Hematology Times

Genome sequencing technologies are providing a valuable new window into the development and progression of pediatric cancers, according to the authors of a review.

In contrast to adult cancers, which are frequently driven by oncogenic mutations, many pediatric cancers have a low burden of somatic mutations, wrote E. Alejandro Sweet-Cordero, MD, from the University of California, San Francisco, and Jaclyn A. Biegel, MD, from the University of Southern California in Science. Instead, large-scale sequencing studies have found that childhood cancers have a much higher likelihood of being caused by germline mutations in genes that predispose development of cancer.

“Particularly surprising was the observation that even high-risk, highly aggressive cancers in many cases had no identifiable driver gene or pathway,” the authors wrote.

Some pediatric cancers do have identified driver genes, but even these are often different to those seen in adult cancers. The authors gave the example of one study of 1,699 patients and six types of cancer: This study identified 142 likely oncogenes, but only 45% of these matched those seen in the adult cancers.

Many pediatric cancers also have unique genetic features, such as the age-dependent gene fusion events, in which two genes join to form an oncogenic hybrid, and focal areas of gene deletion, which are often seen in pediatric acute myeloid leukemia but less so in adult forms of this cancer.

“In some instances, the fusion events involve genes that are known to be cancer drivers; this raises the intriguing possibility that some pediatric cancers are driven by ‘private’ oncogenic fusions,” the authors wrote, pointing out that this has daunting implications for the development of precision medicine. However they also noted that the presence of common gene fusion events could hold significance for choice of therapies; for example, central nervous system gliomas with the common BRAF V600E mutation may respond to specific BRAF inhibitors.

The authors drew particular attention to the role that genomic analysis could play in studying cancer during treatment and relapse, but they said few studies have explored this in pediatric patients.

“Such studies are critical given what we have learned from adult cancers, which show a capacity to evolve rapidly and acquire new driver mutations,” they wrote. One study found that only one-third of tumors with a potentially targetable genetic mutation had retained that target when analyzed at a later time.

On the issue of targeted therapy, the authors noted that no prospective study has yet looked at the use of sequencing approaches to define new therapies for pediatric cancer. However, they did refer to the Pediatric MATCH clinical trial, which is currently evaluating targeted therapies for relapsed solid tumors in children.

They also identified a need for research on predictors of treatment response in pediatric cancer.

“As the genetic variants that are associated with drug response are, by nature and design, variants present in the normal population, they are typically not included in DNA sequencing panels and are filtered out in WES [whole-exome sequencing] or WGS [whole-genome sequencing] bioinformatics pipelines,” they wrote.

They addressed the question of when to do germline testing in pediatric cancer, saying that, for most pediatric cancer patients, germline testing was indicated by the presence of a pathogenic genetic alternative affecting a gene known to be associated with a predisposition for germline cancer.

The authors suggested that data sharing was important to advancing genomic analysis in pediatric cancers because most of the studies so far had been relatively small. However, they highlighted emerging resources for large-scale analysis of pediatric cancer data, such as public portals for investigating discovery genomic data sets and data repositories of clinical-grade sequencing data.

The review was funded by the National Cancer Institute. No conflicts of interest were declared.

SOURCE: Sweet-Cordero A et al. Science 2019;363:1170-5.

Genome sequencing technologies are providing a valuable new window into the development and progression of pediatric cancers, according to the authors of a review.

In contrast to adult cancers, which are frequently driven by oncogenic mutations, many pediatric cancers have a low burden of somatic mutations, wrote E. Alejandro Sweet-Cordero, MD, from the University of California, San Francisco, and Jaclyn A. Biegel, MD, from the University of Southern California in Science. Instead, large-scale sequencing studies have found that childhood cancers have a much higher likelihood of being caused by germline mutations in genes that predispose development of cancer.

“Particularly surprising was the observation that even high-risk, highly aggressive cancers in many cases had no identifiable driver gene or pathway,” the authors wrote.

Some pediatric cancers do have identified driver genes, but even these are often different to those seen in adult cancers. The authors gave the example of one study of 1,699 patients and six types of cancer: This study identified 142 likely oncogenes, but only 45% of these matched those seen in the adult cancers.

Many pediatric cancers also have unique genetic features, such as the age-dependent gene fusion events, in which two genes join to form an oncogenic hybrid, and focal areas of gene deletion, which are often seen in pediatric acute myeloid leukemia but less so in adult forms of this cancer.

“In some instances, the fusion events involve genes that are known to be cancer drivers; this raises the intriguing possibility that some pediatric cancers are driven by ‘private’ oncogenic fusions,” the authors wrote, pointing out that this has daunting implications for the development of precision medicine. However they also noted that the presence of common gene fusion events could hold significance for choice of therapies; for example, central nervous system gliomas with the common BRAF V600E mutation may respond to specific BRAF inhibitors.

The authors drew particular attention to the role that genomic analysis could play in studying cancer during treatment and relapse, but they said few studies have explored this in pediatric patients.

“Such studies are critical given what we have learned from adult cancers, which show a capacity to evolve rapidly and acquire new driver mutations,” they wrote. One study found that only one-third of tumors with a potentially targetable genetic mutation had retained that target when analyzed at a later time.

On the issue of targeted therapy, the authors noted that no prospective study has yet looked at the use of sequencing approaches to define new therapies for pediatric cancer. However, they did refer to the Pediatric MATCH clinical trial, which is currently evaluating targeted therapies for relapsed solid tumors in children.

They also identified a need for research on predictors of treatment response in pediatric cancer.

“As the genetic variants that are associated with drug response are, by nature and design, variants present in the normal population, they are typically not included in DNA sequencing panels and are filtered out in WES [whole-exome sequencing] or WGS [whole-genome sequencing] bioinformatics pipelines,” they wrote.

They addressed the question of when to do germline testing in pediatric cancer, saying that, for most pediatric cancer patients, germline testing was indicated by the presence of a pathogenic genetic alternative affecting a gene known to be associated with a predisposition for germline cancer.

The authors suggested that data sharing was important to advancing genomic analysis in pediatric cancers because most of the studies so far had been relatively small. However, they highlighted emerging resources for large-scale analysis of pediatric cancer data, such as public portals for investigating discovery genomic data sets and data repositories of clinical-grade sequencing data.

The review was funded by the National Cancer Institute. No conflicts of interest were declared.

SOURCE: Sweet-Cordero A et al. Science 2019;363:1170-5.

Genome sequencing technologies are providing a valuable new window into the development and progression of pediatric cancers, according to the authors of a review.

In contrast to adult cancers, which are frequently driven by oncogenic mutations, many pediatric cancers have a low burden of somatic mutations, wrote E. Alejandro Sweet-Cordero, MD, from the University of California, San Francisco, and Jaclyn A. Biegel, MD, from the University of Southern California in Science. Instead, large-scale sequencing studies have found that childhood cancers have a much higher likelihood of being caused by germline mutations in genes that predispose development of cancer.

“Particularly surprising was the observation that even high-risk, highly aggressive cancers in many cases had no identifiable driver gene or pathway,” the authors wrote.

Some pediatric cancers do have identified driver genes, but even these are often different to those seen in adult cancers. The authors gave the example of one study of 1,699 patients and six types of cancer: This study identified 142 likely oncogenes, but only 45% of these matched those seen in the adult cancers.

Many pediatric cancers also have unique genetic features, such as the age-dependent gene fusion events, in which two genes join to form an oncogenic hybrid, and focal areas of gene deletion, which are often seen in pediatric acute myeloid leukemia but less so in adult forms of this cancer.

“In some instances, the fusion events involve genes that are known to be cancer drivers; this raises the intriguing possibility that some pediatric cancers are driven by ‘private’ oncogenic fusions,” the authors wrote, pointing out that this has daunting implications for the development of precision medicine. However they also noted that the presence of common gene fusion events could hold significance for choice of therapies; for example, central nervous system gliomas with the common BRAF V600E mutation may respond to specific BRAF inhibitors.

The authors drew particular attention to the role that genomic analysis could play in studying cancer during treatment and relapse, but they said few studies have explored this in pediatric patients.

“Such studies are critical given what we have learned from adult cancers, which show a capacity to evolve rapidly and acquire new driver mutations,” they wrote. One study found that only one-third of tumors with a potentially targetable genetic mutation had retained that target when analyzed at a later time.

On the issue of targeted therapy, the authors noted that no prospective study has yet looked at the use of sequencing approaches to define new therapies for pediatric cancer. However, they did refer to the Pediatric MATCH clinical trial, which is currently evaluating targeted therapies for relapsed solid tumors in children.

They also identified a need for research on predictors of treatment response in pediatric cancer.

“As the genetic variants that are associated with drug response are, by nature and design, variants present in the normal population, they are typically not included in DNA sequencing panels and are filtered out in WES [whole-exome sequencing] or WGS [whole-genome sequencing] bioinformatics pipelines,” they wrote.

They addressed the question of when to do germline testing in pediatric cancer, saying that, for most pediatric cancer patients, germline testing was indicated by the presence of a pathogenic genetic alternative affecting a gene known to be associated with a predisposition for germline cancer.

The authors suggested that data sharing was important to advancing genomic analysis in pediatric cancers because most of the studies so far had been relatively small. However, they highlighted emerging resources for large-scale analysis of pediatric cancer data, such as public portals for investigating discovery genomic data sets and data repositories of clinical-grade sequencing data.

The review was funded by the National Cancer Institute. No conflicts of interest were declared.

SOURCE: Sweet-Cordero A et al. Science 2019;363:1170-5.

HOUSTON – Acute lymphoblastic leukemia patients with measurable residual disease (MRD) negativity prior to hematopoietic cell transplantation achieve better outcomes than do those who are MRD positive, particularly when total body irradiation (TBI)–based conditioning is used, a large retrospective study suggests.

Of 2,780 ALL patients who underwent hematopoietic cell transplantation (HCT) in first or second complete remission (CR), and who were included in the study, 1,816 were MRD negative before transplantation and 964 were MRD positive.

Overall, with follow-up of 40-44 months, MRD positivity was a significant independent predictor of lower overall survival (OS; hazard ratio, 1.19), leukemia-free survival (LFS; HR, 1.26), and higher relapse incidence (RI; 1.51), Arnon Nagler, MD, reported at the Transplantation & Cellular Therapy Meetings.

Conditioning was TBI-based in 76% of the patients; when these patients were compared with those who received chemotherapy-based conditioning, they were found to have better OS, LFS, and RI (HRs, 0.75, 0.70, and 0.60, respectively), said Dr. Nagler, director of both the division of hematology and the bone marrow transplantation and cord blood bank at the Chaim Sheba Medical Center, Tel-Hashomer, and professor of medicine at Tel Aviv University, both in Israel.

“There was no significant interaction between the MRD status and the conditioning,” he said.


On multivariate analysis, MRD positivity was found to be associated with lower OS and LFS (HRs, 1.26 and 1.3), and higher RI (HR, 1.53) in the TBI group, and with higher RI (HR 1.58) in the chemotherapy group, he said. There was no significant association between MRD and other outcomes in this last cohort, he added, noting that TBI-based conditioning was associated with improved OS, LFS, and RI in both MRD-negative and MRD-positive patients.

“MRD is an extremely important prognostic factor for ALL,” he said, noting that its prognostic value in this setting has been established in multiple studies, and that MRD measured at the end of induction is increasingly used to guide further therapy.

However, although MRD detectable immediately before HCT is known to be associated with poor outcomes, it has been unclear if – or to what extent – this differs with different types of conditioning, he added.

“So the aim of this study was to explore if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in adult patients receiving myeloablative conditioning, either TBI or chemotherapy based,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Patients included in the analysis had a median age of 38 years and underwent HCT between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. None received blinatumomab or inotuzumab, Dr. Nagler said, adding that more patients are likely to achieve MRD negativity with these agents.

It will be interesting to see if the prognostic value of MRD will remain as strong with the new agents, and if TBI will be “a strong factor in overall survival and disease-free survival” with modern immunotherapy, he concluded.

The study was conducted on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Dr. Nagler reported having no relevant financial disclosures.

[email protected]

SOURCE: Nagler A et al. TCT 2019, Abstract 7.

HOUSTON – Acute lymphoblastic leukemia patients with measurable residual disease (MRD) negativity prior to hematopoietic cell transplantation achieve better outcomes than do those who are MRD positive, particularly when total body irradiation (TBI)–based conditioning is used, a large retrospective study suggests.

Of 2,780 ALL patients who underwent hematopoietic cell transplantation (HCT) in first or second complete remission (CR), and who were included in the study, 1,816 were MRD negative before transplantation and 964 were MRD positive.

Overall, with follow-up of 40-44 months, MRD positivity was a significant independent predictor of lower overall survival (OS; hazard ratio, 1.19), leukemia-free survival (LFS; HR, 1.26), and higher relapse incidence (RI; 1.51), Arnon Nagler, MD, reported at the Transplantation & Cellular Therapy Meetings.

Conditioning was TBI-based in 76% of the patients; when these patients were compared with those who received chemotherapy-based conditioning, they were found to have better OS, LFS, and RI (HRs, 0.75, 0.70, and 0.60, respectively), said Dr. Nagler, director of both the division of hematology and the bone marrow transplantation and cord blood bank at the Chaim Sheba Medical Center, Tel-Hashomer, and professor of medicine at Tel Aviv University, both in Israel.

“There was no significant interaction between the MRD status and the conditioning,” he said.


On multivariate analysis, MRD positivity was found to be associated with lower OS and LFS (HRs, 1.26 and 1.3), and higher RI (HR, 1.53) in the TBI group, and with higher RI (HR 1.58) in the chemotherapy group, he said. There was no significant association between MRD and other outcomes in this last cohort, he added, noting that TBI-based conditioning was associated with improved OS, LFS, and RI in both MRD-negative and MRD-positive patients.

“MRD is an extremely important prognostic factor for ALL,” he said, noting that its prognostic value in this setting has been established in multiple studies, and that MRD measured at the end of induction is increasingly used to guide further therapy.

However, although MRD detectable immediately before HCT is known to be associated with poor outcomes, it has been unclear if – or to what extent – this differs with different types of conditioning, he added.

“So the aim of this study was to explore if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in adult patients receiving myeloablative conditioning, either TBI or chemotherapy based,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Patients included in the analysis had a median age of 38 years and underwent HCT between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. None received blinatumomab or inotuzumab, Dr. Nagler said, adding that more patients are likely to achieve MRD negativity with these agents.

It will be interesting to see if the prognostic value of MRD will remain as strong with the new agents, and if TBI will be “a strong factor in overall survival and disease-free survival” with modern immunotherapy, he concluded.

The study was conducted on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Dr. Nagler reported having no relevant financial disclosures.

[email protected]

SOURCE: Nagler A et al. TCT 2019, Abstract 7.

HOUSTON – Acute lymphoblastic leukemia patients with measurable residual disease (MRD) negativity prior to hematopoietic cell transplantation achieve better outcomes than do those who are MRD positive, particularly when total body irradiation (TBI)–based conditioning is used, a large retrospective study suggests.

Of 2,780 ALL patients who underwent hematopoietic cell transplantation (HCT) in first or second complete remission (CR), and who were included in the study, 1,816 were MRD negative before transplantation and 964 were MRD positive.

Overall, with follow-up of 40-44 months, MRD positivity was a significant independent predictor of lower overall survival (OS; hazard ratio, 1.19), leukemia-free survival (LFS; HR, 1.26), and higher relapse incidence (RI; 1.51), Arnon Nagler, MD, reported at the Transplantation & Cellular Therapy Meetings.

Conditioning was TBI-based in 76% of the patients; when these patients were compared with those who received chemotherapy-based conditioning, they were found to have better OS, LFS, and RI (HRs, 0.75, 0.70, and 0.60, respectively), said Dr. Nagler, director of both the division of hematology and the bone marrow transplantation and cord blood bank at the Chaim Sheba Medical Center, Tel-Hashomer, and professor of medicine at Tel Aviv University, both in Israel.

“There was no significant interaction between the MRD status and the conditioning,” he said.


On multivariate analysis, MRD positivity was found to be associated with lower OS and LFS (HRs, 1.26 and 1.3), and higher RI (HR, 1.53) in the TBI group, and with higher RI (HR 1.58) in the chemotherapy group, he said. There was no significant association between MRD and other outcomes in this last cohort, he added, noting that TBI-based conditioning was associated with improved OS, LFS, and RI in both MRD-negative and MRD-positive patients.

“MRD is an extremely important prognostic factor for ALL,” he said, noting that its prognostic value in this setting has been established in multiple studies, and that MRD measured at the end of induction is increasingly used to guide further therapy.

However, although MRD detectable immediately before HCT is known to be associated with poor outcomes, it has been unclear if – or to what extent – this differs with different types of conditioning, he added.

“So the aim of this study was to explore if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in adult patients receiving myeloablative conditioning, either TBI or chemotherapy based,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Patients included in the analysis had a median age of 38 years and underwent HCT between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. None received blinatumomab or inotuzumab, Dr. Nagler said, adding that more patients are likely to achieve MRD negativity with these agents.

It will be interesting to see if the prognostic value of MRD will remain as strong with the new agents, and if TBI will be “a strong factor in overall survival and disease-free survival” with modern immunotherapy, he concluded.

The study was conducted on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Dr. Nagler reported having no relevant financial disclosures.

[email protected]

SOURCE: Nagler A et al. TCT 2019, Abstract 7.

HOUSTON – Secondary acute myeloid leukemia (sAML) predicts outcomes after stem cell transplantation in first complete remission, whereas factors such as age, cytogenetics, and performance status are more relevant predictors of outcomes in patients with de novo AML, according to a large, registry-based analysis.

Sharon Worcester/MDedge News

Of 11,439 patients with de novo AML and 1,325 with sAML identified in the registry, 7,691 and 909, respectively, underwent a stem cell transplant (SCT) in first complete remission (CR1), Bipin Savani, MD, said at the Transplantation & Cellular Therapies Meetings.

The 3-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates in those who underwent SCT in CR1 were higher in the sAML versus de novo AML groups (35% vs. 28.5% for CIR and 23.4% vs. 16.4% for NRM, respectively), said Dr. Savani, professor of medicine, director of the Long-Term Transplant Clinic, and medical director of the Stem Cell Transplant Processing Laboratory at Vanderbilt University Medical Center & Veterans Affairs Medical Center, Nashville, Tenn.

The 3-year overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease/relapse-free survival (GRFS) were significantly lower in the sAML group versus the de novo AML group (46.7% vs. 60.8% for OS; 41.6% vs. 55.1% for LFS; and 28.4% vs. 28.6% for GRFS).


Multivariate analysis controlling for risk factors and stratified by disease stage at SCT showed that sAML in CR1 was significantly associated with higher NRM (hazard ratio, 1.32) and CIR (HR, 1.28), and with lower LFS (HR, 1.30), OS (HR, 1.32) and GRFS (HR, 1.20).

Other significant predictors of OS in the model were age, cytogenetics, patient/donor sex combination, Karnofsky performance status (KPS), and donor, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

In the patients who underwent SCT for primary refractory AML (607 with de novo AML and 199 with sAML) or relapsed AML (1,009 with de novo AML and 124 with sAML), the outcomes were generally inferior to those seen with SCT in CR1. However, sAML in those patients did not predict outcomes, Dr. Savani said, noting that outcome in those cases were predicted by age, cytogenetics, and KPS.

In an analysis of 877 pairs matched for age, disease stage at SCT, KPS, conditioning, in vivo/ex vivo T-cell depletion, donor, donor/recipient sex and cytomegalovirus-status combination, cytogenetics, and graft source, the finding that sAML was associated with significantly higher NRM, and lower LFS, OS, and GRFS overall was confirmed.

However, stratification by stage at the time of SCT again showed that the differences between groups were only seen among those transplanted in CR1, and not in those with advanced disease at the time of transplant.

Patients included in the study were adults aged 18 years and older who underwent SCT for de novo or sAML from a matched related, unrelated, or T-cell replete haploidentical donor between 2000 and 2016.

The findings confirm the general belief that the prognosis in AML secondary to another hematologic neoplasia or malignant disease is poorer than that for de novo AML, and clarify the role of this difference for SCT, Dr. Savani said.

“These data may help to improve risk stratification and prognostic estimates after allogeneic hematopoietic cell transplantation for acute myeloid leukemia,” he concluded.

Dr. Savani reported having no financial disclosures.

[email protected]

SOURCE: Savani B et al. TCT 2019, Abstract 12.

HOUSTON – Secondary acute myeloid leukemia (sAML) predicts outcomes after stem cell transplantation in first complete remission, whereas factors such as age, cytogenetics, and performance status are more relevant predictors of outcomes in patients with de novo AML, according to a large, registry-based analysis.

Sharon Worcester/MDedge News

Of 11,439 patients with de novo AML and 1,325 with sAML identified in the registry, 7,691 and 909, respectively, underwent a stem cell transplant (SCT) in first complete remission (CR1), Bipin Savani, MD, said at the Transplantation & Cellular Therapies Meetings.

The 3-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates in those who underwent SCT in CR1 were higher in the sAML versus de novo AML groups (35% vs. 28.5% for CIR and 23.4% vs. 16.4% for NRM, respectively), said Dr. Savani, professor of medicine, director of the Long-Term Transplant Clinic, and medical director of the Stem Cell Transplant Processing Laboratory at Vanderbilt University Medical Center & Veterans Affairs Medical Center, Nashville, Tenn.

The 3-year overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease/relapse-free survival (GRFS) were significantly lower in the sAML group versus the de novo AML group (46.7% vs. 60.8% for OS; 41.6% vs. 55.1% for LFS; and 28.4% vs. 28.6% for GRFS).


Multivariate analysis controlling for risk factors and stratified by disease stage at SCT showed that sAML in CR1 was significantly associated with higher NRM (hazard ratio, 1.32) and CIR (HR, 1.28), and with lower LFS (HR, 1.30), OS (HR, 1.32) and GRFS (HR, 1.20).

Other significant predictors of OS in the model were age, cytogenetics, patient/donor sex combination, Karnofsky performance status (KPS), and donor, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

In the patients who underwent SCT for primary refractory AML (607 with de novo AML and 199 with sAML) or relapsed AML (1,009 with de novo AML and 124 with sAML), the outcomes were generally inferior to those seen with SCT in CR1. However, sAML in those patients did not predict outcomes, Dr. Savani said, noting that outcome in those cases were predicted by age, cytogenetics, and KPS.

In an analysis of 877 pairs matched for age, disease stage at SCT, KPS, conditioning, in vivo/ex vivo T-cell depletion, donor, donor/recipient sex and cytomegalovirus-status combination, cytogenetics, and graft source, the finding that sAML was associated with significantly higher NRM, and lower LFS, OS, and GRFS overall was confirmed.

However, stratification by stage at the time of SCT again showed that the differences between groups were only seen among those transplanted in CR1, and not in those with advanced disease at the time of transplant.

Patients included in the study were adults aged 18 years and older who underwent SCT for de novo or sAML from a matched related, unrelated, or T-cell replete haploidentical donor between 2000 and 2016.

The findings confirm the general belief that the prognosis in AML secondary to another hematologic neoplasia or malignant disease is poorer than that for de novo AML, and clarify the role of this difference for SCT, Dr. Savani said.

“These data may help to improve risk stratification and prognostic estimates after allogeneic hematopoietic cell transplantation for acute myeloid leukemia,” he concluded.

Dr. Savani reported having no financial disclosures.

[email protected]

SOURCE: Savani B et al. TCT 2019, Abstract 12.

HOUSTON – Secondary acute myeloid leukemia (sAML) predicts outcomes after stem cell transplantation in first complete remission, whereas factors such as age, cytogenetics, and performance status are more relevant predictors of outcomes in patients with de novo AML, according to a large, registry-based analysis.

Sharon Worcester/MDedge News

Of 11,439 patients with de novo AML and 1,325 with sAML identified in the registry, 7,691 and 909, respectively, underwent a stem cell transplant (SCT) in first complete remission (CR1), Bipin Savani, MD, said at the Transplantation & Cellular Therapies Meetings.

The 3-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates in those who underwent SCT in CR1 were higher in the sAML versus de novo AML groups (35% vs. 28.5% for CIR and 23.4% vs. 16.4% for NRM, respectively), said Dr. Savani, professor of medicine, director of the Long-Term Transplant Clinic, and medical director of the Stem Cell Transplant Processing Laboratory at Vanderbilt University Medical Center & Veterans Affairs Medical Center, Nashville, Tenn.

The 3-year overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease/relapse-free survival (GRFS) were significantly lower in the sAML group versus the de novo AML group (46.7% vs. 60.8% for OS; 41.6% vs. 55.1% for LFS; and 28.4% vs. 28.6% for GRFS).


Multivariate analysis controlling for risk factors and stratified by disease stage at SCT showed that sAML in CR1 was significantly associated with higher NRM (hazard ratio, 1.32) and CIR (HR, 1.28), and with lower LFS (HR, 1.30), OS (HR, 1.32) and GRFS (HR, 1.20).

Other significant predictors of OS in the model were age, cytogenetics, patient/donor sex combination, Karnofsky performance status (KPS), and donor, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

In the patients who underwent SCT for primary refractory AML (607 with de novo AML and 199 with sAML) or relapsed AML (1,009 with de novo AML and 124 with sAML), the outcomes were generally inferior to those seen with SCT in CR1. However, sAML in those patients did not predict outcomes, Dr. Savani said, noting that outcome in those cases were predicted by age, cytogenetics, and KPS.

In an analysis of 877 pairs matched for age, disease stage at SCT, KPS, conditioning, in vivo/ex vivo T-cell depletion, donor, donor/recipient sex and cytomegalovirus-status combination, cytogenetics, and graft source, the finding that sAML was associated with significantly higher NRM, and lower LFS, OS, and GRFS overall was confirmed.

However, stratification by stage at the time of SCT again showed that the differences between groups were only seen among those transplanted in CR1, and not in those with advanced disease at the time of transplant.

Patients included in the study were adults aged 18 years and older who underwent SCT for de novo or sAML from a matched related, unrelated, or T-cell replete haploidentical donor between 2000 and 2016.

The findings confirm the general belief that the prognosis in AML secondary to another hematologic neoplasia or malignant disease is poorer than that for de novo AML, and clarify the role of this difference for SCT, Dr. Savani said.

“These data may help to improve risk stratification and prognostic estimates after allogeneic hematopoietic cell transplantation for acute myeloid leukemia,” he concluded.

Dr. Savani reported having no financial disclosures.

[email protected]

SOURCE: Savani B et al. TCT 2019, Abstract 12.

FROM HAEMOPHILIA

Some patients with severe hemophilia A can be managed with weekly injections of the recombinant factor VIII (rFVIII) product turoctocog alfa pegol (N8-GP), based on results from an extension of the pathfinder 2 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In patients who had two or fewer bleeding episodes during the preceding 6 months, N8-GP was effective for prophylaxis and treating bleeding episodes without causing inhibitor development, reported lead author Nicola Curry, MD, of the Oxford (England) Haemophilia and Thrombosis Centre at Churchill Hospital and her colleagues.

The trial exemplifies an ongoing effort to reduce frequency of prophylaxis in hemophilia A.

N8-GP, given every 4 days (or twice weekly in children), was approved by the Food and Drug Administration in February 2019; however, the investigators hypothesized that dose frequency could be stepped down in those who responded well to initial treatment.

“Many patients struggle to integrate prophylactic schedules into their daily lives, leading to missed injections and increased bleeding episodes,” the investigators wrote in a Haemophilia. “Therefore, prophylactic strategies offering effective haemostatic coverage with more convenient administration schedules are needed.”

To this end, the investigators identified 55 patients (at least 12 years old) from the pathfinder 2 trial who had two or fewer bleeding episodes during the preceding 6 months. From this group, 17 patients continued to receive 50 IU/kg of N8-GP every 4 days, as they had done during the main trial, while 38 patients received a higher dose – 75 IU/kg – every 7 days.

When necessary, N8-GP was used to treat bleeding episodes. Primary coendpoints were immunogenicity and efficacy, while all secondary endpoints were safety measures.

For both cohorts, median annualized bleeding rate (ABR) was 0.00 days, and greater than 50% of patients experienced no bleeds (53% every 4 days vs. 58% weekly). No inhibitors developed during the extension phase of the trial.

Along with strong support for weekly prophylaxis, N8-GP demonstrated efficiency in treating bleeding episodes; 87.5% of episodes were controlled with just one injection. This rate increased to 94.7% when including two or fewer injections.

During the study, 108 adverse events were reported in 65.5% of patients, although almost all were mild or moderate in severity, and unrelated to N8-GP. Five adverse events in five patients were related to treatment, including rash, headache, purpura, increased aspartate aminotransferase, and thrombocytopenia. No thromboembolic events were reported.

“These findings suggest that weekly N8-GP may provide effective prophylaxis with a reduced treatment burden for a selected subset of low-bleeding patients with severe haemophilia A,” the investigators wrote.

The study was funded by Novo Nordisk. The investigators reported financial relationships with Bayer, CSL, Novo Nordisk, Octapharma, Genentech, Shire, and others.

SOURCE: Curry N et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13712.

FROM HAEMOPHILIA

Some patients with severe hemophilia A can be managed with weekly injections of the recombinant factor VIII (rFVIII) product turoctocog alfa pegol (N8-GP), based on results from an extension of the pathfinder 2 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In patients who had two or fewer bleeding episodes during the preceding 6 months, N8-GP was effective for prophylaxis and treating bleeding episodes without causing inhibitor development, reported lead author Nicola Curry, MD, of the Oxford (England) Haemophilia and Thrombosis Centre at Churchill Hospital and her colleagues.

The trial exemplifies an ongoing effort to reduce frequency of prophylaxis in hemophilia A.

N8-GP, given every 4 days (or twice weekly in children), was approved by the Food and Drug Administration in February 2019; however, the investigators hypothesized that dose frequency could be stepped down in those who responded well to initial treatment.

“Many patients struggle to integrate prophylactic schedules into their daily lives, leading to missed injections and increased bleeding episodes,” the investigators wrote in a Haemophilia. “Therefore, prophylactic strategies offering effective haemostatic coverage with more convenient administration schedules are needed.”

To this end, the investigators identified 55 patients (at least 12 years old) from the pathfinder 2 trial who had two or fewer bleeding episodes during the preceding 6 months. From this group, 17 patients continued to receive 50 IU/kg of N8-GP every 4 days, as they had done during the main trial, while 38 patients received a higher dose – 75 IU/kg – every 7 days.

When necessary, N8-GP was used to treat bleeding episodes. Primary coendpoints were immunogenicity and efficacy, while all secondary endpoints were safety measures.

For both cohorts, median annualized bleeding rate (ABR) was 0.00 days, and greater than 50% of patients experienced no bleeds (53% every 4 days vs. 58% weekly). No inhibitors developed during the extension phase of the trial.

Along with strong support for weekly prophylaxis, N8-GP demonstrated efficiency in treating bleeding episodes; 87.5% of episodes were controlled with just one injection. This rate increased to 94.7% when including two or fewer injections.

During the study, 108 adverse events were reported in 65.5% of patients, although almost all were mild or moderate in severity, and unrelated to N8-GP. Five adverse events in five patients were related to treatment, including rash, headache, purpura, increased aspartate aminotransferase, and thrombocytopenia. No thromboembolic events were reported.

“These findings suggest that weekly N8-GP may provide effective prophylaxis with a reduced treatment burden for a selected subset of low-bleeding patients with severe haemophilia A,” the investigators wrote.

The study was funded by Novo Nordisk. The investigators reported financial relationships with Bayer, CSL, Novo Nordisk, Octapharma, Genentech, Shire, and others.

SOURCE: Curry N et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13712.

FROM HAEMOPHILIA

Some patients with severe hemophilia A can be managed with weekly injections of the recombinant factor VIII (rFVIII) product turoctocog alfa pegol (N8-GP), based on results from an extension of the pathfinder 2 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In patients who had two or fewer bleeding episodes during the preceding 6 months, N8-GP was effective for prophylaxis and treating bleeding episodes without causing inhibitor development, reported lead author Nicola Curry, MD, of the Oxford (England) Haemophilia and Thrombosis Centre at Churchill Hospital and her colleagues.

The trial exemplifies an ongoing effort to reduce frequency of prophylaxis in hemophilia A.

N8-GP, given every 4 days (or twice weekly in children), was approved by the Food and Drug Administration in February 2019; however, the investigators hypothesized that dose frequency could be stepped down in those who responded well to initial treatment.

“Many patients struggle to integrate prophylactic schedules into their daily lives, leading to missed injections and increased bleeding episodes,” the investigators wrote in a Haemophilia. “Therefore, prophylactic strategies offering effective haemostatic coverage with more convenient administration schedules are needed.”

To this end, the investigators identified 55 patients (at least 12 years old) from the pathfinder 2 trial who had two or fewer bleeding episodes during the preceding 6 months. From this group, 17 patients continued to receive 50 IU/kg of N8-GP every 4 days, as they had done during the main trial, while 38 patients received a higher dose – 75 IU/kg – every 7 days.

When necessary, N8-GP was used to treat bleeding episodes. Primary coendpoints were immunogenicity and efficacy, while all secondary endpoints were safety measures.

For both cohorts, median annualized bleeding rate (ABR) was 0.00 days, and greater than 50% of patients experienced no bleeds (53% every 4 days vs. 58% weekly). No inhibitors developed during the extension phase of the trial.

Along with strong support for weekly prophylaxis, N8-GP demonstrated efficiency in treating bleeding episodes; 87.5% of episodes were controlled with just one injection. This rate increased to 94.7% when including two or fewer injections.

During the study, 108 adverse events were reported in 65.5% of patients, although almost all were mild or moderate in severity, and unrelated to N8-GP. Five adverse events in five patients were related to treatment, including rash, headache, purpura, increased aspartate aminotransferase, and thrombocytopenia. No thromboembolic events were reported.

“These findings suggest that weekly N8-GP may provide effective prophylaxis with a reduced treatment burden for a selected subset of low-bleeding patients with severe haemophilia A,” the investigators wrote.

The study was funded by Novo Nordisk. The investigators reported financial relationships with Bayer, CSL, Novo Nordisk, Octapharma, Genentech, Shire, and others.

SOURCE: Curry N et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13712.

When managed by an experienced team, patients with inherited bleeding disorders undergoing gastrointestinal endoscopy are not at increased bleeding risk, according to researchers reporting the largest series of such patients to date.

The postendoscopy bleeding rate was less than 1% for the patients in this series, many of whom underwent high-risk procedures or had comorbid conditions putting them at risk of bleeding, the researchers reported.

The rate of colonoscopic postpolypectomy bleeding was less than 5%, which is comparable to the general population rate for such high-risk procedures, said investigator Marcel Tomaszewski, MD, of McGill University, Montreal, and colleagues.

Those results favor the use of the “interdisciplinary approach provided by a hemophilia treatment center, communication between services, and the use of periprocedure prophylaxis including tranexamic acid,” Dr. Tomaszewski and coinvestigators said in their report in Haemophilia.

The study cohort included 48 individuals undergoing a total of 104 endoscopies, which is believed to be the largest case series of digestive endoscopy procedures ever reported in patients with congenital bleeding disorders, according to the researchers.

Hemophilia A and von Willebrand disease were the most common bleeding disorders among these patients, accounting for 49 and 40 of the 104 procedures, respectively. The remaining 17 procedures were performed in patients with factor XI deficiency, hemophilia B, or factor VII deficiency.

Before their endoscopies, patients received bleeding prophylaxis, which consisted of combinations of recombinant factor for hemophilia patients, plasma-derived factor for von Willebrand disease patients, desmopressin, and tranexamic acid.

The rate of bleeding within 72 hours of the endoscopic procedure was 0.96% (95% confidence interval, 0.17%-5.25%). The bleeding rate for hemophilia A patients, regardless of severity, was 2.2%, while the rate for hemophilia B, von Willebrand disease, factor VII deficiency and factor XI deficiency was 0%.

The only endoscopic procedures associated with bleeding were colonoscopy, with a bleeding rate of 2%, and colonoscopy with polypectomy, which had a 4.8% bleeding rate, they added, noting that the reported rate of postpolypectomy bleeding in the general population ranges between 0.3% and 10%.

“The very low incidence of bleeding adverse events limited further planned inferential statistical analysis,” the researchers wrote.

These findings stand in contrast to some previous reports, including one series of 19 patients with hemophilia in which 31% experienced gastrointestinal bleeding after colonoscopy polypectomy, despite preprocedure prophylaxis.

“Our approach, particularly with the addition of tranexamic acid, and our patient mix may explain the lower bleeding rate,” they wrote.

The most common indications for endoscopy in the present report were anemia, colorectal cancer screening or polyp surveillance, upper GI symptoms, and screening or surveillance of varices.

Many patients had conditions that might predispose them to bleeding, investigators said. Most commonly, those conditions included hepatitis C virus infection, cirrhosis, esophageal varices, and previous gastrointestinal bleeding.

Dr. Tomaszewski reported that he had no potential conflicts of interest related to the research. Coauthors reported financial disclosures related to AbbVie, Pfizer, Takeda, Janssen, and others.

SOURCE: Tomaszewski M et al. Haemophilia. 2019 Feb 12. doi: 10.1111/hae.13691

When managed by an experienced team, patients with inherited bleeding disorders undergoing gastrointestinal endoscopy are not at increased bleeding risk, according to researchers reporting the largest series of such patients to date.

The postendoscopy bleeding rate was less than 1% for the patients in this series, many of whom underwent high-risk procedures or had comorbid conditions putting them at risk of bleeding, the researchers reported.

The rate of colonoscopic postpolypectomy bleeding was less than 5%, which is comparable to the general population rate for such high-risk procedures, said investigator Marcel Tomaszewski, MD, of McGill University, Montreal, and colleagues.

Those results favor the use of the “interdisciplinary approach provided by a hemophilia treatment center, communication between services, and the use of periprocedure prophylaxis including tranexamic acid,” Dr. Tomaszewski and coinvestigators said in their report in Haemophilia.

The study cohort included 48 individuals undergoing a total of 104 endoscopies, which is believed to be the largest case series of digestive endoscopy procedures ever reported in patients with congenital bleeding disorders, according to the researchers.

Hemophilia A and von Willebrand disease were the most common bleeding disorders among these patients, accounting for 49 and 40 of the 104 procedures, respectively. The remaining 17 procedures were performed in patients with factor XI deficiency, hemophilia B, or factor VII deficiency.

Before their endoscopies, patients received bleeding prophylaxis, which consisted of combinations of recombinant factor for hemophilia patients, plasma-derived factor for von Willebrand disease patients, desmopressin, and tranexamic acid.

The rate of bleeding within 72 hours of the endoscopic procedure was 0.96% (95% confidence interval, 0.17%-5.25%). The bleeding rate for hemophilia A patients, regardless of severity, was 2.2%, while the rate for hemophilia B, von Willebrand disease, factor VII deficiency and factor XI deficiency was 0%.

The only endoscopic procedures associated with bleeding were colonoscopy, with a bleeding rate of 2%, and colonoscopy with polypectomy, which had a 4.8% bleeding rate, they added, noting that the reported rate of postpolypectomy bleeding in the general population ranges between 0.3% and 10%.

“The very low incidence of bleeding adverse events limited further planned inferential statistical analysis,” the researchers wrote.

These findings stand in contrast to some previous reports, including one series of 19 patients with hemophilia in which 31% experienced gastrointestinal bleeding after colonoscopy polypectomy, despite preprocedure prophylaxis.

“Our approach, particularly with the addition of tranexamic acid, and our patient mix may explain the lower bleeding rate,” they wrote.

The most common indications for endoscopy in the present report were anemia, colorectal cancer screening or polyp surveillance, upper GI symptoms, and screening or surveillance of varices.

Many patients had conditions that might predispose them to bleeding, investigators said. Most commonly, those conditions included hepatitis C virus infection, cirrhosis, esophageal varices, and previous gastrointestinal bleeding.

Dr. Tomaszewski reported that he had no potential conflicts of interest related to the research. Coauthors reported financial disclosures related to AbbVie, Pfizer, Takeda, Janssen, and others.

SOURCE: Tomaszewski M et al. Haemophilia. 2019 Feb 12. doi: 10.1111/hae.13691

When managed by an experienced team, patients with inherited bleeding disorders undergoing gastrointestinal endoscopy are not at increased bleeding risk, according to researchers reporting the largest series of such patients to date.

The postendoscopy bleeding rate was less than 1% for the patients in this series, many of whom underwent high-risk procedures or had comorbid conditions putting them at risk of bleeding, the researchers reported.

The rate of colonoscopic postpolypectomy bleeding was less than 5%, which is comparable to the general population rate for such high-risk procedures, said investigator Marcel Tomaszewski, MD, of McGill University, Montreal, and colleagues.

Those results favor the use of the “interdisciplinary approach provided by a hemophilia treatment center, communication between services, and the use of periprocedure prophylaxis including tranexamic acid,” Dr. Tomaszewski and coinvestigators said in their report in Haemophilia.

The study cohort included 48 individuals undergoing a total of 104 endoscopies, which is believed to be the largest case series of digestive endoscopy procedures ever reported in patients with congenital bleeding disorders, according to the researchers.

Hemophilia A and von Willebrand disease were the most common bleeding disorders among these patients, accounting for 49 and 40 of the 104 procedures, respectively. The remaining 17 procedures were performed in patients with factor XI deficiency, hemophilia B, or factor VII deficiency.

Before their endoscopies, patients received bleeding prophylaxis, which consisted of combinations of recombinant factor for hemophilia patients, plasma-derived factor for von Willebrand disease patients, desmopressin, and tranexamic acid.

The rate of bleeding within 72 hours of the endoscopic procedure was 0.96% (95% confidence interval, 0.17%-5.25%). The bleeding rate for hemophilia A patients, regardless of severity, was 2.2%, while the rate for hemophilia B, von Willebrand disease, factor VII deficiency and factor XI deficiency was 0%.

The only endoscopic procedures associated with bleeding were colonoscopy, with a bleeding rate of 2%, and colonoscopy with polypectomy, which had a 4.8% bleeding rate, they added, noting that the reported rate of postpolypectomy bleeding in the general population ranges between 0.3% and 10%.

“The very low incidence of bleeding adverse events limited further planned inferential statistical analysis,” the researchers wrote.

These findings stand in contrast to some previous reports, including one series of 19 patients with hemophilia in which 31% experienced gastrointestinal bleeding after colonoscopy polypectomy, despite preprocedure prophylaxis.

“Our approach, particularly with the addition of tranexamic acid, and our patient mix may explain the lower bleeding rate,” they wrote.

The most common indications for endoscopy in the present report were anemia, colorectal cancer screening or polyp surveillance, upper GI symptoms, and screening or surveillance of varices.

Many patients had conditions that might predispose them to bleeding, investigators said. Most commonly, those conditions included hepatitis C virus infection, cirrhosis, esophageal varices, and previous gastrointestinal bleeding.

Dr. Tomaszewski reported that he had no potential conflicts of interest related to the research. Coauthors reported financial disclosures related to AbbVie, Pfizer, Takeda, Janssen, and others.

SOURCE: Tomaszewski M et al. Haemophilia. 2019 Feb 12. doi: 10.1111/hae.13691

Erectile dysfunction (ED) appears prevalent among men with hemophilia and becomes increasingly common with age, according to results from a recent survey.

Although the findings may not be generalizable because of small sample size (44 respondents), the survey offers a general sense of the sexual health of patients with hemophilia, which is a minimally researched topic, reported lead author Ming Yang, PhD, of the British Columbia Provincial Bleeding Disorders Program at St. Paul’s Hospital in Vancouver and colleagues.

Such data become increasingly important as new hemophilia therapies further extend the lifespan of patients, which thereby exposes them to diseases of old age, the investigators noted in Haemophilia.

Additionally, ED is considered an early sign of endothelial dysfunction in the general population, but data are lacking for patients with hemophilia.

Among the 56 men with hemophilia A or B who were surveyed with the International Index of Erectile Function (IIEF) questionnaire, 44 completed the survey (median age, 49 years). Specifically, respondents completed the “erectile function” component of the questionnaire because this is the only domain that has been validated.

To assess associations between ED and well-established risk factors, the investigators recorded prior surgeries, medications, atherosclerotic diseases, viral infections, and hemophilia-specific factors. To better characterize the population and look for other associations, the investigators had patients undergo baseline laboratory testing and measurements of blood pressure, anthropomorphic indexes, and endothelial function.

According to the IIEF, 38.6% of patients had ED, which was subcategorized as mild and mild to moderate in 4.5% of patients, moderate in 18.2%, and severe in 15.9%.

The investigators found significant associations between ED and coronary artery disease, hypertension, smoking, higher waist/hip ratio, homocysteine level, and age. However, on multivariable analysis, only age was correlated with ED domain score (P = .03). No associations between ED and endothelial dysfunction were reported.

While the findings may offer a rare look at ED rates in patients with hemophilia, they are insufficient for comparisons and generalizations, the investigators cautioned.

“Without comparative studies within the haemophilia population in Canada or elsewhere and due to limited sample size and non‐normalized distribution of our age group, this prevalence cannot reasonably be generalized to the entire haemophilia population,” the investigators wrote.

Instead, the investigators suggested that more studies are needed, especially ones involving customized questionnaires.

The study was funded by Pfizer. Dr. Yang reported having no conflicts of interest. One coauthor reported an unrestricted educational award from the Association of Hemophilia Clinic Directors of Canada/Baxter Canadian Hemostasis Fellowship, and another coauthor reported research funding from Pfizer.

SOURCE: Yang M et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13707.

Erectile dysfunction (ED) appears prevalent among men with hemophilia and becomes increasingly common with age, according to results from a recent survey.

Although the findings may not be generalizable because of small sample size (44 respondents), the survey offers a general sense of the sexual health of patients with hemophilia, which is a minimally researched topic, reported lead author Ming Yang, PhD, of the British Columbia Provincial Bleeding Disorders Program at St. Paul’s Hospital in Vancouver and colleagues.

Such data become increasingly important as new hemophilia therapies further extend the lifespan of patients, which thereby exposes them to diseases of old age, the investigators noted in Haemophilia.

Additionally, ED is considered an early sign of endothelial dysfunction in the general population, but data are lacking for patients with hemophilia.

Among the 56 men with hemophilia A or B who were surveyed with the International Index of Erectile Function (IIEF) questionnaire, 44 completed the survey (median age, 49 years). Specifically, respondents completed the “erectile function” component of the questionnaire because this is the only domain that has been validated.

To assess associations between ED and well-established risk factors, the investigators recorded prior surgeries, medications, atherosclerotic diseases, viral infections, and hemophilia-specific factors. To better characterize the population and look for other associations, the investigators had patients undergo baseline laboratory testing and measurements of blood pressure, anthropomorphic indexes, and endothelial function.

According to the IIEF, 38.6% of patients had ED, which was subcategorized as mild and mild to moderate in 4.5% of patients, moderate in 18.2%, and severe in 15.9%.

The investigators found significant associations between ED and coronary artery disease, hypertension, smoking, higher waist/hip ratio, homocysteine level, and age. However, on multivariable analysis, only age was correlated with ED domain score (P = .03). No associations between ED and endothelial dysfunction were reported.

While the findings may offer a rare look at ED rates in patients with hemophilia, they are insufficient for comparisons and generalizations, the investigators cautioned.

“Without comparative studies within the haemophilia population in Canada or elsewhere and due to limited sample size and non‐normalized distribution of our age group, this prevalence cannot reasonably be generalized to the entire haemophilia population,” the investigators wrote.

Instead, the investigators suggested that more studies are needed, especially ones involving customized questionnaires.

The study was funded by Pfizer. Dr. Yang reported having no conflicts of interest. One coauthor reported an unrestricted educational award from the Association of Hemophilia Clinic Directors of Canada/Baxter Canadian Hemostasis Fellowship, and another coauthor reported research funding from Pfizer.

SOURCE: Yang M et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13707.

Erectile dysfunction (ED) appears prevalent among men with hemophilia and becomes increasingly common with age, according to results from a recent survey.

Although the findings may not be generalizable because of small sample size (44 respondents), the survey offers a general sense of the sexual health of patients with hemophilia, which is a minimally researched topic, reported lead author Ming Yang, PhD, of the British Columbia Provincial Bleeding Disorders Program at St. Paul’s Hospital in Vancouver and colleagues.

Such data become increasingly important as new hemophilia therapies further extend the lifespan of patients, which thereby exposes them to diseases of old age, the investigators noted in Haemophilia.

Additionally, ED is considered an early sign of endothelial dysfunction in the general population, but data are lacking for patients with hemophilia.

Among the 56 men with hemophilia A or B who were surveyed with the International Index of Erectile Function (IIEF) questionnaire, 44 completed the survey (median age, 49 years). Specifically, respondents completed the “erectile function” component of the questionnaire because this is the only domain that has been validated.

To assess associations between ED and well-established risk factors, the investigators recorded prior surgeries, medications, atherosclerotic diseases, viral infections, and hemophilia-specific factors. To better characterize the population and look for other associations, the investigators had patients undergo baseline laboratory testing and measurements of blood pressure, anthropomorphic indexes, and endothelial function.

According to the IIEF, 38.6% of patients had ED, which was subcategorized as mild and mild to moderate in 4.5% of patients, moderate in 18.2%, and severe in 15.9%.

The investigators found significant associations between ED and coronary artery disease, hypertension, smoking, higher waist/hip ratio, homocysteine level, and age. However, on multivariable analysis, only age was correlated with ED domain score (P = .03). No associations between ED and endothelial dysfunction were reported.

While the findings may offer a rare look at ED rates in patients with hemophilia, they are insufficient for comparisons and generalizations, the investigators cautioned.

“Without comparative studies within the haemophilia population in Canada or elsewhere and due to limited sample size and non‐normalized distribution of our age group, this prevalence cannot reasonably be generalized to the entire haemophilia population,” the investigators wrote.

Instead, the investigators suggested that more studies are needed, especially ones involving customized questionnaires.

The study was funded by Pfizer. Dr. Yang reported having no conflicts of interest. One coauthor reported an unrestricted educational award from the Association of Hemophilia Clinic Directors of Canada/Baxter Canadian Hemostasis Fellowship, and another coauthor reported research funding from Pfizer.

SOURCE: Yang M et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13707.

HOUSTON – Haploidentical stem cell transplantation (Haplo-HSCT) outperforms chemotherapy for the treatment of adults with acute lymphoblastic leukemia (ALL) in first complete remission, findings from a prospective multicenter trial suggest.

Sharon Worcester/MDedge News

The 2-year leukemia-free survival (LFS) was about 70% in 49 patients in first remission who received haplo-HSCT vs. 40% in 40 patients who received chemotherapy, and 2-year overall survival (OS) was about 80% vs. 50% in the groups, respectively, Meng Lv, MD, PhD, of Peking University People’s Hospital in Beijing reported at the Transplantation & Cellular Therapy Meetings.

“This result is comparable to results of our previous reports,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

He noted that the findings also support those from other institutions.

Study subjects initially included 112 newly diagnosed standard-risk ALL patients aged 18-39 years without high-risk features who achieved complete remission (CR) after one or two cycles of induction. They were consecutively enrolled at five centers in China, including high-volume centers, between July 2014 and June 2017 and were followed for a median of 24.6 months.

Subjects without a suitable HLA-matched sibling donor (MSD) or HLA-matched unrelated donor after two cycles of consolidation with hyper-CVAD chemotherapy were eligible for haplo-HSCT or further hyper-CVAD chemotherapy.

The final analysis included 89 patients after 23 were excluded because of early relapse (6 patients) or a decision to undergo MSD HSCT (16 patients), or unrelated donor-HSCT (1 patient), Dr. Lv said, noting that landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT with those receiving chemotherapy.

Multivariate analysis with adjustment for a propensity score calculated for each patient showed that treatment (haplo-HSCT vs. chemotherapy) independently predicted LFS (hazard ratio, 0.388), OS (HR, 0.346), and cumulative incidence of relapse (CIR; HR, 0.247). Minimal residual disease (MRD) positivity after the first consolidation was an independent risk factor for LFS (HR, 2.162) and CIR (HR, 3.667). Additionally, diagnosis (T- vs. B-cell) was an independent risk factor for OS (HR, 2.267), Dr. Lv said, adding that nonrelapse mortality was similar in the groups in the propensity score–adjusted analysis.

The findings overall show that haplo-HSCT has variable impact on survival in standard-risk ALL, when compared with traditional chemotherapy, with subgroup analyses showing MRD-positive patients deriving the greatest benefit, he said. Future studies are planned to look more closely at MRD-positive disease and the possible benefits of postponing transplant until the second CR.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Lv reported having no financial disclosures.

[email protected]

SOURCE: Lv M et al. TCT 2019, Abstract 8.

HOUSTON – Haploidentical stem cell transplantation (Haplo-HSCT) outperforms chemotherapy for the treatment of adults with acute lymphoblastic leukemia (ALL) in first complete remission, findings from a prospective multicenter trial suggest.

Sharon Worcester/MDedge News

The 2-year leukemia-free survival (LFS) was about 70% in 49 patients in first remission who received haplo-HSCT vs. 40% in 40 patients who received chemotherapy, and 2-year overall survival (OS) was about 80% vs. 50% in the groups, respectively, Meng Lv, MD, PhD, of Peking University People’s Hospital in Beijing reported at the Transplantation & Cellular Therapy Meetings.

“This result is comparable to results of our previous reports,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

He noted that the findings also support those from other institutions.

Study subjects initially included 112 newly diagnosed standard-risk ALL patients aged 18-39 years without high-risk features who achieved complete remission (CR) after one or two cycles of induction. They were consecutively enrolled at five centers in China, including high-volume centers, between July 2014 and June 2017 and were followed for a median of 24.6 months.

Subjects without a suitable HLA-matched sibling donor (MSD) or HLA-matched unrelated donor after two cycles of consolidation with hyper-CVAD chemotherapy were eligible for haplo-HSCT or further hyper-CVAD chemotherapy.

The final analysis included 89 patients after 23 were excluded because of early relapse (6 patients) or a decision to undergo MSD HSCT (16 patients), or unrelated donor-HSCT (1 patient), Dr. Lv said, noting that landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT with those receiving chemotherapy.

Multivariate analysis with adjustment for a propensity score calculated for each patient showed that treatment (haplo-HSCT vs. chemotherapy) independently predicted LFS (hazard ratio, 0.388), OS (HR, 0.346), and cumulative incidence of relapse (CIR; HR, 0.247). Minimal residual disease (MRD) positivity after the first consolidation was an independent risk factor for LFS (HR, 2.162) and CIR (HR, 3.667). Additionally, diagnosis (T- vs. B-cell) was an independent risk factor for OS (HR, 2.267), Dr. Lv said, adding that nonrelapse mortality was similar in the groups in the propensity score–adjusted analysis.

The findings overall show that haplo-HSCT has variable impact on survival in standard-risk ALL, when compared with traditional chemotherapy, with subgroup analyses showing MRD-positive patients deriving the greatest benefit, he said. Future studies are planned to look more closely at MRD-positive disease and the possible benefits of postponing transplant until the second CR.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Lv reported having no financial disclosures.

[email protected]

SOURCE: Lv M et al. TCT 2019, Abstract 8.

HOUSTON – Haploidentical stem cell transplantation (Haplo-HSCT) outperforms chemotherapy for the treatment of adults with acute lymphoblastic leukemia (ALL) in first complete remission, findings from a prospective multicenter trial suggest.

Sharon Worcester/MDedge News

The 2-year leukemia-free survival (LFS) was about 70% in 49 patients in first remission who received haplo-HSCT vs. 40% in 40 patients who received chemotherapy, and 2-year overall survival (OS) was about 80% vs. 50% in the groups, respectively, Meng Lv, MD, PhD, of Peking University People’s Hospital in Beijing reported at the Transplantation & Cellular Therapy Meetings.

“This result is comparable to results of our previous reports,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

He noted that the findings also support those from other institutions.

Study subjects initially included 112 newly diagnosed standard-risk ALL patients aged 18-39 years without high-risk features who achieved complete remission (CR) after one or two cycles of induction. They were consecutively enrolled at five centers in China, including high-volume centers, between July 2014 and June 2017 and were followed for a median of 24.6 months.

Subjects without a suitable HLA-matched sibling donor (MSD) or HLA-matched unrelated donor after two cycles of consolidation with hyper-CVAD chemotherapy were eligible for haplo-HSCT or further hyper-CVAD chemotherapy.

The final analysis included 89 patients after 23 were excluded because of early relapse (6 patients) or a decision to undergo MSD HSCT (16 patients), or unrelated donor-HSCT (1 patient), Dr. Lv said, noting that landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT with those receiving chemotherapy.

Multivariate analysis with adjustment for a propensity score calculated for each patient showed that treatment (haplo-HSCT vs. chemotherapy) independently predicted LFS (hazard ratio, 0.388), OS (HR, 0.346), and cumulative incidence of relapse (CIR; HR, 0.247). Minimal residual disease (MRD) positivity after the first consolidation was an independent risk factor for LFS (HR, 2.162) and CIR (HR, 3.667). Additionally, diagnosis (T- vs. B-cell) was an independent risk factor for OS (HR, 2.267), Dr. Lv said, adding that nonrelapse mortality was similar in the groups in the propensity score–adjusted analysis.

The findings overall show that haplo-HSCT has variable impact on survival in standard-risk ALL, when compared with traditional chemotherapy, with subgroup analyses showing MRD-positive patients deriving the greatest benefit, he said. Future studies are planned to look more closely at MRD-positive disease and the possible benefits of postponing transplant until the second CR.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Lv reported having no financial disclosures.

[email protected]

SOURCE: Lv M et al. TCT 2019, Abstract 8.

Measurement of factor XIII levels, followed by replacing deficiencies if found, may help to achieve sustained hemostasis in the management of bleeding in patients with acquired hemophilia A.

Jameel Abdulrehman, MD, of the University of Toronto in Ontario and his colleagues retrospectively reviewed cases of acquired hemophilia A with bleeding at a large hospital from 2015-2016. The findings were published in a letter to the editor in Haemophilia.

The researchers reported that depletion of Factor XIII (FXIII) in the setting of acquired hemophilia A has only been reported in a single case. In the present analysis, the researchers identified a total of seven patients with acquired hemophilia A from 2015-2016. FXIII antigen levels were measured in five cases and were found to be low in four cases, and three patients required FXIII replacement to secure hemostasis.

The relationship between acquired hemophilia A and FXIII deficiency was evaluated using descriptive case analysis.

After analysis, the team reported that measuring FXIII levels may be useful in refractory patients, in whom bleeding remains uncontrolled despite the use of standard therapy. Additionally, the results supported FXIII supplementation if a deficiency is detected.

“FXIII replacement was not complicated by any infusion reactions or thromboembolic events,” they wrote.

The replaced FXIII levels dropped more rapidly than expected, the researchers noted. The established half-life of pd-XIII is 6.6 days plus or minus 2.29 days; however, in the most severe of the cases reported, it was depleted “within a few days,” they wrote. “This is compatible with either consumption of FXIII or inhibition/clearance by an autoantibody.”

Dr. Abdulrehman and his colleagues acknowledged that FXIII deficiency can be challenging to identify because the majority of coagulation assays do not measure FXIII levels.

“As we gain a greater appreciation for the role of FXIII in various pathological states, access to accurate FXIII testing will become increasingly important,” they added.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Abdulrehman J et al. Haemophilia. 2019 Mar 7. doi: 10.1111/hae.13690.

Measurement of factor XIII levels, followed by replacing deficiencies if found, may help to achieve sustained hemostasis in the management of bleeding in patients with acquired hemophilia A.

Jameel Abdulrehman, MD, of the University of Toronto in Ontario and his colleagues retrospectively reviewed cases of acquired hemophilia A with bleeding at a large hospital from 2015-2016. The findings were published in a letter to the editor in Haemophilia.

The researchers reported that depletion of Factor XIII (FXIII) in the setting of acquired hemophilia A has only been reported in a single case. In the present analysis, the researchers identified a total of seven patients with acquired hemophilia A from 2015-2016. FXIII antigen levels were measured in five cases and were found to be low in four cases, and three patients required FXIII replacement to secure hemostasis.

The relationship between acquired hemophilia A and FXIII deficiency was evaluated using descriptive case analysis.

After analysis, the team reported that measuring FXIII levels may be useful in refractory patients, in whom bleeding remains uncontrolled despite the use of standard therapy. Additionally, the results supported FXIII supplementation if a deficiency is detected.

“FXIII replacement was not complicated by any infusion reactions or thromboembolic events,” they wrote.

The replaced FXIII levels dropped more rapidly than expected, the researchers noted. The established half-life of pd-XIII is 6.6 days plus or minus 2.29 days; however, in the most severe of the cases reported, it was depleted “within a few days,” they wrote. “This is compatible with either consumption of FXIII or inhibition/clearance by an autoantibody.”

Dr. Abdulrehman and his colleagues acknowledged that FXIII deficiency can be challenging to identify because the majority of coagulation assays do not measure FXIII levels.

“As we gain a greater appreciation for the role of FXIII in various pathological states, access to accurate FXIII testing will become increasingly important,” they added.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Abdulrehman J et al. Haemophilia. 2019 Mar 7. doi: 10.1111/hae.13690.

Measurement of factor XIII levels, followed by replacing deficiencies if found, may help to achieve sustained hemostasis in the management of bleeding in patients with acquired hemophilia A.

Jameel Abdulrehman, MD, of the University of Toronto in Ontario and his colleagues retrospectively reviewed cases of acquired hemophilia A with bleeding at a large hospital from 2015-2016. The findings were published in a letter to the editor in Haemophilia.

The researchers reported that depletion of Factor XIII (FXIII) in the setting of acquired hemophilia A has only been reported in a single case. In the present analysis, the researchers identified a total of seven patients with acquired hemophilia A from 2015-2016. FXIII antigen levels were measured in five cases and were found to be low in four cases, and three patients required FXIII replacement to secure hemostasis.

The relationship between acquired hemophilia A and FXIII deficiency was evaluated using descriptive case analysis.

After analysis, the team reported that measuring FXIII levels may be useful in refractory patients, in whom bleeding remains uncontrolled despite the use of standard therapy. Additionally, the results supported FXIII supplementation if a deficiency is detected.

“FXIII replacement was not complicated by any infusion reactions or thromboembolic events,” they wrote.

The replaced FXIII levels dropped more rapidly than expected, the researchers noted. The established half-life of pd-XIII is 6.6 days plus or minus 2.29 days; however, in the most severe of the cases reported, it was depleted “within a few days,” they wrote. “This is compatible with either consumption of FXIII or inhibition/clearance by an autoantibody.”

Dr. Abdulrehman and his colleagues acknowledged that FXIII deficiency can be challenging to identify because the majority of coagulation assays do not measure FXIII levels.

“As we gain a greater appreciation for the role of FXIII in various pathological states, access to accurate FXIII testing will become increasingly important,” they added.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Abdulrehman J et al. Haemophilia. 2019 Mar 7. doi: 10.1111/hae.13690.

The number of women being screened for von Willebrand disease (VWD) before undergoing hysterectomy for heavy menstrual bleeding is “very low” and appears not to align with current recommendations, according to a retrospective analysis.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

“One essential reason to identify females with VWD prior to hysterectomy or hysterectomy alternative is to avoid peri‐ and postoperative complications,” Amanda E. Jacobson‐Kelly, MD, of Ohio State University in Columbus and her colleagues wrote in a letter to the editor published in Haemophilia.

Current recommendations from the American College of Obstetricians and Gynecologists and other groups call for consideration of underlying bleeding disorders in women with heavy menstrual bleeding and additional risks factors, such as family history of abnormal bleeding.

In this study, researchers retrospectively analyzed 8,998 women under the age of 40 years who had a hysterectomy for heavy menstrual bleeding without a known bleeding disorder. Patient data was collected from a national insurance claims database representative of the entire U.S. population.

“We hypothesized that the overall frequency of VWD screening would be low, despite [more than] 15 years of expert recommendations,” the team wrote.

Study participants were included if they had a diagnosis of anemia or heavy menstrual bleeding before surgery, while women with certain genital malignancies and fibroids were excluded. Other information, such as age, geographical factors, and insurance-related factors were also included to evaluate whether these parameters affected disease screening.

After analysis, the researchers found that just 0.6% (n = 57) of women were screened for VWD in the 12 months leading up to surgery. Additionally, they reported that 14% (n = 1,276) of women underwent other forms of coagulation testing before surgery, such as partial thromboplastin time and prothrombin time.

“We found that greater distance to a [hemophilia treatment center] was strongly predictive of decreased likelihood of undergoing VWD screening,” Dr. Jacobson‐Kelly and her colleagues wrote.

The authors acknowledged that a key limitation of the study was the inability to account for factors not recorded in the database, including drug use, family history of bleeding disorders, and ethnicity.

“This study brings to light the need for the hematology community to improve education and awareness among women’s health providers,” they wrote.

The study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Jacobson-Kelly AE et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13709.

The number of women being screened for von Willebrand disease (VWD) before undergoing hysterectomy for heavy menstrual bleeding is “very low” and appears not to align with current recommendations, according to a retrospective analysis.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

“One essential reason to identify females with VWD prior to hysterectomy or hysterectomy alternative is to avoid peri‐ and postoperative complications,” Amanda E. Jacobson‐Kelly, MD, of Ohio State University in Columbus and her colleagues wrote in a letter to the editor published in Haemophilia.

Current recommendations from the American College of Obstetricians and Gynecologists and other groups call for consideration of underlying bleeding disorders in women with heavy menstrual bleeding and additional risks factors, such as family history of abnormal bleeding.

In this study, researchers retrospectively analyzed 8,998 women under the age of 40 years who had a hysterectomy for heavy menstrual bleeding without a known bleeding disorder. Patient data was collected from a national insurance claims database representative of the entire U.S. population.

“We hypothesized that the overall frequency of VWD screening would be low, despite [more than] 15 years of expert recommendations,” the team wrote.

Study participants were included if they had a diagnosis of anemia or heavy menstrual bleeding before surgery, while women with certain genital malignancies and fibroids were excluded. Other information, such as age, geographical factors, and insurance-related factors were also included to evaluate whether these parameters affected disease screening.

After analysis, the researchers found that just 0.6% (n = 57) of women were screened for VWD in the 12 months leading up to surgery. Additionally, they reported that 14% (n = 1,276) of women underwent other forms of coagulation testing before surgery, such as partial thromboplastin time and prothrombin time.

“We found that greater distance to a [hemophilia treatment center] was strongly predictive of decreased likelihood of undergoing VWD screening,” Dr. Jacobson‐Kelly and her colleagues wrote.

The authors acknowledged that a key limitation of the study was the inability to account for factors not recorded in the database, including drug use, family history of bleeding disorders, and ethnicity.

“This study brings to light the need for the hematology community to improve education and awareness among women’s health providers,” they wrote.

The study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Jacobson-Kelly AE et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13709.

The number of women being screened for von Willebrand disease (VWD) before undergoing hysterectomy for heavy menstrual bleeding is “very low” and appears not to align with current recommendations, according to a retrospective analysis.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

“One essential reason to identify females with VWD prior to hysterectomy or hysterectomy alternative is to avoid peri‐ and postoperative complications,” Amanda E. Jacobson‐Kelly, MD, of Ohio State University in Columbus and her colleagues wrote in a letter to the editor published in Haemophilia.

Current recommendations from the American College of Obstetricians and Gynecologists and other groups call for consideration of underlying bleeding disorders in women with heavy menstrual bleeding and additional risks factors, such as family history of abnormal bleeding.

In this study, researchers retrospectively analyzed 8,998 women under the age of 40 years who had a hysterectomy for heavy menstrual bleeding without a known bleeding disorder. Patient data was collected from a national insurance claims database representative of the entire U.S. population.

“We hypothesized that the overall frequency of VWD screening would be low, despite [more than] 15 years of expert recommendations,” the team wrote.

Study participants were included if they had a diagnosis of anemia or heavy menstrual bleeding before surgery, while women with certain genital malignancies and fibroids were excluded. Other information, such as age, geographical factors, and insurance-related factors were also included to evaluate whether these parameters affected disease screening.

After analysis, the researchers found that just 0.6% (n = 57) of women were screened for VWD in the 12 months leading up to surgery. Additionally, they reported that 14% (n = 1,276) of women underwent other forms of coagulation testing before surgery, such as partial thromboplastin time and prothrombin time.

“We found that greater distance to a [hemophilia treatment center] was strongly predictive of decreased likelihood of undergoing VWD screening,” Dr. Jacobson‐Kelly and her colleagues wrote.

The authors acknowledged that a key limitation of the study was the inability to account for factors not recorded in the database, including drug use, family history of bleeding disorders, and ethnicity.

“This study brings to light the need for the hematology community to improve education and awareness among women’s health providers,” they wrote.

The study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Jacobson-Kelly AE et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13709.

An all-oral, three-drug regimen may be a treatment option for relapsed or refractory multiple myeloma, according to researchers.

Courtesy Wikimedia Commons/KGH/Creative Commons License

The regimen – clarithromycin, pomalidomide, and dexamethasone (ClaPd) – produced an overall response rate (ORR) of 60% in a phase 2 trial of patients with relapsed/refractory multiple myeloma (RRMM). Response rates were similar whether patients were refractory to lenalidomide, bortezomib, or both drugs.

The most common adverse events (AEs) in this trial were hematologic toxicities.

Tomer M. Mark, MD, of the University of Colorado at Denver, Aurora, and his colleagues, reported these results in Blood Advances.

The trial (NCT01159574) included 120 patients with RRMM. They had a median age of 63 years (range, 42-87 years) and were a median of 4.6 years (range, 0.8-21.2 years) from diagnosis at baseline.

The patients had received a median of 5 (range, 3-15) prior lines of therapy. Most patients were refractory to lenalidomide (n = 101), bortezomib (n = 94), or both (n = 81).

The ClaPd regimen consisted of clarithromycin given at 500 mg twice daily, pomalidomide at 4 mg on days 1-21, and dexamethasone at 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. The patients received ClaPd until intolerance or disease progression. In addition to ClaPd, patients received thromboprophylaxis (aspirin at 81 mg daily) and Pneumocystis jiroveci prophylaxis (trimethoprim-sulfamethoxazole or an alternative).

The toxicities were manageable, with low rates of nonhematologic and high-grade events, according to the researchers. The most common grade 3 or higher AEs were lymphopenia (60%), neutropenia (58%), leukopenia (34%), thrombocytopenia (31%), and anemia (28%).

Among all evaluable patients, the ORR was 60% (70/117). One patient had a complete response, 6 had a stringent complete response, 20 had a very good partial response, and 43 had a partial response.

ORRs were similar whether patients were refractory to bortezomib, lenalidomide, or both. The ORR was 58% (n = 59) among lenalidomide-refractory patients, 55% (n = 52) among bortezomib-refractory patients, and 54% (n = 44) among double-refractory patients.

For the entire cohort, the median progression-free survival was 7.7 months and the median overall survival was 19.2 months.

In a multivariate analysis, there were two factors significantly associated with inferior overall survival – having a revised International Staging System score greater than 1 (hazard ratio, 2.75; P = .044) and having at least 5% of CD138 cells positive for Ki67 on immunohistochemistry (hazard ratio, 1.84, P = .030).

“The ClaPd regimen demonstrated high rates of overall response and significant duration of disease control in a heavily pretreated RRMM population while maintaining a toxicity profile similar to Pom-dex [pomalidone-dexamethasone] alone,” Dr. Mark and his colleagues wrote. “The clinical efficacy advantage of adding clarithromycin to Pom-dex should be explored further in a phase 3 clinical trial.”

This research was supported by Celgene; the Myeloma Center at Weill Cornell Medicine, New York; and a grant from the National Institutes of Health. Dr. Mark reported relationships with Amgen, Takeda, Celgene, and Janssen. Other study authors reported relationships with Celgene, Takeda, and Onyx Pharmaceuticals.

[email protected]

SOURCE: Mark TM et al. Blood Adv. 2019 Feb 26;3(4):603-11.

An all-oral, three-drug regimen may be a treatment option for relapsed or refractory multiple myeloma, according to researchers.

Courtesy Wikimedia Commons/KGH/Creative Commons License

The regimen – clarithromycin, pomalidomide, and dexamethasone (ClaPd) – produced an overall response rate (ORR) of 60% in a phase 2 trial of patients with relapsed/refractory multiple myeloma (RRMM). Response rates were similar whether patients were refractory to lenalidomide, bortezomib, or both drugs.

The most common adverse events (AEs) in this trial were hematologic toxicities.

Tomer M. Mark, MD, of the University of Colorado at Denver, Aurora, and his colleagues, reported these results in Blood Advances.

The trial (NCT01159574) included 120 patients with RRMM. They had a median age of 63 years (range, 42-87 years) and were a median of 4.6 years (range, 0.8-21.2 years) from diagnosis at baseline.

The patients had received a median of 5 (range, 3-15) prior lines of therapy. Most patients were refractory to lenalidomide (n = 101), bortezomib (n = 94), or both (n = 81).

The ClaPd regimen consisted of clarithromycin given at 500 mg twice daily, pomalidomide at 4 mg on days 1-21, and dexamethasone at 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. The patients received ClaPd until intolerance or disease progression. In addition to ClaPd, patients received thromboprophylaxis (aspirin at 81 mg daily) and Pneumocystis jiroveci prophylaxis (trimethoprim-sulfamethoxazole or an alternative).

The toxicities were manageable, with low rates of nonhematologic and high-grade events, according to the researchers. The most common grade 3 or higher AEs were lymphopenia (60%), neutropenia (58%), leukopenia (34%), thrombocytopenia (31%), and anemia (28%).

Among all evaluable patients, the ORR was 60% (70/117). One patient had a complete response, 6 had a stringent complete response, 20 had a very good partial response, and 43 had a partial response.

ORRs were similar whether patients were refractory to bortezomib, lenalidomide, or both. The ORR was 58% (n = 59) among lenalidomide-refractory patients, 55% (n = 52) among bortezomib-refractory patients, and 54% (n = 44) among double-refractory patients.

For the entire cohort, the median progression-free survival was 7.7 months and the median overall survival was 19.2 months.

In a multivariate analysis, there were two factors significantly associated with inferior overall survival – having a revised International Staging System score greater than 1 (hazard ratio, 2.75; P = .044) and having at least 5% of CD138 cells positive for Ki67 on immunohistochemistry (hazard ratio, 1.84, P = .030).

“The ClaPd regimen demonstrated high rates of overall response and significant duration of disease control in a heavily pretreated RRMM population while maintaining a toxicity profile similar to Pom-dex [pomalidone-dexamethasone] alone,” Dr. Mark and his colleagues wrote. “The clinical efficacy advantage of adding clarithromycin to Pom-dex should be explored further in a phase 3 clinical trial.”

This research was supported by Celgene; the Myeloma Center at Weill Cornell Medicine, New York; and a grant from the National Institutes of Health. Dr. Mark reported relationships with Amgen, Takeda, Celgene, and Janssen. Other study authors reported relationships with Celgene, Takeda, and Onyx Pharmaceuticals.

[email protected]

SOURCE: Mark TM et al. Blood Adv. 2019 Feb 26;3(4):603-11.

An all-oral, three-drug regimen may be a treatment option for relapsed or refractory multiple myeloma, according to researchers.

Courtesy Wikimedia Commons/KGH/Creative Commons License

The regimen – clarithromycin, pomalidomide, and dexamethasone (ClaPd) – produced an overall response rate (ORR) of 60% in a phase 2 trial of patients with relapsed/refractory multiple myeloma (RRMM). Response rates were similar whether patients were refractory to lenalidomide, bortezomib, or both drugs.

The most common adverse events (AEs) in this trial were hematologic toxicities.

Tomer M. Mark, MD, of the University of Colorado at Denver, Aurora, and his colleagues, reported these results in Blood Advances.

The trial (NCT01159574) included 120 patients with RRMM. They had a median age of 63 years (range, 42-87 years) and were a median of 4.6 years (range, 0.8-21.2 years) from diagnosis at baseline.

The patients had received a median of 5 (range, 3-15) prior lines of therapy. Most patients were refractory to lenalidomide (n = 101), bortezomib (n = 94), or both (n = 81).

The ClaPd regimen consisted of clarithromycin given at 500 mg twice daily, pomalidomide at 4 mg on days 1-21, and dexamethasone at 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. The patients received ClaPd until intolerance or disease progression. In addition to ClaPd, patients received thromboprophylaxis (aspirin at 81 mg daily) and Pneumocystis jiroveci prophylaxis (trimethoprim-sulfamethoxazole or an alternative).

The toxicities were manageable, with low rates of nonhematologic and high-grade events, according to the researchers. The most common grade 3 or higher AEs were lymphopenia (60%), neutropenia (58%), leukopenia (34%), thrombocytopenia (31%), and anemia (28%).

Among all evaluable patients, the ORR was 60% (70/117). One patient had a complete response, 6 had a stringent complete response, 20 had a very good partial response, and 43 had a partial response.

ORRs were similar whether patients were refractory to bortezomib, lenalidomide, or both. The ORR was 58% (n = 59) among lenalidomide-refractory patients, 55% (n = 52) among bortezomib-refractory patients, and 54% (n = 44) among double-refractory patients.

For the entire cohort, the median progression-free survival was 7.7 months and the median overall survival was 19.2 months.

In a multivariate analysis, there were two factors significantly associated with inferior overall survival – having a revised International Staging System score greater than 1 (hazard ratio, 2.75; P = .044) and having at least 5% of CD138 cells positive for Ki67 on immunohistochemistry (hazard ratio, 1.84, P = .030).

“The ClaPd regimen demonstrated high rates of overall response and significant duration of disease control in a heavily pretreated RRMM population while maintaining a toxicity profile similar to Pom-dex [pomalidone-dexamethasone] alone,” Dr. Mark and his colleagues wrote. “The clinical efficacy advantage of adding clarithromycin to Pom-dex should be explored further in a phase 3 clinical trial.”

This research was supported by Celgene; the Myeloma Center at Weill Cornell Medicine, New York; and a grant from the National Institutes of Health. Dr. Mark reported relationships with Amgen, Takeda, Celgene, and Janssen. Other study authors reported relationships with Celgene, Takeda, and Onyx Pharmaceuticals.

[email protected]

SOURCE: Mark TM et al. Blood Adv. 2019 Feb 26;3(4):603-11.