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Genetic markers may help predict allogeneic SCT outcomes
SALT LAKE CITY – The presence of p2X7 receptor single nucleotide polymorphisms (SNPs) associated with gain and loss of function may help predict outcomes after allogeneic stem cell transplantation, according to findings from a clinical correlate analysis of recipient and donor DNA samples.
The findings require validation in future studies, but suggest that the presence of the SNPs and p2X7 haplotypes 2 and 4 could be incorporated into disease risk models to improve transplant decision making, David Stuart Ritchie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The analysis, which specifically looked for the presence of 16 previously identified SNPs and the haplotypes 2 and 4 in p2x7, was performed on pretransplant DNA samples from 333 allogeneic stem cell transplant recipients and 228 donors at a single center between 2002 and 2013. The findings were correlated with patient outcomes.
Five SNPs were excluded from correlation because of low frequency, and of the 11 remaining SNPs, 3 were found to be significantly associated with reduced incidence of acute and/or chronic graft-versus-host disease (GVHD), and 2 were significantly associated with increased relapse or transplant-related mortality, said Dr. Ritchie of the University of Melbourne, Parkville, Australia.
The loss-of-function SNPs rs28360457 and rs3751133 – each linked with decreased inflammation – were significantly associated with a reduced incidence of acute GVHD when comparing grade 0 with grades 1-4 GVHD (P = .0234 and P = .0411, respectively), but not when comparing grades 0-1 and grades 2-4 GVHD.
SNP rs3751133 was also significantly associated with reduced incidence of chronic GVHD when comparing grade 0 with grades 0-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD, he said.
The loss-of-function SNP rs1653624 – which is linked with decreased phagocytosis – was associated with an increased incidence of acute GVHD when comparing grade 0 vs. grade 1-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD (P = NS).
SNP rs7958311, which had increased surface expression, was associated with a trend toward increased relapse risk (P = .053), and the loss-of-function SNP rs1653624 was associated with an excess of early transplant-related mortality (P = .0471).
“Individual SNPs are interesting, but perhaps more interesting are the haplotypes,” Dr. Ritchie said.
Haplotype 4, which was found in 8 recipients, involves rs1718119 and rs7958311. Those SNPs were previously shown to have 300% and 195% increased expression, respectively, with or without rs2230912, which has been shown to be decreased by 72%, and with or without loss of function rs1653624. Haplotype 4 is associated with a net increase in p2X7 activity, he explained.
In the current study, haplotype 4 was only found to involve rs1718119 co-inherited with rs2230912, and was associated with substantially decreased relapse-free survival overall (hazard ratio, 0.6946), when compared with haplotype 2 (HR, 0.2078), he said.
The differences between haplotype 4 and haplotype 2, and between haplotype 4 and patients with neither haplotype, were highly statistically significant.
Relapse-free survival did not differ significantly between those with haplotype 2 and those with neither haplotype (HR, 0.7717). Similarly, overall survival was significantly poorer among those with haplotype 4 versus haplotype 2 or no haplotype (HR, 0.2812 and 0.2882, respectively), but no difference was seen in overall survival between those with haplotype 2 and those with no haplotype (HR, 1.003), he said.
P2X7 is a purinergic signaling receptor located at chromosome 12q24–a region associated with inflammatory disorders. It plays an important role in immunogenic cell death. It is expressed in all leukocytes, with the highest level of expression seen in monocyte lineage. Binding of its ligand – extracellular adenosine 5’-triphosphate – leads to activation of dendritic cells and release of IL1b leading to T cell recruitment and the production of memory T cells.
Both gain- and loss-of-function SNPs in p2X7 have been reported and implicated in GVHD and other inflammatory disorders, Dr. Ritchie said, explaining the rationale for studying their correlations with outcomes after allogeneic stem cell transplantation.
While such transplants are highly effective for treating hematologic malignancies, outcomes can be adversely affected by infection, acute organ dysfunction, and GVHD. Pretransplant conditioning regimens are associated with high levels of immunogenic cell death and the release of extracellular adenosine 5’-triphosphate, therefore signaling through the p2X7 receptor may lead to activation of downstream effectors that influence transplant outcome, he noted.
“We hypothesized that germline gain or loss of function polymorphisms in this receptor in recipients of allogeneic transplantation would result in an adverse outcome,” he said.
The mean age of the recipients whose samples were analyzed was 46 years, and about half were women. Most (83.8%) had a peripheral blood graft source and 64% of transplants were from related donors. The nonrelapse mortality at 24 months was 12.98%, Dr. Ritchie said, noting that their indications for transplantation were “fairly representative of the adult transplant population, dominated by acute leukemia with a range of other acute conditions.”
The findings – particularly those with respect to haplotype 4, which had the most substantial impact – could play a role in patient risk assessment.
“Potentially, although it is a relatively uncommon haplotype, pretransplant identification of haplotype 4 may well have implications for transplant decision making, given the fact that the majority of our patients with this haplotype did not survive posttransplant,” he concluded, noting that an effort to validate the findings is ongoing in an additional 300 patients.
Dr. Ritchie reported having no financial disclosures.
SOURCE: Koldej R et al. The 2018 BMT Tandem Meetings, Abstract 22.
SALT LAKE CITY – The presence of p2X7 receptor single nucleotide polymorphisms (SNPs) associated with gain and loss of function may help predict outcomes after allogeneic stem cell transplantation, according to findings from a clinical correlate analysis of recipient and donor DNA samples.
The findings require validation in future studies, but suggest that the presence of the SNPs and p2X7 haplotypes 2 and 4 could be incorporated into disease risk models to improve transplant decision making, David Stuart Ritchie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The analysis, which specifically looked for the presence of 16 previously identified SNPs and the haplotypes 2 and 4 in p2x7, was performed on pretransplant DNA samples from 333 allogeneic stem cell transplant recipients and 228 donors at a single center between 2002 and 2013. The findings were correlated with patient outcomes.
Five SNPs were excluded from correlation because of low frequency, and of the 11 remaining SNPs, 3 were found to be significantly associated with reduced incidence of acute and/or chronic graft-versus-host disease (GVHD), and 2 were significantly associated with increased relapse or transplant-related mortality, said Dr. Ritchie of the University of Melbourne, Parkville, Australia.
The loss-of-function SNPs rs28360457 and rs3751133 – each linked with decreased inflammation – were significantly associated with a reduced incidence of acute GVHD when comparing grade 0 with grades 1-4 GVHD (P = .0234 and P = .0411, respectively), but not when comparing grades 0-1 and grades 2-4 GVHD.
SNP rs3751133 was also significantly associated with reduced incidence of chronic GVHD when comparing grade 0 with grades 0-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD, he said.
The loss-of-function SNP rs1653624 – which is linked with decreased phagocytosis – was associated with an increased incidence of acute GVHD when comparing grade 0 vs. grade 1-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD (P = NS).
SNP rs7958311, which had increased surface expression, was associated with a trend toward increased relapse risk (P = .053), and the loss-of-function SNP rs1653624 was associated with an excess of early transplant-related mortality (P = .0471).
“Individual SNPs are interesting, but perhaps more interesting are the haplotypes,” Dr. Ritchie said.
Haplotype 4, which was found in 8 recipients, involves rs1718119 and rs7958311. Those SNPs were previously shown to have 300% and 195% increased expression, respectively, with or without rs2230912, which has been shown to be decreased by 72%, and with or without loss of function rs1653624. Haplotype 4 is associated with a net increase in p2X7 activity, he explained.
In the current study, haplotype 4 was only found to involve rs1718119 co-inherited with rs2230912, and was associated with substantially decreased relapse-free survival overall (hazard ratio, 0.6946), when compared with haplotype 2 (HR, 0.2078), he said.
The differences between haplotype 4 and haplotype 2, and between haplotype 4 and patients with neither haplotype, were highly statistically significant.
Relapse-free survival did not differ significantly between those with haplotype 2 and those with neither haplotype (HR, 0.7717). Similarly, overall survival was significantly poorer among those with haplotype 4 versus haplotype 2 or no haplotype (HR, 0.2812 and 0.2882, respectively), but no difference was seen in overall survival between those with haplotype 2 and those with no haplotype (HR, 1.003), he said.
P2X7 is a purinergic signaling receptor located at chromosome 12q24–a region associated with inflammatory disorders. It plays an important role in immunogenic cell death. It is expressed in all leukocytes, with the highest level of expression seen in monocyte lineage. Binding of its ligand – extracellular adenosine 5’-triphosphate – leads to activation of dendritic cells and release of IL1b leading to T cell recruitment and the production of memory T cells.
Both gain- and loss-of-function SNPs in p2X7 have been reported and implicated in GVHD and other inflammatory disorders, Dr. Ritchie said, explaining the rationale for studying their correlations with outcomes after allogeneic stem cell transplantation.
While such transplants are highly effective for treating hematologic malignancies, outcomes can be adversely affected by infection, acute organ dysfunction, and GVHD. Pretransplant conditioning regimens are associated with high levels of immunogenic cell death and the release of extracellular adenosine 5’-triphosphate, therefore signaling through the p2X7 receptor may lead to activation of downstream effectors that influence transplant outcome, he noted.
“We hypothesized that germline gain or loss of function polymorphisms in this receptor in recipients of allogeneic transplantation would result in an adverse outcome,” he said.
The mean age of the recipients whose samples were analyzed was 46 years, and about half were women. Most (83.8%) had a peripheral blood graft source and 64% of transplants were from related donors. The nonrelapse mortality at 24 months was 12.98%, Dr. Ritchie said, noting that their indications for transplantation were “fairly representative of the adult transplant population, dominated by acute leukemia with a range of other acute conditions.”
The findings – particularly those with respect to haplotype 4, which had the most substantial impact – could play a role in patient risk assessment.
“Potentially, although it is a relatively uncommon haplotype, pretransplant identification of haplotype 4 may well have implications for transplant decision making, given the fact that the majority of our patients with this haplotype did not survive posttransplant,” he concluded, noting that an effort to validate the findings is ongoing in an additional 300 patients.
Dr. Ritchie reported having no financial disclosures.
SOURCE: Koldej R et al. The 2018 BMT Tandem Meetings, Abstract 22.
SALT LAKE CITY – The presence of p2X7 receptor single nucleotide polymorphisms (SNPs) associated with gain and loss of function may help predict outcomes after allogeneic stem cell transplantation, according to findings from a clinical correlate analysis of recipient and donor DNA samples.
The findings require validation in future studies, but suggest that the presence of the SNPs and p2X7 haplotypes 2 and 4 could be incorporated into disease risk models to improve transplant decision making, David Stuart Ritchie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The analysis, which specifically looked for the presence of 16 previously identified SNPs and the haplotypes 2 and 4 in p2x7, was performed on pretransplant DNA samples from 333 allogeneic stem cell transplant recipients and 228 donors at a single center between 2002 and 2013. The findings were correlated with patient outcomes.
Five SNPs were excluded from correlation because of low frequency, and of the 11 remaining SNPs, 3 were found to be significantly associated with reduced incidence of acute and/or chronic graft-versus-host disease (GVHD), and 2 were significantly associated with increased relapse or transplant-related mortality, said Dr. Ritchie of the University of Melbourne, Parkville, Australia.
The loss-of-function SNPs rs28360457 and rs3751133 – each linked with decreased inflammation – were significantly associated with a reduced incidence of acute GVHD when comparing grade 0 with grades 1-4 GVHD (P = .0234 and P = .0411, respectively), but not when comparing grades 0-1 and grades 2-4 GVHD.
SNP rs3751133 was also significantly associated with reduced incidence of chronic GVHD when comparing grade 0 with grades 0-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD, he said.
The loss-of-function SNP rs1653624 – which is linked with decreased phagocytosis – was associated with an increased incidence of acute GVHD when comparing grade 0 vs. grade 1-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD (P = NS).
SNP rs7958311, which had increased surface expression, was associated with a trend toward increased relapse risk (P = .053), and the loss-of-function SNP rs1653624 was associated with an excess of early transplant-related mortality (P = .0471).
“Individual SNPs are interesting, but perhaps more interesting are the haplotypes,” Dr. Ritchie said.
Haplotype 4, which was found in 8 recipients, involves rs1718119 and rs7958311. Those SNPs were previously shown to have 300% and 195% increased expression, respectively, with or without rs2230912, which has been shown to be decreased by 72%, and with or without loss of function rs1653624. Haplotype 4 is associated with a net increase in p2X7 activity, he explained.
In the current study, haplotype 4 was only found to involve rs1718119 co-inherited with rs2230912, and was associated with substantially decreased relapse-free survival overall (hazard ratio, 0.6946), when compared with haplotype 2 (HR, 0.2078), he said.
The differences between haplotype 4 and haplotype 2, and between haplotype 4 and patients with neither haplotype, were highly statistically significant.
Relapse-free survival did not differ significantly between those with haplotype 2 and those with neither haplotype (HR, 0.7717). Similarly, overall survival was significantly poorer among those with haplotype 4 versus haplotype 2 or no haplotype (HR, 0.2812 and 0.2882, respectively), but no difference was seen in overall survival between those with haplotype 2 and those with no haplotype (HR, 1.003), he said.
P2X7 is a purinergic signaling receptor located at chromosome 12q24–a region associated with inflammatory disorders. It plays an important role in immunogenic cell death. It is expressed in all leukocytes, with the highest level of expression seen in monocyte lineage. Binding of its ligand – extracellular adenosine 5’-triphosphate – leads to activation of dendritic cells and release of IL1b leading to T cell recruitment and the production of memory T cells.
Both gain- and loss-of-function SNPs in p2X7 have been reported and implicated in GVHD and other inflammatory disorders, Dr. Ritchie said, explaining the rationale for studying their correlations with outcomes after allogeneic stem cell transplantation.
While such transplants are highly effective for treating hematologic malignancies, outcomes can be adversely affected by infection, acute organ dysfunction, and GVHD. Pretransplant conditioning regimens are associated with high levels of immunogenic cell death and the release of extracellular adenosine 5’-triphosphate, therefore signaling through the p2X7 receptor may lead to activation of downstream effectors that influence transplant outcome, he noted.
“We hypothesized that germline gain or loss of function polymorphisms in this receptor in recipients of allogeneic transplantation would result in an adverse outcome,” he said.
The mean age of the recipients whose samples were analyzed was 46 years, and about half were women. Most (83.8%) had a peripheral blood graft source and 64% of transplants were from related donors. The nonrelapse mortality at 24 months was 12.98%, Dr. Ritchie said, noting that their indications for transplantation were “fairly representative of the adult transplant population, dominated by acute leukemia with a range of other acute conditions.”
The findings – particularly those with respect to haplotype 4, which had the most substantial impact – could play a role in patient risk assessment.
“Potentially, although it is a relatively uncommon haplotype, pretransplant identification of haplotype 4 may well have implications for transplant decision making, given the fact that the majority of our patients with this haplotype did not survive posttransplant,” he concluded, noting that an effort to validate the findings is ongoing in an additional 300 patients.
Dr. Ritchie reported having no financial disclosures.
SOURCE: Koldej R et al. The 2018 BMT Tandem Meetings, Abstract 22.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Haplotype 4 was associated with substantially decreased relapse-free survival overall (hazard ratio, 0.6946) versus haplotype 2 (HR, 0.2078).
Study details: A clinical correlate analysis of 561 DNA samples.
Disclosures: Dr. Ritchie reported having no financial disclosures.
Source: Koldej R et al. The 2018 BMT Tandem Meetings, Abstract 22.
Study shows value of pretransplant assessment of function, endurance
SALT LAKE CITY – Comprehensive assessment of functional status and endurance prior to allogeneic hematopoietic cell transplantation (HCT) provides important insights into posttransplant outcomes, and when used in combination with other measures may improve the patient selection process, a chart review suggests.
In 349 patients, results of the prospective assessment of physical performance and endurance, along with HCT Comorbidity Index (HCT-CI) score and Karnofsky Performance Scale score (KPS), were compared with day 100-plus nonrelapse mortality and overall survival. The measures were also compared with the novel measures of hospital length of stay, and death during HCT admission, Shabnam Rehman, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
However, heart rate recovery in less than 3 minutes after performing 25 step-ups on each side was associated with shorter length of stay with 89% of those patients, compared with 11% of patients who were not able to recover their heart rate in less than 3 minutes, being discharged within 30 days, she said.
“Similarly, patients who are able to perform at least 11 sit-to-stands in 30 seconds are more likely to be discharged earlier (63% vs. 14% discharged within 30 days),” she said. “The converse is also true.”
That is, only 16% of those not able to recover their heart rate within 3 minutes had a 30-day or shorter stay, while 31% had at least a 60-day stay. In addition, just 13% of those with limited endurance had a 30-day stay or shorter, while 24% had at least a 60-day stay, she explained.
Further, patients with limited endurance, and those unable to perform 10 or more sit-to-stands in 30 seconds were more likely to die during their first transplant admission. Of those with limited endurance, 31% died during admission and 13% survived, and of those with good endurance 69% died during admission and 87% survived. Among patients who were unable to perform more than 10 sit-to-stands, 42% died during admission and 20% survived, and of those able to perform 11 or more, 38% died during admission, and 53% survived.
Overall survival was associated with age, KPS, HCT-CI, and age-adjusted HCT-CI, she noted.
“Patients who were over age 40 and more, and patients with a KPS of 60 or 70, belong to the high- to intermediate-risk group more likely to have decreased overall survival as has been shown in previous studies,” she said. “In addition to validating these findings, we also found that the semiquantitative measures, including pain and endurance, were also associated with overall survival.”
Those with pain present or limited endurance had significantly poorer overall survival (P = .007 and P = .01, respectively), and this finding was reflected in the quantitative measures of sit-to-stands (P = .01) and step-ups (P = .001), even when stratified by age-adjusted HCT-CI, she said.
In addition, a number of risk factors present at the pretreatment assessment were found to be significantly associated with requirement of an assistive device at discharge. These included pain, weakness in the lower extremities, use of an assistive device, inability to perform 25 step-ups and more than 10 sit-to-stands in 30 seconds, and limited endurance (P values ranging from .02 to less than .0001). Requirement of a device was associated with poorer overall survival (P = .03), she said.
Study participants were adults aged 18 years and older (median, 58 years) undergoing a first allogeneic HCT at a single center between 2010 and 2016. Most (83%) were older than age 40 years and 58% were men. About half (51%) had acute myeloid leukemia, and 64% overall had a KPS score of 60-70.
Physical therapists assessed physical performance of all patients within 4 weeks pre-HCT; testing included 25 7-inch step-ups on each side, unassisted sit-to-stands from an 18-inch chair in 30 seconds, weight-bearing ability, need for assistance with ambulation, motor strength in four extremities, sensory or coordination impairment, self-reported pain, and time to recovery of heart rate and oxygen saturation to pre-exercise levels.
“The HCT-CI is a validated tool that predicts nonrelapse mortality and overall survival, but comorbidity alone as a single domain is not a surrogate of overall health or reflection on the true biological age of our patients,” Dr. Rehman said, noting that studies have shown that functional impairment is associated with shorter overall survival, and that patient-reported physical functioning is predictive of overall survival. “The assessment of functional impairment becomes more critical given the aging U.S. population and older patients receiving transplant.”
Traditionally, functional status has been assessed via the KPS, which is a subjective measure and lacks precision, and the HCT-CI has not been studied in the context of the novel outcome measures addressed in the current study, she noted.
The current findings highlight the prognostic value of a more quantitative pretransplant assessment, which can help improve the patient selection process.
“We are in the process of analyzing some more outcomes of these pretransplant assessments, and developing a score that can, in conjunction with other predictive tools, help us improve pretransplant risk stratification and devise interventions that can improve the endurance and overall survival of the patients,” she concluded.
Dr. Rehman reported having no financial disclosures.
SOURCE: Rehman S et al., The 2018 BTM Tandem Meetings, Abstract 19.
SALT LAKE CITY – Comprehensive assessment of functional status and endurance prior to allogeneic hematopoietic cell transplantation (HCT) provides important insights into posttransplant outcomes, and when used in combination with other measures may improve the patient selection process, a chart review suggests.
In 349 patients, results of the prospective assessment of physical performance and endurance, along with HCT Comorbidity Index (HCT-CI) score and Karnofsky Performance Scale score (KPS), were compared with day 100-plus nonrelapse mortality and overall survival. The measures were also compared with the novel measures of hospital length of stay, and death during HCT admission, Shabnam Rehman, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
However, heart rate recovery in less than 3 minutes after performing 25 step-ups on each side was associated with shorter length of stay with 89% of those patients, compared with 11% of patients who were not able to recover their heart rate in less than 3 minutes, being discharged within 30 days, she said.
“Similarly, patients who are able to perform at least 11 sit-to-stands in 30 seconds are more likely to be discharged earlier (63% vs. 14% discharged within 30 days),” she said. “The converse is also true.”
That is, only 16% of those not able to recover their heart rate within 3 minutes had a 30-day or shorter stay, while 31% had at least a 60-day stay. In addition, just 13% of those with limited endurance had a 30-day stay or shorter, while 24% had at least a 60-day stay, she explained.
Further, patients with limited endurance, and those unable to perform 10 or more sit-to-stands in 30 seconds were more likely to die during their first transplant admission. Of those with limited endurance, 31% died during admission and 13% survived, and of those with good endurance 69% died during admission and 87% survived. Among patients who were unable to perform more than 10 sit-to-stands, 42% died during admission and 20% survived, and of those able to perform 11 or more, 38% died during admission, and 53% survived.
Overall survival was associated with age, KPS, HCT-CI, and age-adjusted HCT-CI, she noted.
“Patients who were over age 40 and more, and patients with a KPS of 60 or 70, belong to the high- to intermediate-risk group more likely to have decreased overall survival as has been shown in previous studies,” she said. “In addition to validating these findings, we also found that the semiquantitative measures, including pain and endurance, were also associated with overall survival.”
Those with pain present or limited endurance had significantly poorer overall survival (P = .007 and P = .01, respectively), and this finding was reflected in the quantitative measures of sit-to-stands (P = .01) and step-ups (P = .001), even when stratified by age-adjusted HCT-CI, she said.
In addition, a number of risk factors present at the pretreatment assessment were found to be significantly associated with requirement of an assistive device at discharge. These included pain, weakness in the lower extremities, use of an assistive device, inability to perform 25 step-ups and more than 10 sit-to-stands in 30 seconds, and limited endurance (P values ranging from .02 to less than .0001). Requirement of a device was associated with poorer overall survival (P = .03), she said.
Study participants were adults aged 18 years and older (median, 58 years) undergoing a first allogeneic HCT at a single center between 2010 and 2016. Most (83%) were older than age 40 years and 58% were men. About half (51%) had acute myeloid leukemia, and 64% overall had a KPS score of 60-70.
Physical therapists assessed physical performance of all patients within 4 weeks pre-HCT; testing included 25 7-inch step-ups on each side, unassisted sit-to-stands from an 18-inch chair in 30 seconds, weight-bearing ability, need for assistance with ambulation, motor strength in four extremities, sensory or coordination impairment, self-reported pain, and time to recovery of heart rate and oxygen saturation to pre-exercise levels.
“The HCT-CI is a validated tool that predicts nonrelapse mortality and overall survival, but comorbidity alone as a single domain is not a surrogate of overall health or reflection on the true biological age of our patients,” Dr. Rehman said, noting that studies have shown that functional impairment is associated with shorter overall survival, and that patient-reported physical functioning is predictive of overall survival. “The assessment of functional impairment becomes more critical given the aging U.S. population and older patients receiving transplant.”
Traditionally, functional status has been assessed via the KPS, which is a subjective measure and lacks precision, and the HCT-CI has not been studied in the context of the novel outcome measures addressed in the current study, she noted.
The current findings highlight the prognostic value of a more quantitative pretransplant assessment, which can help improve the patient selection process.
“We are in the process of analyzing some more outcomes of these pretransplant assessments, and developing a score that can, in conjunction with other predictive tools, help us improve pretransplant risk stratification and devise interventions that can improve the endurance and overall survival of the patients,” she concluded.
Dr. Rehman reported having no financial disclosures.
SOURCE: Rehman S et al., The 2018 BTM Tandem Meetings, Abstract 19.
SALT LAKE CITY – Comprehensive assessment of functional status and endurance prior to allogeneic hematopoietic cell transplantation (HCT) provides important insights into posttransplant outcomes, and when used in combination with other measures may improve the patient selection process, a chart review suggests.
In 349 patients, results of the prospective assessment of physical performance and endurance, along with HCT Comorbidity Index (HCT-CI) score and Karnofsky Performance Scale score (KPS), were compared with day 100-plus nonrelapse mortality and overall survival. The measures were also compared with the novel measures of hospital length of stay, and death during HCT admission, Shabnam Rehman, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
However, heart rate recovery in less than 3 minutes after performing 25 step-ups on each side was associated with shorter length of stay with 89% of those patients, compared with 11% of patients who were not able to recover their heart rate in less than 3 minutes, being discharged within 30 days, she said.
“Similarly, patients who are able to perform at least 11 sit-to-stands in 30 seconds are more likely to be discharged earlier (63% vs. 14% discharged within 30 days),” she said. “The converse is also true.”
That is, only 16% of those not able to recover their heart rate within 3 minutes had a 30-day or shorter stay, while 31% had at least a 60-day stay. In addition, just 13% of those with limited endurance had a 30-day stay or shorter, while 24% had at least a 60-day stay, she explained.
Further, patients with limited endurance, and those unable to perform 10 or more sit-to-stands in 30 seconds were more likely to die during their first transplant admission. Of those with limited endurance, 31% died during admission and 13% survived, and of those with good endurance 69% died during admission and 87% survived. Among patients who were unable to perform more than 10 sit-to-stands, 42% died during admission and 20% survived, and of those able to perform 11 or more, 38% died during admission, and 53% survived.
Overall survival was associated with age, KPS, HCT-CI, and age-adjusted HCT-CI, she noted.
“Patients who were over age 40 and more, and patients with a KPS of 60 or 70, belong to the high- to intermediate-risk group more likely to have decreased overall survival as has been shown in previous studies,” she said. “In addition to validating these findings, we also found that the semiquantitative measures, including pain and endurance, were also associated with overall survival.”
Those with pain present or limited endurance had significantly poorer overall survival (P = .007 and P = .01, respectively), and this finding was reflected in the quantitative measures of sit-to-stands (P = .01) and step-ups (P = .001), even when stratified by age-adjusted HCT-CI, she said.
In addition, a number of risk factors present at the pretreatment assessment were found to be significantly associated with requirement of an assistive device at discharge. These included pain, weakness in the lower extremities, use of an assistive device, inability to perform 25 step-ups and more than 10 sit-to-stands in 30 seconds, and limited endurance (P values ranging from .02 to less than .0001). Requirement of a device was associated with poorer overall survival (P = .03), she said.
Study participants were adults aged 18 years and older (median, 58 years) undergoing a first allogeneic HCT at a single center between 2010 and 2016. Most (83%) were older than age 40 years and 58% were men. About half (51%) had acute myeloid leukemia, and 64% overall had a KPS score of 60-70.
Physical therapists assessed physical performance of all patients within 4 weeks pre-HCT; testing included 25 7-inch step-ups on each side, unassisted sit-to-stands from an 18-inch chair in 30 seconds, weight-bearing ability, need for assistance with ambulation, motor strength in four extremities, sensory or coordination impairment, self-reported pain, and time to recovery of heart rate and oxygen saturation to pre-exercise levels.
“The HCT-CI is a validated tool that predicts nonrelapse mortality and overall survival, but comorbidity alone as a single domain is not a surrogate of overall health or reflection on the true biological age of our patients,” Dr. Rehman said, noting that studies have shown that functional impairment is associated with shorter overall survival, and that patient-reported physical functioning is predictive of overall survival. “The assessment of functional impairment becomes more critical given the aging U.S. population and older patients receiving transplant.”
Traditionally, functional status has been assessed via the KPS, which is a subjective measure and lacks precision, and the HCT-CI has not been studied in the context of the novel outcome measures addressed in the current study, she noted.
The current findings highlight the prognostic value of a more quantitative pretransplant assessment, which can help improve the patient selection process.
“We are in the process of analyzing some more outcomes of these pretransplant assessments, and developing a score that can, in conjunction with other predictive tools, help us improve pretransplant risk stratification and devise interventions that can improve the endurance and overall survival of the patients,” she concluded.
Dr. Rehman reported having no financial disclosures.
SOURCE: Rehman S et al., The 2018 BTM Tandem Meetings, Abstract 19.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: The 30-day discharge rates were 89% versus 11% in those with and without good heart rate recovery, respectively.
Study details: A retrospective review of prospectively collected data for 349 patients.
Disclosures: Dr. Rehman reported having no financial disclosures.
Source: Rehman S et al. The 2018 BMT Tandem Meetings, Abstract 19.
Reduced intensity conditioning doesn’t protect fertility
SALT LAKE CITY – Both male and female recipients of childhood hematopoietic stem cell transplantation (HSCT) were very likely to have severely decreased fertility potential, even in the setting of preserved puberty, according to a recent study of adolescent and young adult HSCT recipients.
A reduced intensity conditioning regimen did not protect this cohort from decreased fertility, a finding that surprised the study’s lead author.
“We had hypothesized that, as compared to myeloablative conditioning, reduced intensity conditioning in children who received HSCT would lower the risk of infertility and lessen gonadal failure,” said Helen Oquendo del Toro, MD. In fact, Dr. Oquendo del Toro and her collaborators found that more than 90% of semen samples available for analysis had results that indicated infertility or severely impaired fertility, regardless of the type of pretransplant conditioning the patient had received.
The study highlights the need for fertility preservation when possible before HSCT, and makes clear that “normal puberty does not equate to normal fertility,” said Dr. Oquendo del Toro, of Cincinnati Children’s Hospital Medical Center.
Dr. Oquendo del Toro presented results of an observational cohort study of late effects of HSCT that included individuals aged 1-40 years old who received a single HSCT at, or after, 1 year of age.
Twenty-one males in the study had semen available for analysis. Of the 10 males who received myeloablative conditioning (MAC), 8 had azoospermia, and 2 more had oligoteratospermia (low sperm count with abnormal morphology). For the 11 males who received reduced intensity conditioning (RIC), eight had azoospermia, two had semen samples that showed oligoteratospermia, and one had a normal semen analysis.
The median age at transplant for these males was 14.5 years, and patients were a median of 19 years old at follow-up, Dr. Oquendo del Toro said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
For females in the study, low levels of anti-Müllerian hormone (AMH) – generally considered the best surrogate lab value for ovarian reserve – were nearly as common. Of 14 females receiving MAC, 13 (93%) had low AMH, as did 6 of 8 (75%) female patients who received RIC.
Individuals with more than one HSCT were excluded, as were those with Fanconi anemia, which itself carries a risk of gonadal failure. The study’s two aims were to investigate gonadal function as well as fertility potential after receipt of either RIC or MAC for HSCT.
Patients were seen by an endocrinologist who assessed testicular volume and assigned a Tanner stage. At age 11 and older, patients’ gonadal function was assessed on an annual basis by obtaining levels of luteinizing hormone and follicle stimulating hormone for all patients; female estradiol levels were tracked, as were male testosterone levels.
Assessment of fertility potential required additional laboratory testing: For females, the investigators obtained AMH levels, while for males, semen analysis was coupled with serum levels of inhibin B, an indicator of Sertoli cell function.
A total of 72 males were more than 1 year post-HSCT in the cohort, and of these, 41 were at least 11 years old and had achieved pubertal status according to laboratory evaluation. In all, 22 of the male patients received RIC, and 19 received MAC.
Males receiving MAC were a median 20 years old at their follow-up evaluation, and a median 6 years post-HSCT, while the RIC group were a median of 18.5 years old and 5.5 years out from their transplant.
Of the 50 females who were more than 1 year post-HSCT, 25 were pubertal and 11 years old or older. Nine of the female patients received RIC, and 16 received MAC.
Females who received MAC were a median 12.1 years old and 4.1 years post-HSCT at their follow-up evaluation. Females receiving RIC were a median 16 years old, and 6.5 years post-HSCT at the time of evaluation.
Patients received their transplants for a variety of malignant and nonmalignant conditions.
“We saw relatively normal gonadotropins after both reduced intensity and myeloablative conditioning in males,” Dr. Oquendo del Toro said. Of the MAC group, 4 of 15 (27%) had elevated follicle stimulating hormone levels, as did 2 of 17 (12%) of the RIC group. Elevated luteinizing hormone levels were seen in 2 of 15 (13%) of the MAC group and 1 of 17 (6%) of the RIC group. Four patients in each group had abnormally low testosterone levels.
However, when the investigators looked at inhibin B levels in males, they found abnormally low levels in 9 of 15 (60%) of those who received MAC, and in 6 of 15 (40%) of those who received RIC. These results meshed with the severely abnormal semen analyses investigators found from those participants for whom a sample was available, Dr. Oquendo del Toro said.
For females, estradiol levels were significantly lower for those who had received MAC, with 7 of 11 (64%) of that group having abnormally low estradiol levels. The levels approached 0 pg/mL for many, said Dr. Oquendo del Toro. None of the eight patients who had received RIC had abnormally low estradiol levels (P = .0008).
“Male puberty is relatively well preserved after both myeloablative and reduced intensity conditioning, but there is a greater than 90% risk of male infertility associated with both reduced intensity and myeloablative conditioning for HSCT,” Dr. Oquendo del Toro said.
For females, the study paints a different picture. “We saw decreased premature ovarian failure after reduced intensity conditioning … but the fertility potential as assessed by anti-Müllerian hormone was decreased” after both conditioning regimens, she said.
Dr. Oquendo del Toro reported having no conflicts of interest.
SOURCE: Oquendo del Toro H et al. The 2018 BMT Tandem Meetings, Abstract 88.
SALT LAKE CITY – Both male and female recipients of childhood hematopoietic stem cell transplantation (HSCT) were very likely to have severely decreased fertility potential, even in the setting of preserved puberty, according to a recent study of adolescent and young adult HSCT recipients.
A reduced intensity conditioning regimen did not protect this cohort from decreased fertility, a finding that surprised the study’s lead author.
“We had hypothesized that, as compared to myeloablative conditioning, reduced intensity conditioning in children who received HSCT would lower the risk of infertility and lessen gonadal failure,” said Helen Oquendo del Toro, MD. In fact, Dr. Oquendo del Toro and her collaborators found that more than 90% of semen samples available for analysis had results that indicated infertility or severely impaired fertility, regardless of the type of pretransplant conditioning the patient had received.
The study highlights the need for fertility preservation when possible before HSCT, and makes clear that “normal puberty does not equate to normal fertility,” said Dr. Oquendo del Toro, of Cincinnati Children’s Hospital Medical Center.
Dr. Oquendo del Toro presented results of an observational cohort study of late effects of HSCT that included individuals aged 1-40 years old who received a single HSCT at, or after, 1 year of age.
Twenty-one males in the study had semen available for analysis. Of the 10 males who received myeloablative conditioning (MAC), 8 had azoospermia, and 2 more had oligoteratospermia (low sperm count with abnormal morphology). For the 11 males who received reduced intensity conditioning (RIC), eight had azoospermia, two had semen samples that showed oligoteratospermia, and one had a normal semen analysis.
The median age at transplant for these males was 14.5 years, and patients were a median of 19 years old at follow-up, Dr. Oquendo del Toro said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
For females in the study, low levels of anti-Müllerian hormone (AMH) – generally considered the best surrogate lab value for ovarian reserve – were nearly as common. Of 14 females receiving MAC, 13 (93%) had low AMH, as did 6 of 8 (75%) female patients who received RIC.
Individuals with more than one HSCT were excluded, as were those with Fanconi anemia, which itself carries a risk of gonadal failure. The study’s two aims were to investigate gonadal function as well as fertility potential after receipt of either RIC or MAC for HSCT.
Patients were seen by an endocrinologist who assessed testicular volume and assigned a Tanner stage. At age 11 and older, patients’ gonadal function was assessed on an annual basis by obtaining levels of luteinizing hormone and follicle stimulating hormone for all patients; female estradiol levels were tracked, as were male testosterone levels.
Assessment of fertility potential required additional laboratory testing: For females, the investigators obtained AMH levels, while for males, semen analysis was coupled with serum levels of inhibin B, an indicator of Sertoli cell function.
A total of 72 males were more than 1 year post-HSCT in the cohort, and of these, 41 were at least 11 years old and had achieved pubertal status according to laboratory evaluation. In all, 22 of the male patients received RIC, and 19 received MAC.
Males receiving MAC were a median 20 years old at their follow-up evaluation, and a median 6 years post-HSCT, while the RIC group were a median of 18.5 years old and 5.5 years out from their transplant.
Of the 50 females who were more than 1 year post-HSCT, 25 were pubertal and 11 years old or older. Nine of the female patients received RIC, and 16 received MAC.
Females who received MAC were a median 12.1 years old and 4.1 years post-HSCT at their follow-up evaluation. Females receiving RIC were a median 16 years old, and 6.5 years post-HSCT at the time of evaluation.
Patients received their transplants for a variety of malignant and nonmalignant conditions.
“We saw relatively normal gonadotropins after both reduced intensity and myeloablative conditioning in males,” Dr. Oquendo del Toro said. Of the MAC group, 4 of 15 (27%) had elevated follicle stimulating hormone levels, as did 2 of 17 (12%) of the RIC group. Elevated luteinizing hormone levels were seen in 2 of 15 (13%) of the MAC group and 1 of 17 (6%) of the RIC group. Four patients in each group had abnormally low testosterone levels.
However, when the investigators looked at inhibin B levels in males, they found abnormally low levels in 9 of 15 (60%) of those who received MAC, and in 6 of 15 (40%) of those who received RIC. These results meshed with the severely abnormal semen analyses investigators found from those participants for whom a sample was available, Dr. Oquendo del Toro said.
For females, estradiol levels were significantly lower for those who had received MAC, with 7 of 11 (64%) of that group having abnormally low estradiol levels. The levels approached 0 pg/mL for many, said Dr. Oquendo del Toro. None of the eight patients who had received RIC had abnormally low estradiol levels (P = .0008).
“Male puberty is relatively well preserved after both myeloablative and reduced intensity conditioning, but there is a greater than 90% risk of male infertility associated with both reduced intensity and myeloablative conditioning for HSCT,” Dr. Oquendo del Toro said.
For females, the study paints a different picture. “We saw decreased premature ovarian failure after reduced intensity conditioning … but the fertility potential as assessed by anti-Müllerian hormone was decreased” after both conditioning regimens, she said.
Dr. Oquendo del Toro reported having no conflicts of interest.
SOURCE: Oquendo del Toro H et al. The 2018 BMT Tandem Meetings, Abstract 88.
SALT LAKE CITY – Both male and female recipients of childhood hematopoietic stem cell transplantation (HSCT) were very likely to have severely decreased fertility potential, even in the setting of preserved puberty, according to a recent study of adolescent and young adult HSCT recipients.
A reduced intensity conditioning regimen did not protect this cohort from decreased fertility, a finding that surprised the study’s lead author.
“We had hypothesized that, as compared to myeloablative conditioning, reduced intensity conditioning in children who received HSCT would lower the risk of infertility and lessen gonadal failure,” said Helen Oquendo del Toro, MD. In fact, Dr. Oquendo del Toro and her collaborators found that more than 90% of semen samples available for analysis had results that indicated infertility or severely impaired fertility, regardless of the type of pretransplant conditioning the patient had received.
The study highlights the need for fertility preservation when possible before HSCT, and makes clear that “normal puberty does not equate to normal fertility,” said Dr. Oquendo del Toro, of Cincinnati Children’s Hospital Medical Center.
Dr. Oquendo del Toro presented results of an observational cohort study of late effects of HSCT that included individuals aged 1-40 years old who received a single HSCT at, or after, 1 year of age.
Twenty-one males in the study had semen available for analysis. Of the 10 males who received myeloablative conditioning (MAC), 8 had azoospermia, and 2 more had oligoteratospermia (low sperm count with abnormal morphology). For the 11 males who received reduced intensity conditioning (RIC), eight had azoospermia, two had semen samples that showed oligoteratospermia, and one had a normal semen analysis.
The median age at transplant for these males was 14.5 years, and patients were a median of 19 years old at follow-up, Dr. Oquendo del Toro said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
For females in the study, low levels of anti-Müllerian hormone (AMH) – generally considered the best surrogate lab value for ovarian reserve – were nearly as common. Of 14 females receiving MAC, 13 (93%) had low AMH, as did 6 of 8 (75%) female patients who received RIC.
Individuals with more than one HSCT were excluded, as were those with Fanconi anemia, which itself carries a risk of gonadal failure. The study’s two aims were to investigate gonadal function as well as fertility potential after receipt of either RIC or MAC for HSCT.
Patients were seen by an endocrinologist who assessed testicular volume and assigned a Tanner stage. At age 11 and older, patients’ gonadal function was assessed on an annual basis by obtaining levels of luteinizing hormone and follicle stimulating hormone for all patients; female estradiol levels were tracked, as were male testosterone levels.
Assessment of fertility potential required additional laboratory testing: For females, the investigators obtained AMH levels, while for males, semen analysis was coupled with serum levels of inhibin B, an indicator of Sertoli cell function.
A total of 72 males were more than 1 year post-HSCT in the cohort, and of these, 41 were at least 11 years old and had achieved pubertal status according to laboratory evaluation. In all, 22 of the male patients received RIC, and 19 received MAC.
Males receiving MAC were a median 20 years old at their follow-up evaluation, and a median 6 years post-HSCT, while the RIC group were a median of 18.5 years old and 5.5 years out from their transplant.
Of the 50 females who were more than 1 year post-HSCT, 25 were pubertal and 11 years old or older. Nine of the female patients received RIC, and 16 received MAC.
Females who received MAC were a median 12.1 years old and 4.1 years post-HSCT at their follow-up evaluation. Females receiving RIC were a median 16 years old, and 6.5 years post-HSCT at the time of evaluation.
Patients received their transplants for a variety of malignant and nonmalignant conditions.
“We saw relatively normal gonadotropins after both reduced intensity and myeloablative conditioning in males,” Dr. Oquendo del Toro said. Of the MAC group, 4 of 15 (27%) had elevated follicle stimulating hormone levels, as did 2 of 17 (12%) of the RIC group. Elevated luteinizing hormone levels were seen in 2 of 15 (13%) of the MAC group and 1 of 17 (6%) of the RIC group. Four patients in each group had abnormally low testosterone levels.
However, when the investigators looked at inhibin B levels in males, they found abnormally low levels in 9 of 15 (60%) of those who received MAC, and in 6 of 15 (40%) of those who received RIC. These results meshed with the severely abnormal semen analyses investigators found from those participants for whom a sample was available, Dr. Oquendo del Toro said.
For females, estradiol levels were significantly lower for those who had received MAC, with 7 of 11 (64%) of that group having abnormally low estradiol levels. The levels approached 0 pg/mL for many, said Dr. Oquendo del Toro. None of the eight patients who had received RIC had abnormally low estradiol levels (P = .0008).
“Male puberty is relatively well preserved after both myeloablative and reduced intensity conditioning, but there is a greater than 90% risk of male infertility associated with both reduced intensity and myeloablative conditioning for HSCT,” Dr. Oquendo del Toro said.
For females, the study paints a different picture. “We saw decreased premature ovarian failure after reduced intensity conditioning … but the fertility potential as assessed by anti-Müllerian hormone was decreased” after both conditioning regimens, she said.
Dr. Oquendo del Toro reported having no conflicts of interest.
SOURCE: Oquendo del Toro H et al. The 2018 BMT Tandem Meetings, Abstract 88.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Of 21 males receiving reduced intensity conditioning or myeloablative conditioning, all but one had azoospermia or oligoteratospermia.
Study details: Observational cohort study of 41 males and 25 females receiving pediatric HSCT.
Disclosures: Dr. Oquendo del Toro reported having no conflicts of interest.
Source: Oquendo del Toro H et al. The 2018 BMT Tandem Meetings, Abstract 88.
High engraftment with new umbilical transplant technique
SALT LAKE CITY – Recipients of hematopoietic cell transplant with umbilical cord blood CD34+ cells expanded with an aryl hydrocarbon receptor (AHR) antagonist had a significantly higher rate of engraftment and comparable survival to a historical cohort of umbilical cord blood recipients.
The robust expansion of donor umbilical cord blood seen with the new technique opens the door for better use of umbilical cord blood inventory with superior human leukocyte antigen (HLA) matching, John Wagner, MD, said at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The new technique still shared the benefits of low rates of graft-versus-host disease (GVHD) and high survival that have been seen in previous umbilical cord blood transplants, with no significant difference in overall survival, relapse, or acute or chronic GVHD.
Compared to historical controls (n = 151), patients receiving the AHR antagonist–expanded umbilical cord blood (UCB) cells with myeloablative conditioning (n = 9) saw complete and more rapid engraftment (100% vs. 89% engraftment at a median 14 days vs. 23 days; P less than .01), reported Dr. Wagner of the University of Minnesota, Minneapolis.
These and other results came from two arms of a phase 2 trial of MGTA-456 (the working name of the AHR-expanded UCB cells). Twenty patients were to receive MGTA-456 derived from partially matched umbilical cord blood units after either myeloablative or nonmyeloablative conditioning; one patient in each arm had low expansion of UCB, so a total of 18 patients received MGTA-456. Each intervention arm was compared with a historical control arm that had received conventional UCB units.
In the myeloablative arm, patient demographics and disease characteristics were similar to the control cohort except that the MGTA-456 patients were significantly heavier (93.8 kg vs. 66.7 kg; P less than .04).
Platelet recovery also rebounded faster with MGTA-456 plus myeloablative conditioning than it did with historical controls: 89% of patients had platelet recovery by a median 46 days, compared with 71% with platelet recovery by a median 64 days in the historical cohort (P less than .01).
Patients achieved rapid complete chimerism if they received myeloablative conditioning, and they had rapid rebound of CD4 counts to at least 200 by 2-3 months posttransplant, Dr. Wagner reported.
The nonmyeloablative arm had a historical control cohort of 132 patients. Characteristics were similar between the two groups except that the MGTA-456 patients were older and more likely to have high-risk disease.
Again, all patients had rapid neutrophil recovery and saw 100% engraftment with MGTA-456. Median time to engraftment was 7 days with MGTA-456 and 15 days for the historical controls (P less than .01). Platelet recovery took longer for the MGTA-456 (median of 47 vs. 107 days), but the difference was not statistically significant.
Complete chimerism was achieved rapidly with the nonmyeloablative regimen as well, and CD4 recovery was brisk, as had been seen with myeloablative conditioning before MGTA-456 transplantation.
Compared with historical controls, “MGTA-456 retains the benefits of low chronic-graft-versus host disease and high survival despite higher disease risk and age” in the study group, Dr. Wagner said. There were no significant differences between the intervention and historical control arms of the nonmyeloablative study in acute or chronic GVHD, relapse, or overall survival.
The use of MGTA-456 occurs against the backdrop of a history of high survival rates with UCB transplantation – about 70% at 5 years, Dr. Wagner said. However, when conventional culture and expansion methods for UCB were used, the median time to engraftment had been reported to be 25 days with a 79% engraftment rate. This contrasts with the mean 13 days to engraftment for peripheral blood transplants and 18 days for bone marrow transplants. All of these transplant sources, regardless of whether the transplant was matched or mismatched, have engraftment rates of 92%-96%, said Dr. Wagner (Lancet Oncol. 2010; 11[7]:653-60).
When an AHR antagonist is used for UCB expansion, hematopoietic stem cell renewal is upped because cell differentiation is blocked, which means expansion is all driven toward hematopoietic stem cell self-renewal, Dr. Wagner said. Of the 36 available samples, MGTA-456 achieved a median 327-fold expansion of CD34+ cells, which enabled investigators to deliver a median CD34+ dose of 17.5 X 106 cells/kg.
The downstream effect of the robust expansion rates is that more cord blood will be available for transplantation, and HLA matches will improve, Dr. Wagner said. Using current expansion techniques, fewer than 5% of cord blood units have a total nucleated cell count sufficient for an adult 80 kg recipient, he said, adding that use of MGTA-456 could make more than 80% of cord blood units available for adults.
According to the UCB transplant history at the University of Minnesota – where Dr. Wagner directs the pediatric blood and marrow transplantation program – of the patients who received 4/6 HLA-matched cord blood, 63% would move to a 5/6 match, and 8% would move to a full HLA match with the MGTA-456 technique. Of patients who received 5/6-matched transplants, almost one in four (23%) would move to a full 6/6 match.
Dr. Wagner and his colleagues had previously shown that adding an AHR antagonist resulted in enhanced T-cell recovery and rapid and sustained engraftment (Science. 2010;329:1345-8).
The researchers then proceeded to a phase 1-2, first-in-human trial of MGTA-456 that used a myeloablative conditioning regimen that met its primary safety endpoint of a lack of infusional toxicity or primary/secondary graft failure (Cell Stem Cell. 2016;18:144-55).
For reasons of safety, this earlier study used a double-transplant platform in which one infusion was uncultured umbilical cord blood and the other was MGTA-456. This study showed rapid neutrophil recovery when MGTA-456 was infused, with median 10.5 days to recovery, compared with a median 26.5 days for historical controls (P less than .001).
Additionally, the study showed a 19-day decrease in duration of the initial hospitalization, and all patients who received MGTA-456 had successful engraftment, Dr. Wagner said. On the strength of these results, the current trials of MGTA-456 alone – with both nonmyeloablative and myeloablative conditioning – were approved.
Multicenter clinical trials of MGTA-456 transplantation are now planned for both malignant and nonmalignant diseases. Enrollment is currently open for a phase 2 clinical trial of MGTA for inherited metabolic disorders (NCT03406962).
The study was funded by Novartis and Magenta Therapeutics. Dr. Wagner reported no other relevant disclosures.
SOURCE: Wagner J et al. 2018 BMT Tandem Meetings, Abstract 4.
SALT LAKE CITY – Recipients of hematopoietic cell transplant with umbilical cord blood CD34+ cells expanded with an aryl hydrocarbon receptor (AHR) antagonist had a significantly higher rate of engraftment and comparable survival to a historical cohort of umbilical cord blood recipients.
The robust expansion of donor umbilical cord blood seen with the new technique opens the door for better use of umbilical cord blood inventory with superior human leukocyte antigen (HLA) matching, John Wagner, MD, said at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The new technique still shared the benefits of low rates of graft-versus-host disease (GVHD) and high survival that have been seen in previous umbilical cord blood transplants, with no significant difference in overall survival, relapse, or acute or chronic GVHD.
Compared to historical controls (n = 151), patients receiving the AHR antagonist–expanded umbilical cord blood (UCB) cells with myeloablative conditioning (n = 9) saw complete and more rapid engraftment (100% vs. 89% engraftment at a median 14 days vs. 23 days; P less than .01), reported Dr. Wagner of the University of Minnesota, Minneapolis.
These and other results came from two arms of a phase 2 trial of MGTA-456 (the working name of the AHR-expanded UCB cells). Twenty patients were to receive MGTA-456 derived from partially matched umbilical cord blood units after either myeloablative or nonmyeloablative conditioning; one patient in each arm had low expansion of UCB, so a total of 18 patients received MGTA-456. Each intervention arm was compared with a historical control arm that had received conventional UCB units.
In the myeloablative arm, patient demographics and disease characteristics were similar to the control cohort except that the MGTA-456 patients were significantly heavier (93.8 kg vs. 66.7 kg; P less than .04).
Platelet recovery also rebounded faster with MGTA-456 plus myeloablative conditioning than it did with historical controls: 89% of patients had platelet recovery by a median 46 days, compared with 71% with platelet recovery by a median 64 days in the historical cohort (P less than .01).
Patients achieved rapid complete chimerism if they received myeloablative conditioning, and they had rapid rebound of CD4 counts to at least 200 by 2-3 months posttransplant, Dr. Wagner reported.
The nonmyeloablative arm had a historical control cohort of 132 patients. Characteristics were similar between the two groups except that the MGTA-456 patients were older and more likely to have high-risk disease.
Again, all patients had rapid neutrophil recovery and saw 100% engraftment with MGTA-456. Median time to engraftment was 7 days with MGTA-456 and 15 days for the historical controls (P less than .01). Platelet recovery took longer for the MGTA-456 (median of 47 vs. 107 days), but the difference was not statistically significant.
Complete chimerism was achieved rapidly with the nonmyeloablative regimen as well, and CD4 recovery was brisk, as had been seen with myeloablative conditioning before MGTA-456 transplantation.
Compared with historical controls, “MGTA-456 retains the benefits of low chronic-graft-versus host disease and high survival despite higher disease risk and age” in the study group, Dr. Wagner said. There were no significant differences between the intervention and historical control arms of the nonmyeloablative study in acute or chronic GVHD, relapse, or overall survival.
The use of MGTA-456 occurs against the backdrop of a history of high survival rates with UCB transplantation – about 70% at 5 years, Dr. Wagner said. However, when conventional culture and expansion methods for UCB were used, the median time to engraftment had been reported to be 25 days with a 79% engraftment rate. This contrasts with the mean 13 days to engraftment for peripheral blood transplants and 18 days for bone marrow transplants. All of these transplant sources, regardless of whether the transplant was matched or mismatched, have engraftment rates of 92%-96%, said Dr. Wagner (Lancet Oncol. 2010; 11[7]:653-60).
When an AHR antagonist is used for UCB expansion, hematopoietic stem cell renewal is upped because cell differentiation is blocked, which means expansion is all driven toward hematopoietic stem cell self-renewal, Dr. Wagner said. Of the 36 available samples, MGTA-456 achieved a median 327-fold expansion of CD34+ cells, which enabled investigators to deliver a median CD34+ dose of 17.5 X 106 cells/kg.
The downstream effect of the robust expansion rates is that more cord blood will be available for transplantation, and HLA matches will improve, Dr. Wagner said. Using current expansion techniques, fewer than 5% of cord blood units have a total nucleated cell count sufficient for an adult 80 kg recipient, he said, adding that use of MGTA-456 could make more than 80% of cord blood units available for adults.
According to the UCB transplant history at the University of Minnesota – where Dr. Wagner directs the pediatric blood and marrow transplantation program – of the patients who received 4/6 HLA-matched cord blood, 63% would move to a 5/6 match, and 8% would move to a full HLA match with the MGTA-456 technique. Of patients who received 5/6-matched transplants, almost one in four (23%) would move to a full 6/6 match.
Dr. Wagner and his colleagues had previously shown that adding an AHR antagonist resulted in enhanced T-cell recovery and rapid and sustained engraftment (Science. 2010;329:1345-8).
The researchers then proceeded to a phase 1-2, first-in-human trial of MGTA-456 that used a myeloablative conditioning regimen that met its primary safety endpoint of a lack of infusional toxicity or primary/secondary graft failure (Cell Stem Cell. 2016;18:144-55).
For reasons of safety, this earlier study used a double-transplant platform in which one infusion was uncultured umbilical cord blood and the other was MGTA-456. This study showed rapid neutrophil recovery when MGTA-456 was infused, with median 10.5 days to recovery, compared with a median 26.5 days for historical controls (P less than .001).
Additionally, the study showed a 19-day decrease in duration of the initial hospitalization, and all patients who received MGTA-456 had successful engraftment, Dr. Wagner said. On the strength of these results, the current trials of MGTA-456 alone – with both nonmyeloablative and myeloablative conditioning – were approved.
Multicenter clinical trials of MGTA-456 transplantation are now planned for both malignant and nonmalignant diseases. Enrollment is currently open for a phase 2 clinical trial of MGTA for inherited metabolic disorders (NCT03406962).
The study was funded by Novartis and Magenta Therapeutics. Dr. Wagner reported no other relevant disclosures.
SOURCE: Wagner J et al. 2018 BMT Tandem Meetings, Abstract 4.
SALT LAKE CITY – Recipients of hematopoietic cell transplant with umbilical cord blood CD34+ cells expanded with an aryl hydrocarbon receptor (AHR) antagonist had a significantly higher rate of engraftment and comparable survival to a historical cohort of umbilical cord blood recipients.
The robust expansion of donor umbilical cord blood seen with the new technique opens the door for better use of umbilical cord blood inventory with superior human leukocyte antigen (HLA) matching, John Wagner, MD, said at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The new technique still shared the benefits of low rates of graft-versus-host disease (GVHD) and high survival that have been seen in previous umbilical cord blood transplants, with no significant difference in overall survival, relapse, or acute or chronic GVHD.
Compared to historical controls (n = 151), patients receiving the AHR antagonist–expanded umbilical cord blood (UCB) cells with myeloablative conditioning (n = 9) saw complete and more rapid engraftment (100% vs. 89% engraftment at a median 14 days vs. 23 days; P less than .01), reported Dr. Wagner of the University of Minnesota, Minneapolis.
These and other results came from two arms of a phase 2 trial of MGTA-456 (the working name of the AHR-expanded UCB cells). Twenty patients were to receive MGTA-456 derived from partially matched umbilical cord blood units after either myeloablative or nonmyeloablative conditioning; one patient in each arm had low expansion of UCB, so a total of 18 patients received MGTA-456. Each intervention arm was compared with a historical control arm that had received conventional UCB units.
In the myeloablative arm, patient demographics and disease characteristics were similar to the control cohort except that the MGTA-456 patients were significantly heavier (93.8 kg vs. 66.7 kg; P less than .04).
Platelet recovery also rebounded faster with MGTA-456 plus myeloablative conditioning than it did with historical controls: 89% of patients had platelet recovery by a median 46 days, compared with 71% with platelet recovery by a median 64 days in the historical cohort (P less than .01).
Patients achieved rapid complete chimerism if they received myeloablative conditioning, and they had rapid rebound of CD4 counts to at least 200 by 2-3 months posttransplant, Dr. Wagner reported.
The nonmyeloablative arm had a historical control cohort of 132 patients. Characteristics were similar between the two groups except that the MGTA-456 patients were older and more likely to have high-risk disease.
Again, all patients had rapid neutrophil recovery and saw 100% engraftment with MGTA-456. Median time to engraftment was 7 days with MGTA-456 and 15 days for the historical controls (P less than .01). Platelet recovery took longer for the MGTA-456 (median of 47 vs. 107 days), but the difference was not statistically significant.
Complete chimerism was achieved rapidly with the nonmyeloablative regimen as well, and CD4 recovery was brisk, as had been seen with myeloablative conditioning before MGTA-456 transplantation.
Compared with historical controls, “MGTA-456 retains the benefits of low chronic-graft-versus host disease and high survival despite higher disease risk and age” in the study group, Dr. Wagner said. There were no significant differences between the intervention and historical control arms of the nonmyeloablative study in acute or chronic GVHD, relapse, or overall survival.
The use of MGTA-456 occurs against the backdrop of a history of high survival rates with UCB transplantation – about 70% at 5 years, Dr. Wagner said. However, when conventional culture and expansion methods for UCB were used, the median time to engraftment had been reported to be 25 days with a 79% engraftment rate. This contrasts with the mean 13 days to engraftment for peripheral blood transplants and 18 days for bone marrow transplants. All of these transplant sources, regardless of whether the transplant was matched or mismatched, have engraftment rates of 92%-96%, said Dr. Wagner (Lancet Oncol. 2010; 11[7]:653-60).
When an AHR antagonist is used for UCB expansion, hematopoietic stem cell renewal is upped because cell differentiation is blocked, which means expansion is all driven toward hematopoietic stem cell self-renewal, Dr. Wagner said. Of the 36 available samples, MGTA-456 achieved a median 327-fold expansion of CD34+ cells, which enabled investigators to deliver a median CD34+ dose of 17.5 X 106 cells/kg.
The downstream effect of the robust expansion rates is that more cord blood will be available for transplantation, and HLA matches will improve, Dr. Wagner said. Using current expansion techniques, fewer than 5% of cord blood units have a total nucleated cell count sufficient for an adult 80 kg recipient, he said, adding that use of MGTA-456 could make more than 80% of cord blood units available for adults.
According to the UCB transplant history at the University of Minnesota – where Dr. Wagner directs the pediatric blood and marrow transplantation program – of the patients who received 4/6 HLA-matched cord blood, 63% would move to a 5/6 match, and 8% would move to a full HLA match with the MGTA-456 technique. Of patients who received 5/6-matched transplants, almost one in four (23%) would move to a full 6/6 match.
Dr. Wagner and his colleagues had previously shown that adding an AHR antagonist resulted in enhanced T-cell recovery and rapid and sustained engraftment (Science. 2010;329:1345-8).
The researchers then proceeded to a phase 1-2, first-in-human trial of MGTA-456 that used a myeloablative conditioning regimen that met its primary safety endpoint of a lack of infusional toxicity or primary/secondary graft failure (Cell Stem Cell. 2016;18:144-55).
For reasons of safety, this earlier study used a double-transplant platform in which one infusion was uncultured umbilical cord blood and the other was MGTA-456. This study showed rapid neutrophil recovery when MGTA-456 was infused, with median 10.5 days to recovery, compared with a median 26.5 days for historical controls (P less than .001).
Additionally, the study showed a 19-day decrease in duration of the initial hospitalization, and all patients who received MGTA-456 had successful engraftment, Dr. Wagner said. On the strength of these results, the current trials of MGTA-456 alone – with both nonmyeloablative and myeloablative conditioning – were approved.
Multicenter clinical trials of MGTA-456 transplantation are now planned for both malignant and nonmalignant diseases. Enrollment is currently open for a phase 2 clinical trial of MGTA for inherited metabolic disorders (NCT03406962).
The study was funded by Novartis and Magenta Therapeutics. Dr. Wagner reported no other relevant disclosures.
SOURCE: Wagner J et al. 2018 BMT Tandem Meetings, Abstract 4.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: The engraftment rate was 100% with both myeloablative and nonmyeloablative conditioning.
Study details: A phase 2 trial of 20 patients receiving MGTA-456, compared with a historical cohort of umbilical cord blood hematopoietic cell transplant recipients.
Disclosures: The study was sponsored by Novartis and Magenta Therapeutics. Dr. Wagner reported no other conflicts of interest.
Source: Wagner J et al. 2018 BMT Tandem Meetings, Abstract 4.
Posttransplant cyclophosphamide helped reduce GVHD rates
SALT LAKE CITY – The combination of mycophenolate mofetil, tacrolimus, and posttransplant cyclophosphamide outperformed other prophylaxis regimens at reducing graft versus host disease with relapse-free survival in a multicenter trial.
The trial’s primary aim was to compare rates of post–hematopoietic stem cell transplant GVHD-free and relapse-free survival (GRFS) in the three study arms, compared with the tacrolimus/methotrexate group, who were receiving a “contemporary control,” Javier Bolaños-Meade, MD, said during a late-breaking abstract session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide group had a hazard ratio of 0.72 for reaching the primary endpoint – GRFS (95% confidence interval, 0.55-0.94; P = .04), compared with patients receiving the control regimen. In the study, GRFS was defined as the amount of time elapsed between transplant and any of: grade III-IV acute GVHD, chronic GVHD severe enough to require systemic therapy, disease relapse or progression, or death. Grade III-IV acute GVHD and GVHD survival were superior with mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide, compared with the control (P = .006 and .01, respectively).
The phase 2 trial enrolled adults aged 18-75 years who had a malignant disease and a matched donor, and were slated to receive reduced intensity conditioning. The study randomized patients 1:1:1 to one of three experimental regimens and 224 to the control tacrolimus/methotrexate regimen. In the experimental arms, 92 patients received mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide; 89 patients received tacrolimus/methotrexate/maraviroc, and 92 patients received tacrolimus/methotrexate/bortezomib.
“According to predetermined parameters for success, tacrolimus/mycophenolate mofetil/cyclophosphamide was superior to control in GRFS, severe acute GVHD, chronic GVHD requiring immunosuppression, and GVHD-free survival, without a negative impact on treatment-related mortality, relapse/progression, overall survival or disease-free survival,” Dr. Bolaños-Meade said.
Patients could be included in the study if they had acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; patients with these diagnoses could have no circulating blasts and had to have less than 10% blasts in bone marrow. Patients with chronic lymphocytic leukemia and lymphoma with sensitive disease at the time of transplant were also eligible. All patients received peripheral blood stem cells, and underwent reduced intensity conditioning.
Permissible conditioning regimens included fludarabine/busulfan dosed at 8 mg/kg or less, fludarabine/cyclophosphamide with or without total body irradiation (TBI), fludarabine/TBI at 200 cGy, or fludarabine/melphalan dosed at less than 150 mg/m2 of body surface area. Alemtuzumab and anti-thymocyte globulin were not permitted.
Patients had to have a cardiac ejection fraction greater than 40%. For inclusion, patients had to have estimated creatinine clearance greater than 40 mL/min, bilirubin less than two times the upper limit of normal, and ALT/AST less than 2.5 times the upper limit of normal. Inclusion criteria also required adequate pulmonary function, defined as hemoglobin-corrected diffused capacity of carbon monoxide of at least 40% and forced expiratory volume in one second of 50% or greater.
Patients’ donors had to be either siblings, or 7/8 or 8/8 human leukocyte antigen-matched unrelated donors.
The patients receiving tacrolimus/methotrexate who served as controls were also collected prospectively, from centers that were not participating in the three-arm clinical trial. These patients also received reduced intensity conditioning and a peripheral blood stem cell transplant. This arm of the study was run through the Center for International Blood & Marrow Transplant Research. “I want to stress that the entry criteria were the same as for the intervention arms of the study,” Dr. Bolaños-Meade said.
Using a baseline rate of 23% for the GRFS endpoint, Dr. Bolaños-Meade and his collaborators established the size of the intervention and control arm so that the study would have 86%-88% power to detect a 20% improvement in the rate of GRFS over the contemporary control GVHD prophylaxis.
Across all study arms, patients were a median of 64 years old and most (58%-67%) were men. A little more than half of the patients had a Karnofsky Performance Status of 90%-100%. The Hematopoietic Cell Transplantation–Comorbidity Index was 3 or greater in about 40% of patients in the intervention arms, and in 62% of those in the control arm.
The phase 2 study was not designed to compare each experimental arm against the others, but only to compare each experimental arm to the control, said Dr. Bolaños-Meade, of the department of oncology at Johns Hopkins University, Baltimore.
“The comparisons that were made in this study ... have a limited power to really show superiority,” he said, adding that the National Clinical Trials Network is beginning a phase 3 trial that directly compares posttransplant cyclophosphamide to tacrolimus/methotrexate.
Dr. Bolaños-Meade reported serving on the data safety monitoring board of Incyte.
SOURCE: Bolaños-Meade J et al. 2018 BMT Tandem Meetings, Abstract LBA1.
SALT LAKE CITY – The combination of mycophenolate mofetil, tacrolimus, and posttransplant cyclophosphamide outperformed other prophylaxis regimens at reducing graft versus host disease with relapse-free survival in a multicenter trial.
The trial’s primary aim was to compare rates of post–hematopoietic stem cell transplant GVHD-free and relapse-free survival (GRFS) in the three study arms, compared with the tacrolimus/methotrexate group, who were receiving a “contemporary control,” Javier Bolaños-Meade, MD, said during a late-breaking abstract session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide group had a hazard ratio of 0.72 for reaching the primary endpoint – GRFS (95% confidence interval, 0.55-0.94; P = .04), compared with patients receiving the control regimen. In the study, GRFS was defined as the amount of time elapsed between transplant and any of: grade III-IV acute GVHD, chronic GVHD severe enough to require systemic therapy, disease relapse or progression, or death. Grade III-IV acute GVHD and GVHD survival were superior with mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide, compared with the control (P = .006 and .01, respectively).
The phase 2 trial enrolled adults aged 18-75 years who had a malignant disease and a matched donor, and were slated to receive reduced intensity conditioning. The study randomized patients 1:1:1 to one of three experimental regimens and 224 to the control tacrolimus/methotrexate regimen. In the experimental arms, 92 patients received mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide; 89 patients received tacrolimus/methotrexate/maraviroc, and 92 patients received tacrolimus/methotrexate/bortezomib.
“According to predetermined parameters for success, tacrolimus/mycophenolate mofetil/cyclophosphamide was superior to control in GRFS, severe acute GVHD, chronic GVHD requiring immunosuppression, and GVHD-free survival, without a negative impact on treatment-related mortality, relapse/progression, overall survival or disease-free survival,” Dr. Bolaños-Meade said.
Patients could be included in the study if they had acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; patients with these diagnoses could have no circulating blasts and had to have less than 10% blasts in bone marrow. Patients with chronic lymphocytic leukemia and lymphoma with sensitive disease at the time of transplant were also eligible. All patients received peripheral blood stem cells, and underwent reduced intensity conditioning.
Permissible conditioning regimens included fludarabine/busulfan dosed at 8 mg/kg or less, fludarabine/cyclophosphamide with or without total body irradiation (TBI), fludarabine/TBI at 200 cGy, or fludarabine/melphalan dosed at less than 150 mg/m2 of body surface area. Alemtuzumab and anti-thymocyte globulin were not permitted.
Patients had to have a cardiac ejection fraction greater than 40%. For inclusion, patients had to have estimated creatinine clearance greater than 40 mL/min, bilirubin less than two times the upper limit of normal, and ALT/AST less than 2.5 times the upper limit of normal. Inclusion criteria also required adequate pulmonary function, defined as hemoglobin-corrected diffused capacity of carbon monoxide of at least 40% and forced expiratory volume in one second of 50% or greater.
Patients’ donors had to be either siblings, or 7/8 or 8/8 human leukocyte antigen-matched unrelated donors.
The patients receiving tacrolimus/methotrexate who served as controls were also collected prospectively, from centers that were not participating in the three-arm clinical trial. These patients also received reduced intensity conditioning and a peripheral blood stem cell transplant. This arm of the study was run through the Center for International Blood & Marrow Transplant Research. “I want to stress that the entry criteria were the same as for the intervention arms of the study,” Dr. Bolaños-Meade said.
Using a baseline rate of 23% for the GRFS endpoint, Dr. Bolaños-Meade and his collaborators established the size of the intervention and control arm so that the study would have 86%-88% power to detect a 20% improvement in the rate of GRFS over the contemporary control GVHD prophylaxis.
Across all study arms, patients were a median of 64 years old and most (58%-67%) were men. A little more than half of the patients had a Karnofsky Performance Status of 90%-100%. The Hematopoietic Cell Transplantation–Comorbidity Index was 3 or greater in about 40% of patients in the intervention arms, and in 62% of those in the control arm.
The phase 2 study was not designed to compare each experimental arm against the others, but only to compare each experimental arm to the control, said Dr. Bolaños-Meade, of the department of oncology at Johns Hopkins University, Baltimore.
“The comparisons that were made in this study ... have a limited power to really show superiority,” he said, adding that the National Clinical Trials Network is beginning a phase 3 trial that directly compares posttransplant cyclophosphamide to tacrolimus/methotrexate.
Dr. Bolaños-Meade reported serving on the data safety monitoring board of Incyte.
SOURCE: Bolaños-Meade J et al. 2018 BMT Tandem Meetings, Abstract LBA1.
SALT LAKE CITY – The combination of mycophenolate mofetil, tacrolimus, and posttransplant cyclophosphamide outperformed other prophylaxis regimens at reducing graft versus host disease with relapse-free survival in a multicenter trial.
The trial’s primary aim was to compare rates of post–hematopoietic stem cell transplant GVHD-free and relapse-free survival (GRFS) in the three study arms, compared with the tacrolimus/methotrexate group, who were receiving a “contemporary control,” Javier Bolaños-Meade, MD, said during a late-breaking abstract session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide group had a hazard ratio of 0.72 for reaching the primary endpoint – GRFS (95% confidence interval, 0.55-0.94; P = .04), compared with patients receiving the control regimen. In the study, GRFS was defined as the amount of time elapsed between transplant and any of: grade III-IV acute GVHD, chronic GVHD severe enough to require systemic therapy, disease relapse or progression, or death. Grade III-IV acute GVHD and GVHD survival were superior with mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide, compared with the control (P = .006 and .01, respectively).
The phase 2 trial enrolled adults aged 18-75 years who had a malignant disease and a matched donor, and were slated to receive reduced intensity conditioning. The study randomized patients 1:1:1 to one of three experimental regimens and 224 to the control tacrolimus/methotrexate regimen. In the experimental arms, 92 patients received mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide; 89 patients received tacrolimus/methotrexate/maraviroc, and 92 patients received tacrolimus/methotrexate/bortezomib.
“According to predetermined parameters for success, tacrolimus/mycophenolate mofetil/cyclophosphamide was superior to control in GRFS, severe acute GVHD, chronic GVHD requiring immunosuppression, and GVHD-free survival, without a negative impact on treatment-related mortality, relapse/progression, overall survival or disease-free survival,” Dr. Bolaños-Meade said.
Patients could be included in the study if they had acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; patients with these diagnoses could have no circulating blasts and had to have less than 10% blasts in bone marrow. Patients with chronic lymphocytic leukemia and lymphoma with sensitive disease at the time of transplant were also eligible. All patients received peripheral blood stem cells, and underwent reduced intensity conditioning.
Permissible conditioning regimens included fludarabine/busulfan dosed at 8 mg/kg or less, fludarabine/cyclophosphamide with or without total body irradiation (TBI), fludarabine/TBI at 200 cGy, or fludarabine/melphalan dosed at less than 150 mg/m2 of body surface area. Alemtuzumab and anti-thymocyte globulin were not permitted.
Patients had to have a cardiac ejection fraction greater than 40%. For inclusion, patients had to have estimated creatinine clearance greater than 40 mL/min, bilirubin less than two times the upper limit of normal, and ALT/AST less than 2.5 times the upper limit of normal. Inclusion criteria also required adequate pulmonary function, defined as hemoglobin-corrected diffused capacity of carbon monoxide of at least 40% and forced expiratory volume in one second of 50% or greater.
Patients’ donors had to be either siblings, or 7/8 or 8/8 human leukocyte antigen-matched unrelated donors.
The patients receiving tacrolimus/methotrexate who served as controls were also collected prospectively, from centers that were not participating in the three-arm clinical trial. These patients also received reduced intensity conditioning and a peripheral blood stem cell transplant. This arm of the study was run through the Center for International Blood & Marrow Transplant Research. “I want to stress that the entry criteria were the same as for the intervention arms of the study,” Dr. Bolaños-Meade said.
Using a baseline rate of 23% for the GRFS endpoint, Dr. Bolaños-Meade and his collaborators established the size of the intervention and control arm so that the study would have 86%-88% power to detect a 20% improvement in the rate of GRFS over the contemporary control GVHD prophylaxis.
Across all study arms, patients were a median of 64 years old and most (58%-67%) were men. A little more than half of the patients had a Karnofsky Performance Status of 90%-100%. The Hematopoietic Cell Transplantation–Comorbidity Index was 3 or greater in about 40% of patients in the intervention arms, and in 62% of those in the control arm.
The phase 2 study was not designed to compare each experimental arm against the others, but only to compare each experimental arm to the control, said Dr. Bolaños-Meade, of the department of oncology at Johns Hopkins University, Baltimore.
“The comparisons that were made in this study ... have a limited power to really show superiority,” he said, adding that the National Clinical Trials Network is beginning a phase 3 trial that directly compares posttransplant cyclophosphamide to tacrolimus/methotrexate.
Dr. Bolaños-Meade reported serving on the data safety monitoring board of Incyte.
SOURCE: Bolaños-Meade J et al. 2018 BMT Tandem Meetings, Abstract LBA1.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: The hazard ratio for GVHD-free and relapse-free survival was 0.72 for those receiving cyclophosphamide, compared with controls (P = .04).
Study details: Randomized, controlled trial of 497 patients receiving one of three intervention arm posttransplant regimens for GVHD prophylaxis, or a control regimen of tacrolimus and methotrexate.
Disclosures: Dr. Bolaños-Meade reported serving on the data safety monitoring board of Incyte.
Source: Bolaños-Meade J et al. 2018 BMT Tandem Meetings, Abstract LB1.
Ibrutinib preserves immune memory while fighting cGVHD
SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.
The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.
Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).
In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.
The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.
“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.
The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.
Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.
The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.
Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127dim Treg cells saw depletion.
Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.
“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.
In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.
“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.
Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.
“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.
Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.
Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.
SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.
SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.
The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.
Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).
In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.
The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.
“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.
The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.
Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.
The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.
Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127dim Treg cells saw depletion.
Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.
“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.
In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.
“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.
Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.
“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.
Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.
Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.
SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.
SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.
The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.
Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).
In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.
The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.
“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.
The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.
Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.
The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.
Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127dim Treg cells saw depletion.
Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.
“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.
In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.
“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.
Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.
“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.
Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.
Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.
SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Inflammatory gene expression dropped between 1.8-fold and 25-fold for individual chemokines after ibrutinib treatment.
Study details: Comprehensive proteomics analysis of data from a phase 1/2 clinical trial of ibrutinib as second-line therapy for cGVHD.
Disclosures: The clinical trial was sponsored by Pharmacyclics LLC, an Abbvie company. Dr. Sahaf reported having patent, royalty, or intellectual property arrangements with Stanford University.
Source: Sahaf B et al. 2018 BMT Tandem Meetings. Abstract 2.
Most patients off transfusions after gene therapy for thalassemia
SALT LAKE CITY – Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.
None of the study participants died, and the majority of patients are now transfusion independent.
The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.
Eight patients had the beta0/beta0 genotype, and had essentially been transfusion dependent from infancy. Six other patients were betaE/beta0, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.
Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.
As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.
The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 106 CD34+ cells/kg (range, 5.2-18.1).
“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.
The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.
The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.
The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).
Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.
However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.
Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.
No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.
The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.
Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.
Of the patients who were able to stop transfusions, just two had the beta0/beta0 genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta0/beta0 genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.
In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.
Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.
“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.
The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.
SOURCE: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.
SALT LAKE CITY – Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.
None of the study participants died, and the majority of patients are now transfusion independent.
The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.
Eight patients had the beta0/beta0 genotype, and had essentially been transfusion dependent from infancy. Six other patients were betaE/beta0, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.
Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.
As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.
The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 106 CD34+ cells/kg (range, 5.2-18.1).
“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.
The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.
The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.
The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).
Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.
However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.
Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.
No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.
The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.
Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.
Of the patients who were able to stop transfusions, just two had the beta0/beta0 genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta0/beta0 genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.
In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.
Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.
“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.
The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.
SOURCE: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.
SALT LAKE CITY – Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.
None of the study participants died, and the majority of patients are now transfusion independent.
The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.
Eight patients had the beta0/beta0 genotype, and had essentially been transfusion dependent from infancy. Six other patients were betaE/beta0, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.
Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.
As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.
The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 106 CD34+ cells/kg (range, 5.2-18.1).
“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.
The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.
The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.
The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).
Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.
However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.
Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.
No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.
The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.
Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.
Of the patients who were able to stop transfusions, just two had the beta0/beta0 genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta0/beta0 genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.
In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.
Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.
“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.
The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.
SOURCE: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point: Major finding: Eleven of 18 patients became transfusion independent, and transfusions were reduced for the remainder of patients.
Study details: Open label, international, single-arm phase 1/2 study of 20 patients with transfusion-dependent beta thalassemia.
Disclosures: The study was funded by bluebird bio. Dr. Walters also reported consulting agreements with several pharmaceutical companies and laboratories.
Source: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.
Low microbiota diversity linked to poor survival after transplant
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: High microbiota diversity post transplant was associated with better overall survival at two sites (P = .006 and P = .015).
Study details: Multicenter study of 5,310 fecal samples obtained from 1,034 hematopoietic cell transplant recipients.
Disclosures: The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics.
Source: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
Xenon imaging could detect lung involvement after HSCT
SALT LAKE CITY – Hyperpolarized xenon-129 magnetic resonance imaging, or 129Xe MRI, showed strong promise for revealing early lung ventilation deficits in pediatric hematopoietic stem cell transplant (HSCT) patients in a proof-of-concept study.
The use of hyperpolarized xenon gas in this setting remains investigational, but is emerging as a safe non-ionizing approach for mapping and quantifying regional airway obstruction in the pediatric population. It has been shown to be more sensitive to early disease than the current clinical gold standard of measuring forced expiratory volume in 1 second (FEV1) by spirometry, Laura L. Walkup, PhD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The 129Xe MRI provides regional information that spirometry cannot, allowing for a targeted approach to planned procedures such as bronchoscopy, said Dr. Walkup of Cincinnati Children’s Hospital Medical Center.
“We hypothesized that hyperpolarized 129Xe MRI would be sensitive to lung abnormalities in the pediatric HSCT population,” she said.
Of 13 patients aged 6-13 years (mean, 10 years) who were enrolled in the study and underwent 129XeMRI, 9 also completed spirometry successfully, and the average FEV1 in those patients was 83% of the predicted value.
Ventilation deficits were apparent on the 129Xe MRI imaging in 8 of the 13 subjects and varied in regional distribution. The whole-lung 129Xe ventilation defect percentage for the HSCT group was 14%, which was significantly greater than the approximately 6% ventilation defect percentage in a cohort of age-matched controls, Dr. Walkup said, noting that ventilation deficits were seen in three of four subjects who were unable to complete reliable spirometry.
“So those are lung abnormalities that may have otherwise gone undetected,” she said, adding that hyperpolarized xenon gas also highlighted the wide individual variation in ventilation, even among cases with similar FEV1 percentages.
The findings are notable, because pulmonary complications such as bronchiolitis obliterans are a major source of morbidity and mortality in the pediatric HSCT population, and an accurate and early diagnostic tool identifying the location and severity of suspected obstructive lung pathology following HSCT is desperately needed, she said.
The HSCT patients in the current study included four boys and nine girls. Isotopically-enriched xenon gas (86% 129Xe) was hyperpolarized using a commercial polarizer and images were acquired during a breath hold of up to 16 seconds and up to 1 L of xenon gas. Conventional anatomic MR images also were acquired.
The 129Xe ventilation was quantified using a less than 60% mean whole-lung 129Xe signal threshold, and was compared to FEV1 percentage predicted as measured via spirometry.
The procedure was well tolerated by all patients, Dr. Walkup said, noting that no patients withdrew from the study, and all were able to maintain the required breath hold.
Drops in blood oxygen saturation level did occur, but were transient and resolved within 10-30 seconds of normal breathing. Further, there were no changes in heart rate during imaging, and any side effects related to xenon, such as tingling in extremities, dizziness, or euphoria, were also quickly resolved with normal breathing, she said.
“There were no serious adverse events related to the study ... these results are in good agreement with previously published safety assessments of xenon in kids and in adults, and at our institution we routinely perform xenon imaging in children as young as age 6,” she added.
The findings, which are consistent with those seen in studies of other conditions such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, suggest that 129Xe MRI is an emerging modality with strong translational potential for detecting early pulmonary involvement following HSCT, she said.
“The real power of the xenon MRI is the spatial information that it provides; we can use that information to plan targeted procedures like bronchoscopy and biopsies ... and since it is non-ionizing, it may be used serially to assess disease progression or response to an intervention,” Dr. Walkup said.
She noted, however, that because it is not yet approved by the Food and Drug Administration, and because it requires specialized expertise and hardware, it is available at only a handful of centers worldwide.
There is a long way to go before the technology will be widely clinically implemented, but work is ongoing at Cincinnati Children’s Hospital to determine how xenon MRI may play a role in pulmonary screening of patients, she said.
Dr. Walkup reported having no financial disclosures.
SOURCE: Walkup L et al. 2018 BMT Tandem Meetings Abstract 56.
SALT LAKE CITY – Hyperpolarized xenon-129 magnetic resonance imaging, or 129Xe MRI, showed strong promise for revealing early lung ventilation deficits in pediatric hematopoietic stem cell transplant (HSCT) patients in a proof-of-concept study.
The use of hyperpolarized xenon gas in this setting remains investigational, but is emerging as a safe non-ionizing approach for mapping and quantifying regional airway obstruction in the pediatric population. It has been shown to be more sensitive to early disease than the current clinical gold standard of measuring forced expiratory volume in 1 second (FEV1) by spirometry, Laura L. Walkup, PhD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The 129Xe MRI provides regional information that spirometry cannot, allowing for a targeted approach to planned procedures such as bronchoscopy, said Dr. Walkup of Cincinnati Children’s Hospital Medical Center.
“We hypothesized that hyperpolarized 129Xe MRI would be sensitive to lung abnormalities in the pediatric HSCT population,” she said.
Of 13 patients aged 6-13 years (mean, 10 years) who were enrolled in the study and underwent 129XeMRI, 9 also completed spirometry successfully, and the average FEV1 in those patients was 83% of the predicted value.
Ventilation deficits were apparent on the 129Xe MRI imaging in 8 of the 13 subjects and varied in regional distribution. The whole-lung 129Xe ventilation defect percentage for the HSCT group was 14%, which was significantly greater than the approximately 6% ventilation defect percentage in a cohort of age-matched controls, Dr. Walkup said, noting that ventilation deficits were seen in three of four subjects who were unable to complete reliable spirometry.
“So those are lung abnormalities that may have otherwise gone undetected,” she said, adding that hyperpolarized xenon gas also highlighted the wide individual variation in ventilation, even among cases with similar FEV1 percentages.
The findings are notable, because pulmonary complications such as bronchiolitis obliterans are a major source of morbidity and mortality in the pediatric HSCT population, and an accurate and early diagnostic tool identifying the location and severity of suspected obstructive lung pathology following HSCT is desperately needed, she said.
The HSCT patients in the current study included four boys and nine girls. Isotopically-enriched xenon gas (86% 129Xe) was hyperpolarized using a commercial polarizer and images were acquired during a breath hold of up to 16 seconds and up to 1 L of xenon gas. Conventional anatomic MR images also were acquired.
The 129Xe ventilation was quantified using a less than 60% mean whole-lung 129Xe signal threshold, and was compared to FEV1 percentage predicted as measured via spirometry.
The procedure was well tolerated by all patients, Dr. Walkup said, noting that no patients withdrew from the study, and all were able to maintain the required breath hold.
Drops in blood oxygen saturation level did occur, but were transient and resolved within 10-30 seconds of normal breathing. Further, there were no changes in heart rate during imaging, and any side effects related to xenon, such as tingling in extremities, dizziness, or euphoria, were also quickly resolved with normal breathing, she said.
“There were no serious adverse events related to the study ... these results are in good agreement with previously published safety assessments of xenon in kids and in adults, and at our institution we routinely perform xenon imaging in children as young as age 6,” she added.
The findings, which are consistent with those seen in studies of other conditions such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, suggest that 129Xe MRI is an emerging modality with strong translational potential for detecting early pulmonary involvement following HSCT, she said.
“The real power of the xenon MRI is the spatial information that it provides; we can use that information to plan targeted procedures like bronchoscopy and biopsies ... and since it is non-ionizing, it may be used serially to assess disease progression or response to an intervention,” Dr. Walkup said.
She noted, however, that because it is not yet approved by the Food and Drug Administration, and because it requires specialized expertise and hardware, it is available at only a handful of centers worldwide.
There is a long way to go before the technology will be widely clinically implemented, but work is ongoing at Cincinnati Children’s Hospital to determine how xenon MRI may play a role in pulmonary screening of patients, she said.
Dr. Walkup reported having no financial disclosures.
SOURCE: Walkup L et al. 2018 BMT Tandem Meetings Abstract 56.
SALT LAKE CITY – Hyperpolarized xenon-129 magnetic resonance imaging, or 129Xe MRI, showed strong promise for revealing early lung ventilation deficits in pediatric hematopoietic stem cell transplant (HSCT) patients in a proof-of-concept study.
The use of hyperpolarized xenon gas in this setting remains investigational, but is emerging as a safe non-ionizing approach for mapping and quantifying regional airway obstruction in the pediatric population. It has been shown to be more sensitive to early disease than the current clinical gold standard of measuring forced expiratory volume in 1 second (FEV1) by spirometry, Laura L. Walkup, PhD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The 129Xe MRI provides regional information that spirometry cannot, allowing for a targeted approach to planned procedures such as bronchoscopy, said Dr. Walkup of Cincinnati Children’s Hospital Medical Center.
“We hypothesized that hyperpolarized 129Xe MRI would be sensitive to lung abnormalities in the pediatric HSCT population,” she said.
Of 13 patients aged 6-13 years (mean, 10 years) who were enrolled in the study and underwent 129XeMRI, 9 also completed spirometry successfully, and the average FEV1 in those patients was 83% of the predicted value.
Ventilation deficits were apparent on the 129Xe MRI imaging in 8 of the 13 subjects and varied in regional distribution. The whole-lung 129Xe ventilation defect percentage for the HSCT group was 14%, which was significantly greater than the approximately 6% ventilation defect percentage in a cohort of age-matched controls, Dr. Walkup said, noting that ventilation deficits were seen in three of four subjects who were unable to complete reliable spirometry.
“So those are lung abnormalities that may have otherwise gone undetected,” she said, adding that hyperpolarized xenon gas also highlighted the wide individual variation in ventilation, even among cases with similar FEV1 percentages.
The findings are notable, because pulmonary complications such as bronchiolitis obliterans are a major source of morbidity and mortality in the pediatric HSCT population, and an accurate and early diagnostic tool identifying the location and severity of suspected obstructive lung pathology following HSCT is desperately needed, she said.
The HSCT patients in the current study included four boys and nine girls. Isotopically-enriched xenon gas (86% 129Xe) was hyperpolarized using a commercial polarizer and images were acquired during a breath hold of up to 16 seconds and up to 1 L of xenon gas. Conventional anatomic MR images also were acquired.
The 129Xe ventilation was quantified using a less than 60% mean whole-lung 129Xe signal threshold, and was compared to FEV1 percentage predicted as measured via spirometry.
The procedure was well tolerated by all patients, Dr. Walkup said, noting that no patients withdrew from the study, and all were able to maintain the required breath hold.
Drops in blood oxygen saturation level did occur, but were transient and resolved within 10-30 seconds of normal breathing. Further, there were no changes in heart rate during imaging, and any side effects related to xenon, such as tingling in extremities, dizziness, or euphoria, were also quickly resolved with normal breathing, she said.
“There were no serious adverse events related to the study ... these results are in good agreement with previously published safety assessments of xenon in kids and in adults, and at our institution we routinely perform xenon imaging in children as young as age 6,” she added.
The findings, which are consistent with those seen in studies of other conditions such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, suggest that 129Xe MRI is an emerging modality with strong translational potential for detecting early pulmonary involvement following HSCT, she said.
“The real power of the xenon MRI is the spatial information that it provides; we can use that information to plan targeted procedures like bronchoscopy and biopsies ... and since it is non-ionizing, it may be used serially to assess disease progression or response to an intervention,” Dr. Walkup said.
She noted, however, that because it is not yet approved by the Food and Drug Administration, and because it requires specialized expertise and hardware, it is available at only a handful of centers worldwide.
There is a long way to go before the technology will be widely clinically implemented, but work is ongoing at Cincinnati Children’s Hospital to determine how xenon MRI may play a role in pulmonary screening of patients, she said.
Dr. Walkup reported having no financial disclosures.
SOURCE: Walkup L et al. 2018 BMT Tandem Meetings Abstract 56.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point: Hyperpolarized 129Xe MRI shows promise for revealing lung ventilation deficits in pediatric HSCT patients.
Major finding: The whole-lung 129Xe ventilation defect percentage was 14% for HSCT group versus 6% for controls; deficits were seen in three of four subjects who were who were unable to complete reliable spirometry.
Study details: A proof-of-concept study involving 13 children.
Disclosures: Dr. Walkup reported having no financial disclosures.
Source: Walkup L et al. 2018 BMT Tandem Meetings. Abstract 56.
CAR T before transplant yields durable remission in B-cell malignancies
SALT LAKE CITY – Chimeric antigen receptor (CAR) T-cell therapy may be an effective bridge to hematopoietic cell transplant (HCT) for high-risk B-cell malignancies, according to a systematic analysis of patient data from the National Cancer Institute.
Additionally, patients who have received CAR T-cell therapy are likely to enter HCT with a minimal residual disease (MRD)–negative complete response, which raises the possibility of a significantly less intense conditioning regimen that could omit total body irradiation (TBI), Haneen Shalabi, DO, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“Patients who underwent HCT post–CAR T therapy did not have increased transplant-related morbidity or mortality,” said Dr. Shalabi, a pediatric oncologist in the hematologic diseases division of the National Cancer Institute’s pediatric oncology branch.
The combined approach also overcomes the frequent relapses seen after CAR T-cell therapy in this population. Of the 45 patients who received CAR T-cell therapy and achieved MRD-negative complete response as measured by flow cytometry, 20 did not go on to receive HCT. Of the 20 who didn’t receive HCT, 16 (80%) relapsed; 19 of the 20 (95%) had received prior HCT, said Dr. Shalabi.
However, of the 25 patients who proceeded on to receive HCT, 15 (60%) were in ongoing remission, with a median duration of 35 months (range, 11-55 months). Six patients (24%) experienced transplant-related mortality; four of these patients had no prior HCT. Ten patients (40%) experienced acute graft-versus-host disease (GVHD); two of these patients experienced grade 4 GVHD, and one experienced grade 3 GVHD.
Of the 25 patients who went on to HCT, 19 were receiving their first transplant, with a median time to transplant after CAR T-cell therapy of 57 days. Five patients (20%) had primary refractory disease. Most patients (n = 18; 72%) had TBI-based conditioning prior to their post–CAR T-cell therapy HCT. The median patient age was 15 (range, 5-30) years.
The systematic review included patients from two phase 1 studies; one was of CD19-28z CAR T-cell therapy for children and young adults with B-cell leukemia or lymphoma, and the other was of CD22-41BB CAR T-cell therapy for children and young adults with recurrent or refractory B-cell malignancies expressing CD22.
To weigh the benefit of the combined CAR T-cell therapy/HCT approach, Dr. Shalabi and her colleagues used a competing risk analysis to determine the risk of relapse post-HCT versus the risk of transplant-related mortality. Among patients undergoing their first HCT, the researchers found a 12-month cumulative incidence of relapse of 5.3% with the combined CAR T-cell therapy/HCT approach (95% confidence interval, 0.3%-22.1%). The 24-month cumulative incidence of relapse was 11.3% (95% CI, 1.7%-31.1%).
The analysis also showed the value of next-generation sequencing (NGS). “As we think about utilizing CAR T therapy as a bridge to transplant, we wanted to study the depth of CAR T–induced remission by next-gen sequencing,” Dr. Shalabi said.
Eight patients on the CD22 CAR trial had MRD analyses based on both flow cytometry and NGS. According to flow cytometry, all eight were MRD negative by 1 month; however, according to NGS, two did have detectable disease, which decreased with time. “Next-gen sequencing can identify earlier time points for relapse or ongoing remission” than flow cytometry can, she said.
An additional finding was that two-thirds of the patients who received the CD19/CD28z CAR T cells had no detectable CAR T cells when the pre-HCT conditioning regimen was initiated, said Dr. Shalabi. “CAR persistence – or lack thereof – didn’t impact post-HCT outcomes,” she said, adding that shorter-acting CAR T cells may actually be preferable when HCT is readily available as an option.
“The impact of CAR persistence peritransplant requires further analysis,” Dr. Shalabi said. It’s possible, though, that “consolidative HCT following CAR may synergistically improve event-free and overall survival for this high-risk population.”
Looking forward, Dr. Shalabi and her team are asking bigger questions: “For future directions – and this is a very big question that those in the room would probably like to know – by inducing NGS-negativity, can CAR T therapy allow for HCT conditioning deintensification, potentially reducing the risk of TRM [transplant-related mortality] and long term comorbidities?”
A future trial will explore outcomes for a conditioning regimen that omits TBI for patients who are MRD-negative by NGS, said Dr. Shalabi.
Another direction for her team’s research is to see whether introducing CAR T-cell therapy earlier in a very-high-risk population may improve outcomes; the current study population was heavily pretreated, Dr. Shalabi said.
Dr. Shalabi is employed by the National Cancer Institute. She reported no conflicts of interest.
SOURCE: Shalabi H et al. 2018 BMT Tandem Meetings, Abstract 6.
SALT LAKE CITY – Chimeric antigen receptor (CAR) T-cell therapy may be an effective bridge to hematopoietic cell transplant (HCT) for high-risk B-cell malignancies, according to a systematic analysis of patient data from the National Cancer Institute.
Additionally, patients who have received CAR T-cell therapy are likely to enter HCT with a minimal residual disease (MRD)–negative complete response, which raises the possibility of a significantly less intense conditioning regimen that could omit total body irradiation (TBI), Haneen Shalabi, DO, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“Patients who underwent HCT post–CAR T therapy did not have increased transplant-related morbidity or mortality,” said Dr. Shalabi, a pediatric oncologist in the hematologic diseases division of the National Cancer Institute’s pediatric oncology branch.
The combined approach also overcomes the frequent relapses seen after CAR T-cell therapy in this population. Of the 45 patients who received CAR T-cell therapy and achieved MRD-negative complete response as measured by flow cytometry, 20 did not go on to receive HCT. Of the 20 who didn’t receive HCT, 16 (80%) relapsed; 19 of the 20 (95%) had received prior HCT, said Dr. Shalabi.
However, of the 25 patients who proceeded on to receive HCT, 15 (60%) were in ongoing remission, with a median duration of 35 months (range, 11-55 months). Six patients (24%) experienced transplant-related mortality; four of these patients had no prior HCT. Ten patients (40%) experienced acute graft-versus-host disease (GVHD); two of these patients experienced grade 4 GVHD, and one experienced grade 3 GVHD.
Of the 25 patients who went on to HCT, 19 were receiving their first transplant, with a median time to transplant after CAR T-cell therapy of 57 days. Five patients (20%) had primary refractory disease. Most patients (n = 18; 72%) had TBI-based conditioning prior to their post–CAR T-cell therapy HCT. The median patient age was 15 (range, 5-30) years.
The systematic review included patients from two phase 1 studies; one was of CD19-28z CAR T-cell therapy for children and young adults with B-cell leukemia or lymphoma, and the other was of CD22-41BB CAR T-cell therapy for children and young adults with recurrent or refractory B-cell malignancies expressing CD22.
To weigh the benefit of the combined CAR T-cell therapy/HCT approach, Dr. Shalabi and her colleagues used a competing risk analysis to determine the risk of relapse post-HCT versus the risk of transplant-related mortality. Among patients undergoing their first HCT, the researchers found a 12-month cumulative incidence of relapse of 5.3% with the combined CAR T-cell therapy/HCT approach (95% confidence interval, 0.3%-22.1%). The 24-month cumulative incidence of relapse was 11.3% (95% CI, 1.7%-31.1%).
The analysis also showed the value of next-generation sequencing (NGS). “As we think about utilizing CAR T therapy as a bridge to transplant, we wanted to study the depth of CAR T–induced remission by next-gen sequencing,” Dr. Shalabi said.
Eight patients on the CD22 CAR trial had MRD analyses based on both flow cytometry and NGS. According to flow cytometry, all eight were MRD negative by 1 month; however, according to NGS, two did have detectable disease, which decreased with time. “Next-gen sequencing can identify earlier time points for relapse or ongoing remission” than flow cytometry can, she said.
An additional finding was that two-thirds of the patients who received the CD19/CD28z CAR T cells had no detectable CAR T cells when the pre-HCT conditioning regimen was initiated, said Dr. Shalabi. “CAR persistence – or lack thereof – didn’t impact post-HCT outcomes,” she said, adding that shorter-acting CAR T cells may actually be preferable when HCT is readily available as an option.
“The impact of CAR persistence peritransplant requires further analysis,” Dr. Shalabi said. It’s possible, though, that “consolidative HCT following CAR may synergistically improve event-free and overall survival for this high-risk population.”
Looking forward, Dr. Shalabi and her team are asking bigger questions: “For future directions – and this is a very big question that those in the room would probably like to know – by inducing NGS-negativity, can CAR T therapy allow for HCT conditioning deintensification, potentially reducing the risk of TRM [transplant-related mortality] and long term comorbidities?”
A future trial will explore outcomes for a conditioning regimen that omits TBI for patients who are MRD-negative by NGS, said Dr. Shalabi.
Another direction for her team’s research is to see whether introducing CAR T-cell therapy earlier in a very-high-risk population may improve outcomes; the current study population was heavily pretreated, Dr. Shalabi said.
Dr. Shalabi is employed by the National Cancer Institute. She reported no conflicts of interest.
SOURCE: Shalabi H et al. 2018 BMT Tandem Meetings, Abstract 6.
SALT LAKE CITY – Chimeric antigen receptor (CAR) T-cell therapy may be an effective bridge to hematopoietic cell transplant (HCT) for high-risk B-cell malignancies, according to a systematic analysis of patient data from the National Cancer Institute.
Additionally, patients who have received CAR T-cell therapy are likely to enter HCT with a minimal residual disease (MRD)–negative complete response, which raises the possibility of a significantly less intense conditioning regimen that could omit total body irradiation (TBI), Haneen Shalabi, DO, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“Patients who underwent HCT post–CAR T therapy did not have increased transplant-related morbidity or mortality,” said Dr. Shalabi, a pediatric oncologist in the hematologic diseases division of the National Cancer Institute’s pediatric oncology branch.
The combined approach also overcomes the frequent relapses seen after CAR T-cell therapy in this population. Of the 45 patients who received CAR T-cell therapy and achieved MRD-negative complete response as measured by flow cytometry, 20 did not go on to receive HCT. Of the 20 who didn’t receive HCT, 16 (80%) relapsed; 19 of the 20 (95%) had received prior HCT, said Dr. Shalabi.
However, of the 25 patients who proceeded on to receive HCT, 15 (60%) were in ongoing remission, with a median duration of 35 months (range, 11-55 months). Six patients (24%) experienced transplant-related mortality; four of these patients had no prior HCT. Ten patients (40%) experienced acute graft-versus-host disease (GVHD); two of these patients experienced grade 4 GVHD, and one experienced grade 3 GVHD.
Of the 25 patients who went on to HCT, 19 were receiving their first transplant, with a median time to transplant after CAR T-cell therapy of 57 days. Five patients (20%) had primary refractory disease. Most patients (n = 18; 72%) had TBI-based conditioning prior to their post–CAR T-cell therapy HCT. The median patient age was 15 (range, 5-30) years.
The systematic review included patients from two phase 1 studies; one was of CD19-28z CAR T-cell therapy for children and young adults with B-cell leukemia or lymphoma, and the other was of CD22-41BB CAR T-cell therapy for children and young adults with recurrent or refractory B-cell malignancies expressing CD22.
To weigh the benefit of the combined CAR T-cell therapy/HCT approach, Dr. Shalabi and her colleagues used a competing risk analysis to determine the risk of relapse post-HCT versus the risk of transplant-related mortality. Among patients undergoing their first HCT, the researchers found a 12-month cumulative incidence of relapse of 5.3% with the combined CAR T-cell therapy/HCT approach (95% confidence interval, 0.3%-22.1%). The 24-month cumulative incidence of relapse was 11.3% (95% CI, 1.7%-31.1%).
The analysis also showed the value of next-generation sequencing (NGS). “As we think about utilizing CAR T therapy as a bridge to transplant, we wanted to study the depth of CAR T–induced remission by next-gen sequencing,” Dr. Shalabi said.
Eight patients on the CD22 CAR trial had MRD analyses based on both flow cytometry and NGS. According to flow cytometry, all eight were MRD negative by 1 month; however, according to NGS, two did have detectable disease, which decreased with time. “Next-gen sequencing can identify earlier time points for relapse or ongoing remission” than flow cytometry can, she said.
An additional finding was that two-thirds of the patients who received the CD19/CD28z CAR T cells had no detectable CAR T cells when the pre-HCT conditioning regimen was initiated, said Dr. Shalabi. “CAR persistence – or lack thereof – didn’t impact post-HCT outcomes,” she said, adding that shorter-acting CAR T cells may actually be preferable when HCT is readily available as an option.
“The impact of CAR persistence peritransplant requires further analysis,” Dr. Shalabi said. It’s possible, though, that “consolidative HCT following CAR may synergistically improve event-free and overall survival for this high-risk population.”
Looking forward, Dr. Shalabi and her team are asking bigger questions: “For future directions – and this is a very big question that those in the room would probably like to know – by inducing NGS-negativity, can CAR T therapy allow for HCT conditioning deintensification, potentially reducing the risk of TRM [transplant-related mortality] and long term comorbidities?”
A future trial will explore outcomes for a conditioning regimen that omits TBI for patients who are MRD-negative by NGS, said Dr. Shalabi.
Another direction for her team’s research is to see whether introducing CAR T-cell therapy earlier in a very-high-risk population may improve outcomes; the current study population was heavily pretreated, Dr. Shalabi said.
Dr. Shalabi is employed by the National Cancer Institute. She reported no conflicts of interest.
SOURCE: Shalabi H et al. 2018 BMT Tandem Meetings, Abstract 6.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Of 20 patients receiving CAR T before HCT, 15 (60%) were in ongoing remission of a median 35 months.
Study details: Systematic analysis of 42 patients with B-cell malignancies receiving CAR T-cell therapy at the National Cancer Institute.
Disclosures: The study was conducted at the National Cancer Institute, where Dr. Shalabi is employed.
Source: Shalabi H et al. 2018 BMT Tandem Meetings, Abstract 6.