 113 patients treated and all were grade 1 or 2 events, Dr Gore pointed out.
In the R/I cohort, one patient had osteopenia and gynecomastia. At the time of data analysis, this event had resolved even though the patient continued on dasatinib.
“We believe our data suggests that dasatinib could be considered as a new standard of care for children with CML in chronic phase,” she said.
“It includes the advantage of a liquid formulation as well as the advantages of once daily dosing and administration without regard to fed or fasting state,” she added, “which for all of us who treat children know could be quite important.”
The study was funded by Bristol-Myers Squibb.
CHICAGO—The largest ongoing and prospective trial of pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP), according to the best knowledge of the investigators, has found dasatinib to be safe and effective as first- or second-line therapy for these children.
Patients refractory to or intolerant of imatinib had a major cytogenetic response (MCyR) by 3 months and responses at 12 and 24 months exceeded 90%.
Newly diagnosed patients had a complete cytogenetic response (CCyR) by 6 months.
“We believe our data suggests that dasatinib could be considered as a new standard of care (SOC) for children with CML in chronic phase,” said study author Lia Gore, MD, of the University of Colorado School of Medicine/Children’s Hospital Colorado in Aurora.
She presented the findings of the study at the ASCO 2017 Annual Meeting (abstract 10511).
Study design
CA 180-226 is a phase 2, open-label, nonrandomized, prospective study conducted in 18 countries. Patients younger than 18 years with newly diagnosed CML-CP, or imatinib-resistant/intolerant (R/I) CML-CP, or CML in accelerated phase, or Ph+ acute lymphoblastic leukemia (ALL) were enrolled on the study between March 2009 and September 2014.
Dr Gore’s presentation focused on the CML-CP patients in the study, both the newly diagnosed and the imatinib-R/I patients.
The imatinib-R/I patients received dasatinib 60 mg/m2 tablets once daily, and the newly diagnosed patients received the same tablet dosage daily or a powdered formulation for oral suspension (PFOS) of dasatinib at 72 mg/m2 daily.
Dr Gore noted the different dosage in the oral suspension formulation is based on bioavailability studies performed in adults, which was determined to be equivalent to the 60 mg/m2 tablet formulation.
Once accrual was reached in the tablet cohort, newly diagnosed patients were accrued to the PFOS cohort. The patients on PFOS could switch to tablets after a year or more on the oral suspension.
Patients remained on treatment until disease progression, unacceptable toxicity occurred, or the patient/physician preference.
All patients had a minimum follow-up of 2 years. The longest follow-up was more than 90 months.
Primary objectives of the study were MCyR greater than 30% for imatinib-R/I patients and complete CCyR greater than 55% for newly diagnosed patients.
Secondary objectives included time to and duration of response, major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety.
Baseline patient characteristics
One hundred thirteen patients were treated across the 3 cohorts—29 in the imatinib-R/I receiving tablets, 51 newly diagnosed patients receiving tablets, and 33 newly diagnosed patients in the PFOS arm. A total of 84 patients had newly diagnosed disease.
Of the 29 imatinib-R/I patients, 25 were resistant, 2 intolerant, and 2 undetermined. And 6 of the 25 resistant patients had defined imatinib-resistance mutations.
Median age was 13.8 years in the imatinib-R/I cohort, 12.9 years in the newly diagnosed on tablets, and 11.7 years in the PFOS group. Other baseline characteristics were similar among the cohorts.
“Importantly, there were 3 patients less than 2 years of age, and a substantial proportion of patients were actually less than 12 years of age,” Dr Gore pointed out.
Dasatinib exposure
The median duration of therapy was 50 months and 42 months in the R/I and newly diagnosed cohorts, respectively.
Forty-eight percent of the imatinib-R/I patients and 73% of the newly diagnosed patients are still on treatment. A relatively small number of patients discontinued therapy.
The median duration of therapy was shorter in the PFOS cohort because they were enrolled only after accrual to the tablet cohort. However, they were also followed up for more than 2 years.
Of the 33 patients on PFOS, 22 eventually switched to tablet formulation.
Results
The primary endpoint for imatinib-R/I patients—MCyR greater than 30%—was reached by 3 months, and MCyR at 12 and 24 months exceeded 90%. The median time to response was 3.1 months (range, 2.8 – 4.1), and median duration of response was not yet reached (range, 54.9 – not estimable).
For newly diagnosed patients, the preset defined rate of interest of 55% for CCyR was reached as early as 6 months, and exceeded 90% by 12 and 24 months.
Dr Gore pointed out that intolerant patients also reached CCyR relatively quickly, although it was not a specified endpoint.
Data indicate that responses occurred relatively quickly and continued to increase over time of follow-up.
MMR also continued to increase over time and showed no difference between formulation and response rate.
Median PFS has not been reached, as only 7 patients in each cohort had disease progression.
One imatinib-R/I patient died 1 year after stopping treatment. The patient, who had a GI bleed unrelated to dasatinib, had discontinued therapy for progressive disease with loss of MCyR.
Safety
Overall safety was very similar to the dasatinib exposure and experience in adults, Dr Gore said, and there were no differences in events between PFOS and tablets.
One patient in the PFOS cohort had a dasatinib-related grade 3 hypersensitivity reaction, which resolved after discontinuation of dasatinib.
“What’s important here,” she said, “is that there were almost no adverse events of severity in either cohort, only 1 in the imatinib refractory and intolerant and 1 in the newly diagnosed cohorts.”
“Most importantly for those of us with a lot of experience in this field,” she added, “there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, pulmonary hypertension, or any vascular occlusive events in patients noted on this trial.”
“Additionally, for pediatricians, we care a lot about what happens to growth in these patients and prospectively we collected a lot of data related to growth parameters in bone growth and development."
Of the dasatinib-related adverse events occurring in 10% or more of patients, there were only 5 growth and development events noted out of the 113 patients treated and all were grade 1 or 2 events, Dr Gore pointed out.
In the R/I cohort, one patient had osteopenia and gynecomastia. At the time of data analysis, this event had resolved even though the patient continued on dasatinib.
“We believe our data suggests that dasatinib could be considered as a new standard of care for children with CML in chronic phase,” she said.
“It includes the advantage of a liquid formulation as well as the advantages of once daily dosing and administration without regard to fed or fasting state,” she added, “which for all of us who treat children know could be quite important.”
The study was funded by Bristol-Myers Squibb.
Team finds inappropriate dosing of blood thinners
Patients with atrial fibrillation (AF) and renal impairment require dose reductions of non-vitamin K antagonist oral anticoagulants (NOACs).
But researchers found that 43% of these patients were potentially overdosed, and as many as 1 in 6 (13%) without renal impairment are potentially under dosed.
Failing to reduce the dose for patients with kidney disease increases their risk of bleeding, while under dosing patients without kidney disease puts them at greater risk of stroke. These inappropriate prescribing patterns may impact patient safety without providing benefit in effectiveness.
Using a large US database of de-identified, linked clinical and administrative claims information, the research team found 14,865 patients with AF who were prescribed apixaban, dabigatran, or rivaroxaban between October 1, 2020, and September 30, 2015. Of these, 1,473 had renal impairment.
All three drugs have a standard dose for most patients and a lower dose for patients with kidney issues. And their analysis revealed that 16% percent of all patients received a dose inconsistent with US Food and Drug Administration labeling.
The research team published its findings in the Journal of the American College of Cardiology.
“We conducted this study to highlight the prevalence of inappropriate dosing in routine clinical practice and the associated adverse outcomes,” said Peter Noseworthy, MD, of the Mayo Clinic in Rochester, Minnesota, and senior author of the paper.
“This study underscores the importance for physicians to be vigilant of kidney function when selecting or adjusting dose.”
Dr Noseworthy explained that overdosing is a fairly straightforward problem that can be avoided by regularly monitoring kidney function.
In the kidney-impaired patients who were potentially overdosed, the hazard ratio for the risk of major bleeding was 2.19 (95% confidence interval: 1.07 to 4.46). There was no statistically significant difference in stroke with the 3 NOACs pooled.
However, under dosing is more complex because a balance needs to be established between stroke reduction and bleeding risk, Dr Noseworthy pointed out.
Among the 13,392 patients without renal impairment and no indication for dose reduction, the hazard ratio for a higher risk of stroke was 4.87 (95% confidence interval: 1.30 to 18.26). There was no statistically significant difference in major bleeding in apixaban-treated patients nor statistically significant relationships in dabigatran- or rivaroxaban-treated patients without renal impairment.
“I think physicians often choose to reduce the dose,” Dr Noseworthy explained, “when they anticipate their patients are at a particularly high bleeding risk—independent of kidney function.”
“Dosing errors of these blood-thinning medications in patients with atrial fibrillation are common and have concerning adverse outcomes,” said Xiaoxi Yao, PhD, also of the Mayo Clinic in Rochester, Minnesota, and lead author of the paper.
Dr Yao noted that the number of patients using these drugs has increased since their introduction in 2010. Before that, the standard blood-thinning drug was warfarin, which requires constant monitoring and doctor visits.
Patients with atrial fibrillation (AF) and renal impairment require dose reductions of non-vitamin K antagonist oral anticoagulants (NOACs).
But researchers found that 43% of these patients were potentially overdosed, and as many as 1 in 6 (13%) without renal impairment are potentially under dosed.
Failing to reduce the dose for patients with kidney disease increases their risk of bleeding, while under dosing patients without kidney disease puts them at greater risk of stroke. These inappropriate prescribing patterns may impact patient safety without providing benefit in effectiveness.
Using a large US database of de-identified, linked clinical and administrative claims information, the research team found 14,865 patients with AF who were prescribed apixaban, dabigatran, or rivaroxaban between October 1, 2020, and September 30, 2015. Of these, 1,473 had renal impairment.
All three drugs have a standard dose for most patients and a lower dose for patients with kidney issues. And their analysis revealed that 16% percent of all patients received a dose inconsistent with US Food and Drug Administration labeling.
The research team published its findings in the Journal of the American College of Cardiology.
“We conducted this study to highlight the prevalence of inappropriate dosing in routine clinical practice and the associated adverse outcomes,” said Peter Noseworthy, MD, of the Mayo Clinic in Rochester, Minnesota, and senior author of the paper.
“This study underscores the importance for physicians to be vigilant of kidney function when selecting or adjusting dose.”
Dr Noseworthy explained that overdosing is a fairly straightforward problem that can be avoided by regularly monitoring kidney function.
In the kidney-impaired patients who were potentially overdosed, the hazard ratio for the risk of major bleeding was 2.19 (95% confidence interval: 1.07 to 4.46). There was no statistically significant difference in stroke with the 3 NOACs pooled.
However, under dosing is more complex because a balance needs to be established between stroke reduction and bleeding risk, Dr Noseworthy pointed out.
Among the 13,392 patients without renal impairment and no indication for dose reduction, the hazard ratio for a higher risk of stroke was 4.87 (95% confidence interval: 1.30 to 18.26). There was no statistically significant difference in major bleeding in apixaban-treated patients nor statistically significant relationships in dabigatran- or rivaroxaban-treated patients without renal impairment.
“I think physicians often choose to reduce the dose,” Dr Noseworthy explained, “when they anticipate their patients are at a particularly high bleeding risk—independent of kidney function.”
“Dosing errors of these blood-thinning medications in patients with atrial fibrillation are common and have concerning adverse outcomes,” said Xiaoxi Yao, PhD, also of the Mayo Clinic in Rochester, Minnesota, and lead author of the paper.
Dr Yao noted that the number of patients using these drugs has increased since their introduction in 2010. Before that, the standard blood-thinning drug was warfarin, which requires constant monitoring and doctor visits.
Patients with atrial fibrillation (AF) and renal impairment require dose reductions of non-vitamin K antagonist oral anticoagulants (NOACs).
But researchers found that 43% of these patients were potentially overdosed, and as many as 1 in 6 (13%) without renal impairment are potentially under dosed.
Failing to reduce the dose for patients with kidney disease increases their risk of bleeding, while under dosing patients without kidney disease puts them at greater risk of stroke. These inappropriate prescribing patterns may impact patient safety without providing benefit in effectiveness.
Using a large US database of de-identified, linked clinical and administrative claims information, the research team found 14,865 patients with AF who were prescribed apixaban, dabigatran, or rivaroxaban between October 1, 2020, and September 30, 2015. Of these, 1,473 had renal impairment.
All three drugs have a standard dose for most patients and a lower dose for patients with kidney issues. And their analysis revealed that 16% percent of all patients received a dose inconsistent with US Food and Drug Administration labeling.
The research team published its findings in the Journal of the American College of Cardiology.
“We conducted this study to highlight the prevalence of inappropriate dosing in routine clinical practice and the associated adverse outcomes,” said Peter Noseworthy, MD, of the Mayo Clinic in Rochester, Minnesota, and senior author of the paper.
“This study underscores the importance for physicians to be vigilant of kidney function when selecting or adjusting dose.”
Dr Noseworthy explained that overdosing is a fairly straightforward problem that can be avoided by regularly monitoring kidney function.
In the kidney-impaired patients who were potentially overdosed, the hazard ratio for the risk of major bleeding was 2.19 (95% confidence interval: 1.07 to 4.46). There was no statistically significant difference in stroke with the 3 NOACs pooled.
However, under dosing is more complex because a balance needs to be established between stroke reduction and bleeding risk, Dr Noseworthy pointed out.
Among the 13,392 patients without renal impairment and no indication for dose reduction, the hazard ratio for a higher risk of stroke was 4.87 (95% confidence interval: 1.30 to 18.26). There was no statistically significant difference in major bleeding in apixaban-treated patients nor statistically significant relationships in dabigatran- or rivaroxaban-treated patients without renal impairment.
“I think physicians often choose to reduce the dose,” Dr Noseworthy explained, “when they anticipate their patients are at a particularly high bleeding risk—independent of kidney function.”
“Dosing errors of these blood-thinning medications in patients with atrial fibrillation are common and have concerning adverse outcomes,” said Xiaoxi Yao, PhD, also of the Mayo Clinic in Rochester, Minnesota, and lead author of the paper.
Dr Yao noted that the number of patients using these drugs has increased since their introduction in 2010. Before that, the standard blood-thinning drug was warfarin, which requires constant monitoring and doctor visits.
Pembrolizumab enhances CAR T-cell persistence in relapsed ALL
CHICAGO—Three of 6 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) whose CD19 chimeric antigen receptor (CAR) T cells did not persist even after reinfusion demonstrated persistence when the PD-1 checkpoint inhibitor pembrolizumab was added to the regimen.
CAR T cells can persist for months or even years and have the potential to mediate long-term disease control.
But some patients recover their normal B cells, which is a marker of loss of functional CAR T cells. These patients are at a higher risk of disease relapse.
Investigators, therefore, undertook a pilot study to determine whether PD-1 checkpoint pathway inhibition can improve CAR T persistence in these patients.
Shannon L. Maude, MD, of the Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, shared some of the patient cases in this pilot study at the ASCO 2017 Annual Meeting (Abstract 103*).
The investigators hypothesized that possible anti-murine immunogenicity could be causing poor CAR T-cell persistence, since the first CAR T developed used scFv domains of murine origin.
If T-cell exhaustion caused poor CAR T-cell persistence, immune checkpoints might play a role. In this case, combination with PD-1 checkpoint blockade could improve persistence, they hypothesized.
The investigators proposed to administer a repeat CAR T-cell infusion for relapsed or refractory ALL patients with poor persistence and add pembrolizumab after retreatment if the patients still had poor persistence. Patients were offered the option of another reinfusion prior to treatment with pembrolizumab if their CAR T-cell persistence continued to be poor.
Investigators added pembrolizumab no earlier than 14 days after infusion and only after patients recovered from cytokine release syndrome (CRS).
The infusions in the pilot study were humanized CART19 (huCART19, CTL119), unless otherwise specified.
Patient 1 – Pembrolizumab for partial response
This patient had no response to the prior murine CD19 CAR infusion, but responded well to infusion with huCART19 with good CAR T-cell proliferation.
By day 28, the patient had achieved a complete response (CR) in bone marrow but had a minimal residual disease (MRD) level of 1.2%.
At 7 weeks, the patient had a CD19+ relapse with low levels of huCART19.
Investigators added pembrolizumb on day 52 after infusion, and the patient had a modest increase in huCART19.
The patient had a temporary clearance of peripheral blasts followed by disease progression.
Patient 2 – Pembrolizumab for no response
This patient had a CD19+ relapse at 12 months after prior murine CD19 CAR infusion.
The patient was treated with huCART19, had good proliferation, but a rapid drop of CART19, and no response of the disease with a CD19+ relapse.
The patient had a reinfusion of huCART19 at 6 weeks and investigators added pembrolizumab on day 14 after reinfusion.
The patient experienced good huCART19 proliferation and prolonged persistence, but by day 28 had persistent disease, this time with decreased expression of CD19+ cells.
Patient 3 – Pembrolizumab for poor persistence
This patient had a CR with a prior murine CD19 CAR, but had poor persistence and early B cell recovery at 2 months.
The patient had a CD19+ relapse, was treated with huCART19, and had good proliferation again.
The patient achieved an MRD-negative CR, but because of short persistence and early B-cell recovery at 2 months, relapsed at 15 months.
The patient was reinfused at 17 months and pembrolizumab was added on day 14. The patient entered CR with prolonged persistence, but ultimately B-cell recovery occurred.
The patient was reinfused a third time, and pembrolizumab was added to the regimen every 3 weeks. The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 4 – Pembrolizumab for poor persistence
This patient had achieved a CR with murine CAR19, but had a CD19+ relapse at 9 months. The patient then received huCART19, had good proliferation and achieved a CR, but had short persistence and B-cell recovery at 2 months.
The patient relapsed at 12 months and was reinfused with huCART19 at 14 months.
Pembrolizumab was added on day 14 after reinfusion, but the patient had no huCART19 proliferation, no response, and CD19+ MRD.
Patient 5 – Pembrolizumab for poor persistence
The patient responded to a prior murine CART19, but had a CD19+ relapse at 12 months.
The patient was infused with huCART19 and had good proliferation but short persistence. The patient was reinfused at 6 months, but again had short persistence.
The patient was reinfused again at 8 months because of B-cell recovery, and pembrolizumab was added on day 14 and administered every 3 weeks thereafter.
The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 6 – Pembrolizumab for lymphomatous disease
This patient, who had widespread lymphadenopathy and M3 bone marrow, had not received prior CAR T cells and was treated for the first time with a murine CART19 for r/r ALL.
The patient had good expansion of CART19, but by day 28, PET scan showed widespread lymph node disease despite CR in the bone marrow.
The patient was given pembrolizumab on day 32 after infusion and every 2-3 weeks thereafter. After the addition of pembrolizumab, the patient had increased CART19 cells in blood and a significant decrease in PET-avid disease.
Summary
Three of six patients achieved objective clinical responses with pembrolizumab: 2 had prolonged B-cell aplasia, and another had a decrease in PET-avid lymphomatous disease.
The addition of pembrolizumab was also well tolerated by the patients, with minimal side effects of fever in 2 patients, cytopenias in 2 patients, and no instances of severe CRS.
The investigators believe the addition of checkpoint pathway inhibitors has the potential to prolong CAR T-cell persistence and warrants further investigation.
CHICAGO—Three of 6 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) whose CD19 chimeric antigen receptor (CAR) T cells did not persist even after reinfusion demonstrated persistence when the PD-1 checkpoint inhibitor pembrolizumab was added to the regimen.
CAR T cells can persist for months or even years and have the potential to mediate long-term disease control.
But some patients recover their normal B cells, which is a marker of loss of functional CAR T cells. These patients are at a higher risk of disease relapse.
Investigators, therefore, undertook a pilot study to determine whether PD-1 checkpoint pathway inhibition can improve CAR T persistence in these patients.
Shannon L. Maude, MD, of the Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, shared some of the patient cases in this pilot study at the ASCO 2017 Annual Meeting (Abstract 103*).
The investigators hypothesized that possible anti-murine immunogenicity could be causing poor CAR T-cell persistence, since the first CAR T developed used scFv domains of murine origin.
If T-cell exhaustion caused poor CAR T-cell persistence, immune checkpoints might play a role. In this case, combination with PD-1 checkpoint blockade could improve persistence, they hypothesized.
The investigators proposed to administer a repeat CAR T-cell infusion for relapsed or refractory ALL patients with poor persistence and add pembrolizumab after retreatment if the patients still had poor persistence. Patients were offered the option of another reinfusion prior to treatment with pembrolizumab if their CAR T-cell persistence continued to be poor.
Investigators added pembrolizumab no earlier than 14 days after infusion and only after patients recovered from cytokine release syndrome (CRS).
The infusions in the pilot study were humanized CART19 (huCART19, CTL119), unless otherwise specified.
Patient 1 – Pembrolizumab for partial response
This patient had no response to the prior murine CD19 CAR infusion, but responded well to infusion with huCART19 with good CAR T-cell proliferation.
By day 28, the patient had achieved a complete response (CR) in bone marrow but had a minimal residual disease (MRD) level of 1.2%.
At 7 weeks, the patient had a CD19+ relapse with low levels of huCART19.
Investigators added pembrolizumb on day 52 after infusion, and the patient had a modest increase in huCART19.
The patient had a temporary clearance of peripheral blasts followed by disease progression.
Patient 2 – Pembrolizumab for no response
This patient had a CD19+ relapse at 12 months after prior murine CD19 CAR infusion.
The patient was treated with huCART19, had good proliferation, but a rapid drop of CART19, and no response of the disease with a CD19+ relapse.
The patient had a reinfusion of huCART19 at 6 weeks and investigators added pembrolizumab on day 14 after reinfusion.
The patient experienced good huCART19 proliferation and prolonged persistence, but by day 28 had persistent disease, this time with decreased expression of CD19+ cells.
Patient 3 – Pembrolizumab for poor persistence
This patient had a CR with a prior murine CD19 CAR, but had poor persistence and early B cell recovery at 2 months.
The patient had a CD19+ relapse, was treated with huCART19, and had good proliferation again.
The patient achieved an MRD-negative CR, but because of short persistence and early B-cell recovery at 2 months, relapsed at 15 months.
The patient was reinfused at 17 months and pembrolizumab was added on day 14. The patient entered CR with prolonged persistence, but ultimately B-cell recovery occurred.
The patient was reinfused a third time, and pembrolizumab was added to the regimen every 3 weeks. The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 4 – Pembrolizumab for poor persistence
This patient had achieved a CR with murine CAR19, but had a CD19+ relapse at 9 months. The patient then received huCART19, had good proliferation and achieved a CR, but had short persistence and B-cell recovery at 2 months.
The patient relapsed at 12 months and was reinfused with huCART19 at 14 months.
Pembrolizumab was added on day 14 after reinfusion, but the patient had no huCART19 proliferation, no response, and CD19+ MRD.
Patient 5 – Pembrolizumab for poor persistence
The patient responded to a prior murine CART19, but had a CD19+ relapse at 12 months.
The patient was infused with huCART19 and had good proliferation but short persistence. The patient was reinfused at 6 months, but again had short persistence.
The patient was reinfused again at 8 months because of B-cell recovery, and pembrolizumab was added on day 14 and administered every 3 weeks thereafter.
The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 6 – Pembrolizumab for lymphomatous disease
This patient, who had widespread lymphadenopathy and M3 bone marrow, had not received prior CAR T cells and was treated for the first time with a murine CART19 for r/r ALL.
The patient had good expansion of CART19, but by day 28, PET scan showed widespread lymph node disease despite CR in the bone marrow.
The patient was given pembrolizumab on day 32 after infusion and every 2-3 weeks thereafter. After the addition of pembrolizumab, the patient had increased CART19 cells in blood and a significant decrease in PET-avid disease.
Summary
Three of six patients achieved objective clinical responses with pembrolizumab: 2 had prolonged B-cell aplasia, and another had a decrease in PET-avid lymphomatous disease.
The addition of pembrolizumab was also well tolerated by the patients, with minimal side effects of fever in 2 patients, cytopenias in 2 patients, and no instances of severe CRS.
The investigators believe the addition of checkpoint pathway inhibitors has the potential to prolong CAR T-cell persistence and warrants further investigation.
CHICAGO—Three of 6 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) whose CD19 chimeric antigen receptor (CAR) T cells did not persist even after reinfusion demonstrated persistence when the PD-1 checkpoint inhibitor pembrolizumab was added to the regimen.
CAR T cells can persist for months or even years and have the potential to mediate long-term disease control.
But some patients recover their normal B cells, which is a marker of loss of functional CAR T cells. These patients are at a higher risk of disease relapse.
Investigators, therefore, undertook a pilot study to determine whether PD-1 checkpoint pathway inhibition can improve CAR T persistence in these patients.
Shannon L. Maude, MD, of the Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, shared some of the patient cases in this pilot study at the ASCO 2017 Annual Meeting (Abstract 103*).
The investigators hypothesized that possible anti-murine immunogenicity could be causing poor CAR T-cell persistence, since the first CAR T developed used scFv domains of murine origin.
If T-cell exhaustion caused poor CAR T-cell persistence, immune checkpoints might play a role. In this case, combination with PD-1 checkpoint blockade could improve persistence, they hypothesized.
The investigators proposed to administer a repeat CAR T-cell infusion for relapsed or refractory ALL patients with poor persistence and add pembrolizumab after retreatment if the patients still had poor persistence. Patients were offered the option of another reinfusion prior to treatment with pembrolizumab if their CAR T-cell persistence continued to be poor.
Investigators added pembrolizumab no earlier than 14 days after infusion and only after patients recovered from cytokine release syndrome (CRS).
The infusions in the pilot study were humanized CART19 (huCART19, CTL119), unless otherwise specified.
Patient 1 – Pembrolizumab for partial response
This patient had no response to the prior murine CD19 CAR infusion, but responded well to infusion with huCART19 with good CAR T-cell proliferation.
By day 28, the patient had achieved a complete response (CR) in bone marrow but had a minimal residual disease (MRD) level of 1.2%.
At 7 weeks, the patient had a CD19+ relapse with low levels of huCART19.
Investigators added pembrolizumb on day 52 after infusion, and the patient had a modest increase in huCART19.
The patient had a temporary clearance of peripheral blasts followed by disease progression.
Patient 2 – Pembrolizumab for no response
This patient had a CD19+ relapse at 12 months after prior murine CD19 CAR infusion.
The patient was treated with huCART19, had good proliferation, but a rapid drop of CART19, and no response of the disease with a CD19+ relapse.
The patient had a reinfusion of huCART19 at 6 weeks and investigators added pembrolizumab on day 14 after reinfusion.
The patient experienced good huCART19 proliferation and prolonged persistence, but by day 28 had persistent disease, this time with decreased expression of CD19+ cells.
Patient 3 – Pembrolizumab for poor persistence
This patient had a CR with a prior murine CD19 CAR, but had poor persistence and early B cell recovery at 2 months.
The patient had a CD19+ relapse, was treated with huCART19, and had good proliferation again.
The patient achieved an MRD-negative CR, but because of short persistence and early B-cell recovery at 2 months, relapsed at 15 months.
The patient was reinfused at 17 months and pembrolizumab was added on day 14. The patient entered CR with prolonged persistence, but ultimately B-cell recovery occurred.
The patient was reinfused a third time, and pembrolizumab was added to the regimen every 3 weeks. The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 4 – Pembrolizumab for poor persistence
This patient had achieved a CR with murine CAR19, but had a CD19+ relapse at 9 months. The patient then received huCART19, had good proliferation and achieved a CR, but had short persistence and B-cell recovery at 2 months.
The patient relapsed at 12 months and was reinfused with huCART19 at 14 months.
Pembrolizumab was added on day 14 after reinfusion, but the patient had no huCART19 proliferation, no response, and CD19+ MRD.
Patient 5 – Pembrolizumab for poor persistence
The patient responded to a prior murine CART19, but had a CD19+ relapse at 12 months.
The patient was infused with huCART19 and had good proliferation but short persistence. The patient was reinfused at 6 months, but again had short persistence.
The patient was reinfused again at 8 months because of B-cell recovery, and pembrolizumab was added on day 14 and administered every 3 weeks thereafter.
The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 6 – Pembrolizumab for lymphomatous disease
This patient, who had widespread lymphadenopathy and M3 bone marrow, had not received prior CAR T cells and was treated for the first time with a murine CART19 for r/r ALL.
The patient had good expansion of CART19, but by day 28, PET scan showed widespread lymph node disease despite CR in the bone marrow.
The patient was given pembrolizumab on day 32 after infusion and every 2-3 weeks thereafter. After the addition of pembrolizumab, the patient had increased CART19 cells in blood and a significant decrease in PET-avid disease.
Summary
Three of six patients achieved objective clinical responses with pembrolizumab: 2 had prolonged B-cell aplasia, and another had a decrease in PET-avid lymphomatous disease.
The addition of pembrolizumab was also well tolerated by the patients, with minimal side effects of fever in 2 patients, cytopenias in 2 patients, and no instances of severe CRS.
The investigators believe the addition of checkpoint pathway inhibitors has the potential to prolong CAR T-cell persistence and warrants further investigation.
Recombinant coagulation factor IX approved for hemophilia B
Nonacog beta pegol (N9-GP, Rebinyn®), a recombinant, GlycoPEGylated coagulation factor IX, has been approved by the US Food and Drug Administration (FDA) for on-demand treatment and control of bleeding episodes in adults and children with hemophilia B.
It is also indicated for the perioperative management of bleeding in these individuals. However, it is not indicated for routine prophylaxis or for immune tolerance induction.
NovoNordisk, the manufacturer of the drug, expects the launch of the coagulation factor in the United States to take place in the first half of 2018.
N9-GP earlier this year had been recommended for marketing authorization by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) as Refixia.® On June 6 it was actually granted marketing authorization, which covers all 28 European Union member states.
The FDA based its approval on the efficacy and safety evaluation of 115 previously treated patients across the four paradigmTM clinical trials. Results from the paradigm 4 trial were published in Thrombosis Research in May 2016.
Of 597 new bleeding episodes in 79 of 105 patients, 551 (93%) were resolved successfully with good or excellent ratings by the patients or study site investigator. Forty (7%) were rated as moderate or poor.
Most (87%) were resolved with 1 injection, 60 (10%) with 2 injections, and 16 (3%) with more than 2 injections.
The median dose to treat a bleeding episode was 42.3 IU/kg.
On-demand treatment had a success rate of 95%, with 120 (84%) of the 143 bleeds treated with one injection.
For perioperative management, N9-GP was rated as excellent or good for 13 surgeries, for a success rate of 100%.
Patients received a preoperative dose of 80 IU/kg. No patient required additional doses on the day of surgery.
During the postoperative period, patients required additional 40 IU/kg doses. The mean total consumption of factor in the pre- and postoperative period was 241 IU/kg (range, 8 – 460 IU/kg.
No unexpected postoperative bleeding occurred.
For full prescribing information, see the package insert.
Nonacog beta pegol (N9-GP, Rebinyn®), a recombinant, GlycoPEGylated coagulation factor IX, has been approved by the US Food and Drug Administration (FDA) for on-demand treatment and control of bleeding episodes in adults and children with hemophilia B.
It is also indicated for the perioperative management of bleeding in these individuals. However, it is not indicated for routine prophylaxis or for immune tolerance induction.
NovoNordisk, the manufacturer of the drug, expects the launch of the coagulation factor in the United States to take place in the first half of 2018.
N9-GP earlier this year had been recommended for marketing authorization by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) as Refixia.® On June 6 it was actually granted marketing authorization, which covers all 28 European Union member states.
The FDA based its approval on the efficacy and safety evaluation of 115 previously treated patients across the four paradigmTM clinical trials. Results from the paradigm 4 trial were published in Thrombosis Research in May 2016.
Of 597 new bleeding episodes in 79 of 105 patients, 551 (93%) were resolved successfully with good or excellent ratings by the patients or study site investigator. Forty (7%) were rated as moderate or poor.
Most (87%) were resolved with 1 injection, 60 (10%) with 2 injections, and 16 (3%) with more than 2 injections.
The median dose to treat a bleeding episode was 42.3 IU/kg.
On-demand treatment had a success rate of 95%, with 120 (84%) of the 143 bleeds treated with one injection.
For perioperative management, N9-GP was rated as excellent or good for 13 surgeries, for a success rate of 100%.
Patients received a preoperative dose of 80 IU/kg. No patient required additional doses on the day of surgery.
During the postoperative period, patients required additional 40 IU/kg doses. The mean total consumption of factor in the pre- and postoperative period was 241 IU/kg (range, 8 – 460 IU/kg.
No unexpected postoperative bleeding occurred.
For full prescribing information, see the package insert.
Nonacog beta pegol (N9-GP, Rebinyn®), a recombinant, GlycoPEGylated coagulation factor IX, has been approved by the US Food and Drug Administration (FDA) for on-demand treatment and control of bleeding episodes in adults and children with hemophilia B.
It is also indicated for the perioperative management of bleeding in these individuals. However, it is not indicated for routine prophylaxis or for immune tolerance induction.
NovoNordisk, the manufacturer of the drug, expects the launch of the coagulation factor in the United States to take place in the first half of 2018.
N9-GP earlier this year had been recommended for marketing authorization by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) as Refixia.® On June 6 it was actually granted marketing authorization, which covers all 28 European Union member states.
The FDA based its approval on the efficacy and safety evaluation of 115 previously treated patients across the four paradigmTM clinical trials. Results from the paradigm 4 trial were published in Thrombosis Research in May 2016.
Of 597 new bleeding episodes in 79 of 105 patients, 551 (93%) were resolved successfully with good or excellent ratings by the patients or study site investigator. Forty (7%) were rated as moderate or poor.
Most (87%) were resolved with 1 injection, 60 (10%) with 2 injections, and 16 (3%) with more than 2 injections.
The median dose to treat a bleeding episode was 42.3 IU/kg.
On-demand treatment had a success rate of 95%, with 120 (84%) of the 143 bleeds treated with one injection.
For perioperative management, N9-GP was rated as excellent or good for 13 surgeries, for a success rate of 100%.
Patients received a preoperative dose of 80 IU/kg. No patient required additional doses on the day of surgery.
During the postoperative period, patients required additional 40 IU/kg doses. The mean total consumption of factor in the pre- and postoperative period was 241 IU/kg (range, 8 – 460 IU/kg.
No unexpected postoperative bleeding occurred.
For full prescribing information, see the package insert.
Addition of ublituximab to ibrutinib improves response in r/r CLL
Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
Other adverse events of all grades occurring in 10% of patients or more for the combination and monotherapy arms, respectively, were: diarrhea (42% and 40%), fatigue (27% and 33%), insomnia (24% and 10%), nausea (22% and 21%), headache (20% and 28%), arthralgia (19% and 17%), cough (19% and 24%), abdominal pain (15% and 9%), stomatitis (15% and 9%), upper respiratory infection (15% and 12%), dizziness (15% and 22%), contusion (15% and 29%), anemia (14% and 17%), and peripheral edema (10% and 21%).
Neutropenia was higher in the experimental arm, 22% any grade, compared with 12% in the ibrutinib arm, although grade 3 or higher neutropenia was similar in the 2 arms. Other laboratory abnormalities were similar between the arms.
Efficacy
The best ORR in the combination arm was 78%, with 7% achieving CR compared with 45% in the monotherapy arm with no CRs (P<0.001).
Nineteen percent of the combination arm achieved MRD negativity in peripheral blood compared with 2% of the monotherapy arm (P<0.01).
The reduction in lymph node size was similar between the arms.
In contrast, lymphocytosis was very different between the arms.
“As has been reported multiple times with targeted B-cell receptor signaling inhibitors,” Dr Sharman said, “patients treated with ibrutinib experienced rapid increase in their lymphocytes, returning approximately to baseline by 3 months and decreasing thereafter.”
“By contrast,” he continued, “those patients treated with the additional antibody had much more rapid resolution of their lymphocytosis. This was true whether patients were considered rituximab refractory or not.”
The investigators performed an additional analysis of ORR, this time including patients who achieved partial response with lymphocytosis (PR-L). These patients were not included in the primary endpoint because the iwCLL 2008 criteria had not yet been updated to include PR-L.
The best overall response including active PR-L patients was 83% in the experimental arm and 59% in the ibrutinib monotherapy arm (P<0.01).
PFS showed a trend toward improvement in the patients treated with the combination, with a hazard ratio of 0.559, which was not of statistical significance at the time of analysis.
The investigators concluded that the study met its primary endpoint, with a greater response rate and a greater depth of response than ibrutinib alone.
And the addition of ublituximab did not alter the safety profile of ibrutinib monotherapy.
TG Therapeutics, Inc, funded the study.
*Data in the abstract differ from the meeting presentation.
Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
Other adverse events of all grades occurring in 10% of patients or more for the combination and monotherapy arms, respectively, were: diarrhea (42% and 40%), fatigue (27% and 33%), insomnia (24% and 10%), nausea (22% and 21%), headache (20% and 28%), arthralgia (19% and 17%), cough (19% and 24%), abdominal pain (15% and 9%), stomatitis (15% and 9%), upper respiratory infection (15% and 12%), dizziness (15% and 22%), contusion (15% and 29%), anemia (14% and 17%), and peripheral edema (10% and 21%).
Neutropenia was higher in the experimental arm, 22% any grade, compared with 12% in the ibrutinib arm, although grade 3 or higher neutropenia was similar in the 2 arms. Other laboratory abnormalities were similar between the arms.
Efficacy
The best ORR in the combination arm was 78%, with 7% achieving CR compared with 45% in the monotherapy arm with no CRs (P<0.001).
Nineteen percent of the combination arm achieved MRD negativity in peripheral blood compared with 2% of the monotherapy arm (P<0.01).
The reduction in lymph node size was similar between the arms.
In contrast, lymphocytosis was very different between the arms.
“As has been reported multiple times with targeted B-cell receptor signaling inhibitors,” Dr Sharman said, “patients treated with ibrutinib experienced rapid increase in their lymphocytes, returning approximately to baseline by 3 months and decreasing thereafter.”
“By contrast,” he continued, “those patients treated with the additional antibody had much more rapid resolution of their lymphocytosis. This was true whether patients were considered rituximab refractory or not.”
The investigators performed an additional analysis of ORR, this time including patients who achieved partial response with lymphocytosis (PR-L). These patients were not included in the primary endpoint because the iwCLL 2008 criteria had not yet been updated to include PR-L.
The best overall response including active PR-L patients was 83% in the experimental arm and 59% in the ibrutinib monotherapy arm (P<0.01).
PFS showed a trend toward improvement in the patients treated with the combination, with a hazard ratio of 0.559, which was not of statistical significance at the time of analysis.
The investigators concluded that the study met its primary endpoint, with a greater response rate and a greater depth of response than ibrutinib alone.
And the addition of ublituximab did not alter the safety profile of ibrutinib monotherapy.
TG Therapeutics, Inc, funded the study.
*Data in the abstract differ from the meeting presentation.
Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
Other adverse events of all grades occurring in 10% of patients or more for the combination and monotherapy arms, respectively, were: diarrhea (42% and 40%), fatigue (27% and 33%), insomnia (24% and 10%), nausea (22% and 21%), headache (20% and 28%), arthralgia (19% and 17%), cough (19% and 24%), abdominal pain (15% and 9%), stomatitis (15% and 9%), upper respiratory infection (15% and 12%), dizziness (15% and 22%), contusion (15% and 29%), anemia (14% and 17%), and peripheral edema (10% and 21%).
Neutropenia was higher in the experimental arm, 22% any grade, compared with 12% in the ibrutinib arm, although grade 3 or higher neutropenia was similar in the 2 arms. Other laboratory abnormalities were similar between the arms.
Efficacy
The best ORR in the combination arm was 78%, with 7% achieving CR compared with 45% in the monotherapy arm with no CRs (P<0.001).
Nineteen percent of the combination arm achieved MRD negativity in peripheral blood compared with 2% of the monotherapy arm (P<0.01).
The reduction in lymph node size was similar between the arms.
In contrast, lymphocytosis was very different between the arms.
“As has been reported multiple times with targeted B-cell receptor signaling inhibitors,” Dr Sharman said, “patients treated with ibrutinib experienced rapid increase in their lymphocytes, returning approximately to baseline by 3 months and decreasing thereafter.”
“By contrast,” he continued, “those patients treated with the additional antibody had much more rapid resolution of their lymphocytosis. This was true whether patients were considered rituximab refractory or not.”
The investigators performed an additional analysis of ORR, this time including patients who achieved partial response with lymphocytosis (PR-L). These patients were not included in the primary endpoint because the iwCLL 2008 criteria had not yet been updated to include PR-L.
The best overall response including active PR-L patients was 83% in the experimental arm and 59% in the ibrutinib monotherapy arm (P<0.01).
PFS showed a trend toward improvement in the patients treated with the combination, with a hazard ratio of 0.559, which was not of statistical significance at the time of analysis.
The investigators concluded that the study met its primary endpoint, with a greater response rate and a greater depth of response than ibrutinib alone.
And the addition of ublituximab did not alter the safety profile of ibrutinib monotherapy.
TG Therapeutics, Inc, funded the study.
*Data in the abstract differ from the meeting presentation.
New type of CAR for multiple myeloma
CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).
BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.
This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.
“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of Nanjing Legend Biotech in China, the developer of LCAR-B38M.
“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.
To date the objective response rate is 100%.
The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.
The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.
Efficacy
Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.
One patient who achieved a VGPR relapsed due to an extramedullary lesion.
Investigators observed no evidence of relapse among patients who achieved sCR.
Five patients have been followed for more than a year and all have maintained sCR.
Safety
Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).
Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.
Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.
A clinical trial of LCAR-B38M is planned in the United States.
CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).
BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.
This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.
“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of Nanjing Legend Biotech in China, the developer of LCAR-B38M.
“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.
To date the objective response rate is 100%.
The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.
The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.
Efficacy
Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.
One patient who achieved a VGPR relapsed due to an extramedullary lesion.
Investigators observed no evidence of relapse among patients who achieved sCR.
Five patients have been followed for more than a year and all have maintained sCR.
Safety
Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).
Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.
Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.
A clinical trial of LCAR-B38M is planned in the United States.
CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).
BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.
This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.
“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of Nanjing Legend Biotech in China, the developer of LCAR-B38M.
“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.
To date the objective response rate is 100%.
The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.
The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.
Efficacy
Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.
One patient who achieved a VGPR relapsed due to an extramedullary lesion.
Investigators observed no evidence of relapse among patients who achieved sCR.
Five patients have been followed for more than a year and all have maintained sCR.
Safety
Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).
Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.
Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.
A clinical trial of LCAR-B38M is planned in the United States.
Malaria infection can lead to chronic bone loss
Malaria infection caused by Plasmodium falciparum, even after a one-time illness, can cause long-term bone loss, researchers report.
Parasite byproducts remain in the bone marrow and induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, resulting in bone resorption.
Researchers found that treatment with the vitamin D3 analog alfacalcidol can prevent bone loss related to malaria, at least in animals.
They suggest that bone therapies combined with anti-malarial drugs may prevent bone loss in infected individuals.
Cevayir Coban, MD, from Osaka University in Japan, and colleagues reported their findings in Science Immunology.
"Although chronic inflammatory conditions are known to facilitate bone disorders, our study—for the first time—shows that malaria can do the same thing,” Dr Coban said.
“One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered,” she said. “However, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long-term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones."
To study the effect of Plasmodium infection on bone, the team used two mouse models, Plasmodium yoelii nonlethal (PyNL) and Plasmodium chabaudi chabaudi (Pcc).
PyNL infection invades reticulocytes and resembles Plasmodium vivax infection in humans. Pcc infection more closely resembles Plasmodium falciparum infection in humans. The investigators used Pcc infection to evaluate the effect of low-level chronic infection on bone homeostasis.
They infected 6-week-old adult mice with these parasite species and assessed changes in bone during the acute, convalescent, and chronic phases of infection.
Both parasites caused significantly reduced trabecular bone volume and increased trabecular bone spacing in infected mice. This continued for over 60 days after parasite clearance.
Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche, which turns the bone noticeably black in color, and results in it being ‘eaten-up’ by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis".
The research team also investigated the impact of malaria infection on bone growth at a young age by infecting 3-week-old mice with PyNL. These mice had significantly shorter femurs and lower trabecular bone volume compared with uninfected litter mates 3 weeks after infection, when the mice were 6 weeks old.
A key finding of the study, investigators report, is that although Plasmodium infection resolves systemically, a state of chronic inflammation evolves in the bone marrow that may be associated with continued accumulation of Plasmodium byproducts—proteins, hemozoin, and nucleic acids—in the bone marrow. These byproducts are capable of modulating immune responses.
The team also evaluated whether vitamin D supplementation would alleviate bone loss caused by Plasmodium. They treated mice with alfacalcidol, which is used to treat osteoporosis. Treatment with lower doses of oral alfacalcidol was sufficient to prevent malaria-induced bone loss, while higher doses enhanced bone growth despite infection.
This work was supported by the Grants-in-Aid for Scientific Research, the Japan Agency for Medical Research and Development, the Uehara Memorial and Yamada Science, the Grant-in-Aid for Young Scientists, and a Japanese Government Scholarship (Ministry of Education, Culture, Sports, Science and Technology).
Malaria infection caused by Plasmodium falciparum, even after a one-time illness, can cause long-term bone loss, researchers report.
Parasite byproducts remain in the bone marrow and induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, resulting in bone resorption.
Researchers found that treatment with the vitamin D3 analog alfacalcidol can prevent bone loss related to malaria, at least in animals.
They suggest that bone therapies combined with anti-malarial drugs may prevent bone loss in infected individuals.
Cevayir Coban, MD, from Osaka University in Japan, and colleagues reported their findings in Science Immunology.
"Although chronic inflammatory conditions are known to facilitate bone disorders, our study—for the first time—shows that malaria can do the same thing,” Dr Coban said.
“One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered,” she said. “However, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long-term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones."
To study the effect of Plasmodium infection on bone, the team used two mouse models, Plasmodium yoelii nonlethal (PyNL) and Plasmodium chabaudi chabaudi (Pcc).
PyNL infection invades reticulocytes and resembles Plasmodium vivax infection in humans. Pcc infection more closely resembles Plasmodium falciparum infection in humans. The investigators used Pcc infection to evaluate the effect of low-level chronic infection on bone homeostasis.
They infected 6-week-old adult mice with these parasite species and assessed changes in bone during the acute, convalescent, and chronic phases of infection.
Both parasites caused significantly reduced trabecular bone volume and increased trabecular bone spacing in infected mice. This continued for over 60 days after parasite clearance.
Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche, which turns the bone noticeably black in color, and results in it being ‘eaten-up’ by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis".
The research team also investigated the impact of malaria infection on bone growth at a young age by infecting 3-week-old mice with PyNL. These mice had significantly shorter femurs and lower trabecular bone volume compared with uninfected litter mates 3 weeks after infection, when the mice were 6 weeks old.
A key finding of the study, investigators report, is that although Plasmodium infection resolves systemically, a state of chronic inflammation evolves in the bone marrow that may be associated with continued accumulation of Plasmodium byproducts—proteins, hemozoin, and nucleic acids—in the bone marrow. These byproducts are capable of modulating immune responses.
The team also evaluated whether vitamin D supplementation would alleviate bone loss caused by Plasmodium. They treated mice with alfacalcidol, which is used to treat osteoporosis. Treatment with lower doses of oral alfacalcidol was sufficient to prevent malaria-induced bone loss, while higher doses enhanced bone growth despite infection.
This work was supported by the Grants-in-Aid for Scientific Research, the Japan Agency for Medical Research and Development, the Uehara Memorial and Yamada Science, the Grant-in-Aid for Young Scientists, and a Japanese Government Scholarship (Ministry of Education, Culture, Sports, Science and Technology).
Malaria infection caused by Plasmodium falciparum, even after a one-time illness, can cause long-term bone loss, researchers report.
Parasite byproducts remain in the bone marrow and induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, resulting in bone resorption.
Researchers found that treatment with the vitamin D3 analog alfacalcidol can prevent bone loss related to malaria, at least in animals.
They suggest that bone therapies combined with anti-malarial drugs may prevent bone loss in infected individuals.
Cevayir Coban, MD, from Osaka University in Japan, and colleagues reported their findings in Science Immunology.
"Although chronic inflammatory conditions are known to facilitate bone disorders, our study—for the first time—shows that malaria can do the same thing,” Dr Coban said.
“One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered,” she said. “However, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long-term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones."
To study the effect of Plasmodium infection on bone, the team used two mouse models, Plasmodium yoelii nonlethal (PyNL) and Plasmodium chabaudi chabaudi (Pcc).
PyNL infection invades reticulocytes and resembles Plasmodium vivax infection in humans. Pcc infection more closely resembles Plasmodium falciparum infection in humans. The investigators used Pcc infection to evaluate the effect of low-level chronic infection on bone homeostasis.
They infected 6-week-old adult mice with these parasite species and assessed changes in bone during the acute, convalescent, and chronic phases of infection.
Both parasites caused significantly reduced trabecular bone volume and increased trabecular bone spacing in infected mice. This continued for over 60 days after parasite clearance.
Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche, which turns the bone noticeably black in color, and results in it being ‘eaten-up’ by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis".
The research team also investigated the impact of malaria infection on bone growth at a young age by infecting 3-week-old mice with PyNL. These mice had significantly shorter femurs and lower trabecular bone volume compared with uninfected litter mates 3 weeks after infection, when the mice were 6 weeks old.
A key finding of the study, investigators report, is that although Plasmodium infection resolves systemically, a state of chronic inflammation evolves in the bone marrow that may be associated with continued accumulation of Plasmodium byproducts—proteins, hemozoin, and nucleic acids—in the bone marrow. These byproducts are capable of modulating immune responses.
The team also evaluated whether vitamin D supplementation would alleviate bone loss caused by Plasmodium. They treated mice with alfacalcidol, which is used to treat osteoporosis. Treatment with lower doses of oral alfacalcidol was sufficient to prevent malaria-induced bone loss, while higher doses enhanced bone growth despite infection.
This work was supported by the Grants-in-Aid for Scientific Research, the Japan Agency for Medical Research and Development, the Uehara Memorial and Yamada Science, the Grant-in-Aid for Young Scientists, and a Japanese Government Scholarship (Ministry of Education, Culture, Sports, Science and Technology).